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FIXED‐DOSE COMBINATIONS
FOR HIV/AIDS,
TUBERCULOSIS, AND
MALARIA

Report of a meeting held
16‐18 December 2003
Geneva

World Health Organization
Geneva
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Contents
Summary: Observations and some ways forward................................................................... 1
A. Overall observations ......................................................................................................... 1
B. Experiences with fixed‐dose combinations ................................................................... 2
C. Public health priorities ..................................................................................................... 4
D. IP and legal options .......................................................................................................... 5
E. Pharmaceutical development, quality assurance, and regulatory requirements ..... 7
Welcome.......................................................................................................................................... 9
Objectives of the meeting ............................................................................................................ 10
Expected outcomes....................................................................................................................... 10
Presentations on TB FDC issues ................................................................................................. 11
Presentations and discussions on malaria FDC issues............................................................ 12
Presentations and discussions concerning ARV FDCs ........................................................... 14
Presentation and discussion of cross‐cutting issues related to logistics, adherence and
resistance with FDCs ................................................................................................................... 17
Procurement experiences ............................................................................................................ 19
Intellectual property and industry issues ................................................................................. 20
Regulatory issues ......................................................................................................................... 22
Concluding session ...................................................................................................................... 24
Fixed‐dose combinations for tuberculosis: lessons learned from a clinical,
formulation and regulatory perspective ................................................................................. 29
Abstract.......................................................................................................................................... 30
Tuberculosis in the world of today............................................................................................ 30
Combination therapy and fixed‐dose combination (FDC) formulations in the
management of TB ....................................................................................................................... 35
Continuation Phase...................................................................................................................... 40
Registration requirements for rifampicin‐containing FDC formulations............................. 45
Conclusions................................................................................................................................... 46
Acknowledgments ....................................................................................................................... 47
Annex: Bioavailability of rifampicin, the Biopharmaceutic Classification System
and the 4D approach to disease management.......................................................................... 48
Results/c results/comments......................................................................................................... 53
References...................................................................................................................................... 63
Product costs of fixed‐dose combination tablets in comparison with separate
dispensing and or co‐blistering of antituberculosis drugs.................................................. 67
Introduction .................................................................................................................................. 67
Method........................................................................................................................................... 68
Results............................................................................................................................................ 69
Discussion ..................................................................................................................................... 70
References:..................................................................................................................................... 75
Fixed‐dose combinations: artemisinin‐based combination therapies for malaria
treatment ....................................................................................................................................... 77
Introduction .................................................................................................................................. 77
Background ................................................................................................................................... 78
Implementation issues................................................................................................................. 82
Process leading to the development of guidelines on the use of artemisinin‐based
combination therapies (ACTs).................................................................................................... 85
Support to countries in the implementation of ACTs ............................................................. 87
Challenges/way forward ............................................................................................................. 88
Recommendations for further research..................................................................................... 89
Conclusion..................................................................................................................................... 89
References...................................................................................................................................... 90
Developing combinations of drugs for malaria examination of critical issues and
lessons learnt................................................................................................................................ 91
Background ................................................................................................................................... 91
Parasite resistance to antimalarial drugs: a major impediment to effective control ........... 92
Strategies to overcome resistance............................................................................................... 92
Evidence – the key to sensible recommendations.................................................................... 93
Further work on the artemisinins .............................................................................................. 95
Recommendations & outstanding challenges .......................................................................... 96
References...................................................................................................................................... 97
Safety and long‐term effectiveness of generic fixed‐dose formulations of nevirapine‐
based HAART amongst antiretroviral‐naïve HIV‐infected patients in India ................. 99
Abstract.......................................................................................................................................... 99
Introduction ................................................................................................................................ 100
Methods ....................................................................................................................................... 104
Results.......................................................................................................................................... 106
Discussion ................................................................................................................................... 109
Immunological improvement................................................................................................... 110
Viral load ..................................................................................................................................... 110
Clinical findings ......................................................................................................................... 110
Conclusions................................................................................................................................. 111
References.................................................................................................................................... 112
Effect of introduction of fixed‐dose combinations on the drug supply chain:
experiences from the field ....................................................................................................... 113
Abstract........................................................................................................................................ 113
Intoduction.................................................................................................................................. 113
Procurement................................................................................................................................ 114
Distribution ................................................................................................................................. 115
Prescribing................................................................................................................................... 116
Dispensing to patients ............................................................................................................... 116
Cost to patient............................................................................................................................. 116
Patient use ................................................................................................................................... 117
Consumption data...................................................................................................................... 117
Conclusion................................................................................................................................... 118
References.................................................................................................................................... 118

Effect of fixed‐dose combination (FDC) medications on adherence and treatment
outcomes ..................................................................................................................................... 119
Introduction ................................................................................................................................ 119
Evidence of effect of FDCs or unit‐of‐use packaging on adherence and treatment
outcomes...................................................................................................................................... 121
Research needs............................................................................................................................ 124
Conclusion................................................................................................................................... 126
Acknowledgements ................................................................................................................... 131
References:................................................................................................................................... 132
Effect of fixed‐dose combination (FDC) drugs on development of clinical
antimicrobial resistance: a review paper............................................................................... 135
Executive summary.................................................................................................................... 135
Introduction ................................................................................................................................ 137
Biological basis for drug resistance to anti‐TB, HIV/AIDS and malaria drugs.................. 138
Combination drugs in the context of AMR............................................................................. 140
Overcoming clinical resistance using combinations: what is the evidence? ...................... 143
Future research needs................................................................................................................ 145
Conclusion................................................................................................................................... 146
Selected studies comparing combinations, FDCs, blister packs and monotherapy with
regard to development of antimicrobial resistance ............................................................... 147
References.................................................................................................................................... 151
Fixed‐dose combination (FDC) drugs availability and use as a global public health
necessity : intellectual property and other legal issues...................................................... 155
Executive summary.................................................................................................................... 155
Introduction ................................................................................................................................ 156
IPRs and Fixed‐dose Combinations: Introduction to the “Anticommons Problem” ........ 157
IPRs and Fixed‐dose Combinations: The “Anticommons Problem” (II) ............................ 158
Overcoming IP/Legal barriers .................................................................................................. 160
Back to the Future: TRIPS, Public Health, Access to Medicines .......................................... 163
Recommendations...................................................................................................................... 165
Conclusions................................................................................................................................. 166
References.................................................................................................................................... 167
Pharmaceutical development and quality assurance of FDCs.......................................... 169
Abstract........................................................................................................................................ 169
Introduction ................................................................................................................................ 170
Preformulation studies .............................................................................................................. 171
Some examples of the relevance of the properties of the API to product formulation! ... 174
Good Manufacturing Practice (GMP)...................................................................................... 176
Issues that may arise in the formulation of FDCs that do not arise for single entity
products include:........................................................................................................................ 176
Changes to registered products (variations) .......................................................................... 177
Quality control of FDCs............................................................................................................. 178
Recommendations...................................................................................................................... 180
References.................................................................................................................................... 180
Annotated agenda ..................................................................................................................... 183
List of participants .................................................................................................................... 189

Summary
Summary:
Observations and some ways forward
A. Overall observations
The overall objectives of treatment for HIV/AIDS, malaria and

tuberculosis:
1. Safe, effective, quality treatment of three major communicable diseases,

HIV/AIDS, TB and malaria, which together claim six million lives each
year.
2. Formulations and packaging that help to ensure effective use, contain
resistance and thereby keep existing medicines available for use for as
long as possible.
3. Formulations and packaging that support massive scaling‐up of
treatment will make the best use of limited human and financial
resources. At present, very few patients who would benefit from effective
treatment of AIDS, TB and malaria actually receive optimal treatment.
Provisional observations concerning fixed‐dose combinations
1. Combination therapy has become the standard for treating HIV/AIDS and
TB, and is rapidly becoming the standard for malaria. Combination
therapy has recognized benefits in slowing resistance, improving clinical
outcomes and facilitating logistics. In the case of antiretroviral (ARV)
triple therapy, fixed‐dose combinations (FDCs) usually offer the most
affordable option.
2. The key question for the meeting was: are there additional benefits in
presenting combination therapy as FDCs or co‐blistered combinations
(CBCs)? This would enhance the likelihood that all active ingredients in
the combination travel together from producer, through the supply
system, to the prescriber, to the dispenser, and into the patient’s hands.
3. In response to this question, the following main observations were made:
a. FDCs/CBCs are very important tools for scaling‐up treatment for
HIV/AIDS, TB and malaria. FDCs remain the first choice when
they are available, CBCs are a second choice and single products
are a third, but least desirable choice.
b. FDCs/CBCs alone are not going to be enough; separate medicines
will continue to be needed in specific circumstances, as discussed
below.
c. FDCs/CBCs must be considered as one element in an effort to
ensure adherence that also includes supportive counselling,
appropriate information and other measures.
1

Fixed‐dose combinations for HIV/AIDS, tuberculosis, and malaria
d. FDCs should be based on combinations of clinically proven safety
and efficacy, and they must have demonstrated quality and
bioequivalence. Where CBCs are used, the requirement is for a
logical combination of products of proven safety, efficacy and
assured quality.
e. To achieve “3 by 5”, many approaches will be needed. There will
be a need for FDCs, CBCs and single products in differing
circumstances.
B. Experiences with fixed‐dose combinations
Provisional observations
1. Combination treatment can be delivered in any of four presentations: (a)
individual medicines in bulk; (b) individual medicines in blister packs; (c)
co‐blistering of the 2, 3 or 4 needed medicines in a single pack (CBCs); (d)
fixed‐dose combination of the 2, 3 or 4 active ingredients into one tablet or
capsule (FDCs).
2. The possible benefits of FDCs and/or CBCs are that they can:
a. Increase patient adherence to treatment (especially FDCs)
b. Delay the development of resistance (especially FDCs)
c. Lower the total cost, including production, storage, transport,
dispensing and other health system costs
d. Reduce the risk of medication errors by prescribers, dispensers or
patients themselves
e. Simplify and increase security of supply systems (especially FDCs)
f. Facilitate patient counselling and education, reduce waiting time
g. Help in scaling‐up access to ARVs, as their use has been associated
with a significant increase in enrollment in some pilot ARV
programmes.
3. The strength of experiential and scientific evidence presented in support
of these benefits varied. Specifically, clinical trial evidence on the effect of
FDC use on clinical outcomes, patient adherence and resistance is limited;
but what does exist supports a benefit from FDC use.
4. For FDCs, even where measured benefits are not seen, patients and
providers appear to prefer them to loose combinations. No significant
negative evidence is available against the use of quality assured FDCs.
5. Operational arguments for FDCs and the need for “common sense”
approaches concerning cost, supply logistics and patient counselling may
be stronger in resource‐limited settings.
2

Summary
6. In practice, pharmaceutical companies have routinely developed and

marketed FDCs when combination therapy has proven advantages,
companies have access to all components of the combination (through
ownership or licensing), and an FDC is technically feasible.
7. It was noted, however, that it is, “not simple to make things simple.”
FDCs/CBCs can create significant challenges for:
a. Toxicity management
b. Paediatric and weight‐based dosing
c. Drug interactions (e.g., with rifampicin, nevirapine, other
medicines)
d. Adjustment of regimens in response to resistance
e. Lead‐in dosing
f. Dose and frequency adjustment for renal and hepatic impairment
(this is not only true for FDCs but for all products)
g. Management of ARV therapies in child‐bearing women
h. Management of co‐infections of HIV with TB and HBV.
8. Adherence depends on a combination of approaches, including
counselling; packaging and labelling to promote understanding.
9. In addition, there are a variety of dispensing options including “co‐
ziplocking”, “MEMS caps”, pill boxes and unit dose packaging. These
should be implemented in the context of Good Dispensing Practices.
Some ways forward
1. For HIV/AIDS, TB and malaria, FDCs and CBCs should be developed
according to standard treatment guidelines.
2. Each national programme needs to establish the role of FDCs, CBCs and
individual medicines within the context of its health‐care providers and
health‐care system. WHO’s guidance may be crucial to support this
needed development. National programmes should build‐in ways of
overcoming or slowing antimicrobial resistance. FDCs are one of the
important tools for achieving this objective.
3. There remains a place for combination dispensing packs according to
individual patient needs.
4. Clinical and operational research is needed to expand the evidence base
and, using natural experiments in combination with monitoring and
resistance surveillance systems, including post‐marketing surveillance of
FDCs when they are first introduced.
5. Pharmacoviligance needs to be considerably strengthened, since these
systems are not well‐developed in many of the countries that are or will
be using modern medicines for HIV/AIDS, malaria and TB.
3

6. Monitoring outcomes of the programmes in health‐care systems is

necessary as a feedback to update and possibly modify treatment plans
using FDCs and/or CBCs. This should include documentation of the role
of FDCs in increasing enrollment in ARV treatment programmes.
7. The role of dispensing and co‐packaging systems as complementary
approaches to FDCs and CBCs should be further developed.
C. Public health priorities
1. WHO has developed a public health approach to ART that has identified
four first‐line therapies using five specific medicines. These guidelines
considered a range of factors including: demonstrated efficacy, adherence
potential, side‐effects, co‐existing conditions such as TB or pregnancy,
availability of FDCs, concomitant medications, presence of resistant viral
strains, cost and availability, and infrastructure needs including
possibilities of rural delivery.
2. WHO guidelinesi indicate a preference for FDCs (or CBCs as interim) of
proven quality and bioequivalence for first‐line ART. This is an
experience‐based recommendation taking into account the total health‐
care delivery system in developing countries.
3. Management of toxicities, resistance and other treatment challenges will
require alternative 3‐drug FDCs, 2‐drug FDCs and single product
formulations.
4. FDCs, co‐blistering and loose combinations will co‐exist and can be
transitional.
5. Paediatric preparations for HIV/AIDS are sorely lacking. While more
clinical evidence is desirable, there is sufficient evidence to make
operational paediatric treatment guidelines. The greater problem is that of
convenient paediatric dosing. Issues around the treatment of mothers
who have received ARVs to prevent MTCT remain unclear.
6. Recent developments for uncomplicated malaria have focused on
combination therapies and there are at least seven new FDC therapies
recently developed or under development.
Some ways forward
1. WHO treatment guidelines provide indications of desirable FDCs and

CBCs. Guidelines, based on the best available clinical and public health
evidence, should be widely communicated to national disease control
programmes, procurement agencies and the pharmaceutical industry.

i Scaling up antiretroviral therapy in resource-limited settings: Treatment guidelines for a
public health approach 2003. Revision
http://www.who.int/3by5/publications/guidelines/en/arv_guidelines.pdf.
4

Summary
2. It is essential to continue to build the evidence base within the health‐care
system regarding procurement, distribution, use and outcomes of FDCs
and CBCs, moving from initial successful pilot projects, to the practical, to
the proven.
3. Research is needed to develop and modify policy – e.g., malaria/ACT.
This will include operational research.
4. From the client perspective there is a preference for simplicity in the
choice of delivery system.
5. There is an urgent need for the development of paediatric formulations
and specifically paediatric FDCs.
6. Special attention must be given to the packaging and dispensing of the
“combination of combinations” needed for simultaneous treatment of
HIV/AIDS and TB – perhaps through co‐blistering of TB 4‐FDCs and
HIV/AIDS 3‐FDCs.
7. Tiered guidelines providing practical information to health workers
operating at different levels of the health system on how to use the
available medicines need to be developed within each country and within
each health system.
8. There are multiple modalities to promote adherence which includes but is
not limited to FDCs.
9. Operational research is needed to clarify options, particularly for the
treatment of mothers who have received ARVs to prevent MTCT and the
issue of women of childbearing ages or women who are pregnant and
coinfected with HIV and TB. The interactions between contraception and
therapies for TB and HIV need to be investigated.
10. Pharmacovigilance is required for new products and formulation releases.
D. IP and legal options
1. For HIV/AIDS, WHO‐recommended combinations involve one or more

constituents that are widely patented in some countries, including some
least‐developed countries. Formulation of these FDCs, and perhaps CBCs
with these constituents, may require licensing agreements or other
arrangements that would enable their legal production.
2. Most existing active ingredients for combination products for TB and
malaria are not patented, although some important ones are, such as the
antimalarial combination of artemether and lumefantrine known as
Coartem/Riamet (Novartis). This situation may change over time as new
chemical entities are developed. New FDCs and/or constituents in the
pipeline may be patented and their IP will have to be properly managed
to assure access.
5

3. Property holders may be reluctant to provide information about the
number and nature of their IP portfolios. This lack of transparency as to
the existence and scope of these IP rights creates uncertainty for potential
competitors thereby decreasing the likelihood that such competition will
occur. It is also often time consuming and difficult for procurement
organizations to verify the existence and legal status of patents. Much of
the relevant information should be available in the public domain, but in
practice it can be difficult to obtain and/or it is just not accessible in a form
which is easily understood by non‐experts.
4. Various mechanisms exist that can be used to ensure that patents and
other intellectual property rights do not prevent but rather facilitate the
development, access and marketing of FDCs and CBCs. These
mechanisms can include voluntary and non‐voluntary licensing, cross
licensing, pooled licensing, and other measures consistent with TRIPS
safeguards (interpreted in conjunction with the Doha Declaration on the
TRIPS Agreement and Public Health).
5. When specific needs and products are identified and collaborative
negotiations are pursued, the IP problems may be overcome in a mutually
acceptable fashion. Where collaborative negotiation does not lead to a
voluntary solution however, it may be necessary to use public policy tools
(including the TRIPS/Doha safeguards) to enable the necessary solution to
the problem.
6. Post‐2005, there will be a need to effectively manage access to certain
future FDCs and constituents, including those using newly patented
active ingredients, as the options for countries will have changed.
7. Least developed countries who are members of the WTO are under no
obligation to enforce patents for any pharmaceutical products until at
least 2016, as agreed by the World Trade Organization (WTO) Members
in paragraph 7 of the Doha Declaration on the TRIPS Agreement and
Public Health.
Some ways forward
1. Explore feasibility and mechanisms for public listing of licence, patent
and registration status. This may involve more cooperation between
countries, international organizations, national organizations (including
patent offices) and companies.
2. Licensing and other IP arrangements for FDC and CBC would be
facilitated by a clear identification of the priority products and
formulations to be selected for licence negotiations.
3. The feasibility of expanded IP licensing arrangements should be explored
with WHO and WIPO, including identification of (a) the IP needed, (b)
potential licensors (IP holders), and potential licensees (other producers).
Other mechanisms for technology transfer may also be possible.
4. Explore the possibility of consultations between individual industries and
other stakeholders on specific IP issues for specific products.
6

Summary
5. If used, voluntary licensing, patent pools, and other IP sharing
arrangements generally should be implemented in a manner that
stimulates competition among various qualified producers. Such
arrangements should include the necessary IP to manufacture specifically
defined products.
6. Explore other mechanisms that would effectively address the multiple IP
ownership issues of FDCs and promote innovation, which may include
mechanisms for joint or collective management of IP rights.
E. Pharmaceutical development, quality assurance, and regulatory
requirements
1. Quality must be built into the product – it cannot be tested, inspected or
assessed into the product. Scientifically‐based formulation and
production will minimize problems with product quality. Quality
assurance needs to extend beyond product quality to include programme
quality.
2. Serious product quality problems have been documented for several
malaria, TB and ARV single ingredient products as well as fixed‐dose
combinations.
3. FDCs are more technically demanding than single‐ingredient
preparations to develop and to produce.
4. The WHO‐managed UN Prequalification Project assesses the quality of
selected medicines for HIV/AIDS, TB and malaria to produce a positive
list of prequalified products and manufacturers assessed according to
established criteria of safety, efficacy and quality (including
bioequivalence). WHO prequalification work and standard‐setting are
clearly endorsed by established regulators.
5. Targeted sampling and testing to monitor the market should be actively
expanded. Test results conducted by procurement agencies should be
shared with national regulatory authorities.
6. A single comparator based on the original single dose innovator product
should be used to determine the bioequivalence of FDCs. In general, this
should be the product (s) that was used for the original clinical trials.
7. The Prequalification Project includes ongoing monitoring of prequalified
products and manufacturers; strengthens local regulatory and production
capacity; and provides innovator companies with a fast‐track process
when their product has been already evaluated by a stringent agencies.
8. As yet, too few products meet WHO prequalification standards,
especially in the case of TB and newer antimalarials.
7

9. In addition to the WHO Prequalification Project, quality specifications

need to be made available to national drug regulatory authorities
(NDRAs). WHO has developed an abbreviated protocol for TB
bioequivalence testing. Such protocols may be necessary for ARV and
malarial FDCs.
10. Countries are encouraged to use the results of WHO prequalification to
provide fast track registration.
Some ways forward
1. Improved medicines quality requires substantial political commitment

and commitment of resources, both nationally and internationally.
2. Development of CBCs is a practical step towards development of FDCs; it
may avoid some of the more time‐consuming and costly steps in product
development and regulatory approval.
3. Specifications for APIs and finished products as well as methods of
analysis and reference standards need to be made available to national
drug regulatory authorities.
4. Under some unusual circumstances, a new product study may be needed
when a new FDC is produced. This may require both preclinical and
clinical trials to be undertaken.
5. Packaging is also an important part of quality. Defining the storage
conditions for new products, especially FDCs and CBCs, should be a
priority.

8

Welcome
Welcome
The meeting was opened by Dr Jonathan Quick, Director of the Department of
Essential Drugs and Medicines Policy (EDM) who welcomed more than 90
participants from all continents, from differing backgrounds, including public
health, regulation, the innovative and generic pharmaceutical industry,
government, and UN organizations. He spoke of the tremendous interest fuelled
by fixed‐dose combinations (FDCs) for antiretrovirals (ARVs) and also by recent
experiences related to malaria and TB products.

He noted the long history of FDC production. One of the most far‐reaching
events of the 20th century occurred in May 1960 with the marketing of the first
combined oral contraceptive (COC) in the USA. This was also one of the first
widely marketed blister packed products. Maloprim (pyrimethamine + dapsone)
was developed as a malaria prophylactic agent with activity against parasites
that had become resistant to pyrimethamine alone in the early 1960s. In 1969
cotrimoxazole (Bactrim or Septrin) was launched as an FDC antibiotic which
resulted from the cross licensing of components by Wellcome (now GSK) and
Roche. This compound was the top antibacterial of its time (grossing more than
US$5 billion in sales).

During the 1960s the pendulum began to swing away from FDCs. The FDA was
mandated to review the effectiveness of drugs approved between 1938 and 1962
in the Drug Efficacy Study Implementation (DESI) Programme. This resulted in
medicines being withdrawn and new FDCs facing a difficult passage to
registration.

In 1978, the first WHO Expert Committee on the Use of Essential Drugs laid
down demanding criteria for inclusion of FDCs. These were:

• clinical documentation of efficacy
• therapeutic effect greater than the sum of the components
• cheaper than the sum of individual products
• improved compliance
• dosage adjustments possible for the majority of the population.

Every Expert Committee maintained this position until 2002, when it changed to:
ʺMost essential medicines should be formulated as single compounds. Fixed‐dose
combination products are selected only when the combination has a proven advantage
over single compounds administered separately in therapeutic effect, safety, adherence or
in delaying the development of drug resistance in malaria, TB and HIV/AIDS.

Jonathan Quick reminded participants that FDC products are not limited to
AIDS, TB or malaria. One recent blockbuster has been an FDC asthma inhalant.
And a recent controversial BMJ article has proposed a 4‐FDC “polypill” for the
9

primary or secondary prevention of heart disease, which could be for everyone
over the age of 55!

Especially in the area of HIV/AIDS but also for TB and malaria, FDCs have been
identified as highly desirable in terms of adherence and ease of treatment,
containment of resistance, reducing diversions and possibly reducing costs.

The purpose of the meeting was to bring together the many different groups with
an interest in FDCs to share information and propose how WHO and its partners
could work to address barriers and to optimize the benefits of FDCs. The areas to
be discussed at the meeting were reviewed. These included the scientific issues
around the production of FDCs, and issues of compliance and adherence, patents
and licensing, production and formulation, and quality and regulation.

There had been debate on whether to have multiple small meetings for each of
the three diseases or to have a single large meeting. It was decided to hold a large
meeting because of the interaction between the issues and the actors. Individuals
working on malaria, TB and HIV/AIDS were coming to EDM to discuss the same
technical issues and were often unaware that problems had been solved by other
disease groups.
Objectives of the meeting
The objectives of the meeting were:

1. To define the public health needs, and their evidence base, for FDCs for
priority communicable diseases;
2. To determine the issues to be addressed from clinical, regulatory,
intellectual property and production perspectives to overcome barriers to
the availability of required/preferred FDCs.
Expected outcomes
He suggested that the expected outcomes of the meeting would be:
1. Analysis of the rationale for using FDCs for treating priority
communicable diseases from a public health perspective;
2. Analysis of the existing evidence supporting use of FDCs for priority
communicable diseases;
3. Analysis of the legal, regulatory and manufacturing possibilities and
constraints in creating, producing and making available FDCs;
4. Identification of specific issues for which additional work is required,
some of which may develop and be published in Expert Committee
documents.

10

Welcome
He acknowledged support received from the Rockefeller Foundation and the
various WHO partnerships, particularly Stop TB, Roll Back Malaria and the 3 by
5 Initiative.

Dr Jim Kim brought greetings from WHOʹs Director‐General and highlighted the
interest of the D‐G in the issues being discussed at the meeting. He emphasised
that FDCs should be seen as one of the components of success and not as the only
approach. He encourage participants to act quickly but not at the expense of
quality or safety. Jack Chow greeted participants on behalf of WHOʹs HTM
cluster. He pointed out that FDCs would be a crucial component of the fight
against AIDS, TB and malaria. During the meeting, the Director‐General of
WHO, Dr LEE Jong‐wook, intervened. He highlighted the need to act now,
saying that the goal was to make products available and to resolve the
intellectual property (IP) issues. He urged participants to work constructively to
solve the difficulties that were being experienced by people in poor countries
facing AIDS, TB and malaria epidemics.

Richard Wilder briefly introduced antitrust issues. He stressed that competing
companies should not make any prior agreements which would reduce
competition.
Presentations on TB FDC issues
FDCs for TB: lessons learned from a clinical, formulation and regulatory
perspective was presented by Ramesh Panchagnula from NIPER in India.i (p. 29)

This extensive paper reviewed the history of the development of TB drugs, the
rapid emergence of resistance, the use of combination therapy and the evolution
of FDC products. He provided a detailed account as to how the WHO
formulation for 2 and 4FDC products had been developed for TB. He highlighted
the many benefits of FDCs but also identified related issues, such as the variable
bioavailability of some products, resulting in the production of WHO Guidelines
for establishing bioavailability of rifampicin.

Bernard Fourie from the MRC in South Africa highlighted the importance of
quality in the production of TB 4FDCs, including issues around batch to batch
variation. He also stressed the importance of clinical factors, such as drug
interactions. He highlighted the fact that some patients may receive over doses of
some products, pointing out that for patients at the extremes of weight
determining the dosage of FDCs was difficult, and that there was a lack of
evidence to address this issue. He suggested that a limited number of tablets was
desirable but that tablet size was a factor.

i http://www.who.int/medicines/organization/par/FDC/Panchagnula_FDCs.ppt
11

Michiel de Goije of IDA Netherlands raised the relationship between dissolution
and bioavailability. Ramesh Panchangula confirmed that dissolution served as a
good proxy for bioavailability. The issue of variation in individual response was
discussed.

Comparison of the product cost of FDCs in comparison with separate
dispensing and/or co‐blistering was presented by Robert Bwire.i (p. 67)

He provided data on the changes in the costs of TB FDCs, and presented a study
on the differences between blistered TB FDC products and loose products. The
balance between blister packs increasing costs compared to the savings in
delivering products was discussed.

Erik Nordberg (IFPMA) discussed the issue of tariffs and anti‐dumping duties as
important factors in determining the end price. His organization opposed taxes
or duties being applied to medicines.
Presentations and discussions on malaria FDC issues
FDCs for malaria: translating clinical recommendations to product supply was
presented by Andrea Bosman from the Roll Back Malaria Programme.ii (p. 77)

He highlighted how many of the available drugs had been lost due to resistance,
and pointed out that the shift from single to combination therapy had occurred
later than for TB. Only since 2000 has there been a commitment to combination
therapy. This new policy had created challenges because only one FDC product
exists at present. The other products are only available as single products, and
there is limited experience with the new drugs. The issue of malaria treatment
was also complicated by a 10‐fold increase in price. WHO had reached a special
agreement on prices with Novartis, and had done collaborative work on
packaging. The WHO Prequalification Project was working on issues around the
new ACT products. In the first 17 months only one out of 26 products had been
prequalified, creating a challenge for countries wishing to use these new
products. An interim solution is to promote the procurement of individual
products.

Another area of work for the RBM programme has been in forecasting for
patients needing treatments and for individual treatments. He highlighted the
fact that the Global Fund is the major funder of ACT purchases. Countries are
following WHO’s guidelines for malaria therapy.

In discussion Clive Ondari highlighted a key concern about the poor quality of
antimalarial drugs used in Africa being a possible cause of drug resistance. He
reported that seven countries were surveyed for the quality of chloroquine and

i http://www.who.int/medicines/organization/par/FDC/Bwire.ppt
ii http://www.who.int/medicines/organization/par/FDC/FDC‐Malaria1.ppt
12

Welcome
sulfadoxine/pyrimethamine (S/P). He reported that quality varied greatly, with a
substantial number of products failing, in particular dissolution of SP. He
pointed out that this problem was well recognized by regulators and
manufacturers and was primarily due to poor quality APIs and the poor
production process. He emphasized that as more complex FDCs are produced
there is a need to ensure the quality of the APIs, to monitor the production and
delivery process and to ensure a pharmacovigilance programme to monitor the
quality of the new FDCs.

Susan Walters from Australia added that the method of manufacture was equally
important as the formulation. This meant that GMP was critical. She pointed out
that products change over time and that dissolution testing was needed to
monitor changes in formulation or production. Roger Williams from USP in the
USA commented that single dissolution tests cannot ensure bioavailability

The issue of access to antimalarials being delivered through other sectors was
discussed. Andrea Bosman suggested that the rollout of new antimalarials
should be through the public sector and should ideally include products that are
not available as single products.

Developing combination drugs for malaria: examination of critical issues and
lessons learnt was presented by Robert Taylor from WHO/TDR (p. 91)

He described the process of generating evidence through a series of clinical trials
which demonstrated the efficacy of ACT products. He highlighted the demands
for coordination that an overall programme to develop FDCs requires.

Andrea Bosman discussed the importance of multi‐centre trials being undertaken
at 10 sites for 4,500 patients. He highlighted the importance of keeping decision‐
makers involved in the development process and in providing information about
future products. He identified a tension between marketing forces and the need
to keep products available for treatment in other areas, also pointing out that
PPV were driving much malaria work because of the limited interest in
developed countries. He suggested that the research community need to be
involved in issues around pricing, commenting that under some circumstances
the development of new products that are not in the research mainstream may
cause problems. He identified the need for Phase 4 studies related to specific
aspects of the use of these drugs.

The choice between FDCs and co‐blistering was discussed and issues related to
formulation, registration and intellectual property were raised. Alan Schapira
(WHO/RBM) highlighted the fact that most antimalarials are taken at home and
that co‐blistered preparations are frequently separated and shared between
patients. The need for FDCs for short‐course therapy was questioned. Conversely
the suggestion was made that as malaria is an acute life‐threatening disease
therapy needs to be immediately accessible.

13

The issue of post‐marketing surveillance for antimalarials was raised and Alan
Schapira reported that due to the shortage of good quality products there were
limited choices available. Andrea Bosman reported that about eight companies
are involved in the prequalification process but that difficulties remain. Lembit
Rago (WHO/QSM) reported that the WHO requirements are often higher than
national standards, and that WHO is not willing to have different standards.

There was discussion to whether new antimalarials should be brought to
registration as single entities or only as FDCs. The Medicines for Malaria venture
(MMV) reported that the intention is to bring these molecules to market as FDCs.
Presentations and discussions concerning ARV FDCs
Fixed‐dose combinations for HIV/AIDS: the pros and cons of experiences to
date was presented by Sanjay Pujari, Director, HIV Project, Ruby Hall, Pune,
India (p. 99)

He reported on the treatment of 1253 patients treated in two private tertiary care
institutions in India with generic FDC products.i There had been a substantial
increase in CD4 counts during the study. The incidence of mortality and
morbidity of patients on these FDC products was 5.2 and 28.1 per 100 person
years, which is comparable to results obtained with single ARV products.

Professor Joep Lange discussed the determinants of long‐term HAART efficacy.
He pointed out that if viral load is not monitored resistance may develop before
clinical changes occur. He pointed out that DOT can increase positive outcomes
from 70% to over 95%. There was lively discussion of the details of the clinical
trial described by Dr Pujari, with the overall conclusion that, despite limitations,
the report confirmed that FDC products were clinically effective in the relatively
large cohort study.

Preferred fixed‐dose combinations of ARVs for first‐line use in HIV/AIDS was
presented on the second day of the meeting by Jos Perriens (WHO, HIV/AIDS
Department)

This was a detailed presentation on the preferred FDCs of ARVs for first‐line use
in HIV/AIDS.ii He emphasized the need to build systems that would allow the
initiation and continuation of ARV therapy down to health centre level.

Andrew Clark (Bristol Myers Squibb) presented the slides prepared by Joep
Lange, iii highlighting the practical challenges faced in developing treatment
regimens to cater for varied situations. He stated that although it is

i http://www.who.int/medicines/organization/par/FDC/Pujari‐WHOFDC2003edited.ppt
ii http://www.who.int/medicines/organization/par/FDC/
1st_line_ARVinWHOGuidelines_JosPres.ppt
iii http://www.who.int/medicines/organization/par/FDC/FDCLangeFinal.ppt
14

Welcome
unquestionable that we need to simplify HIV treatment as much as possible to
achieve the goal of treating the millions in need in a responsible manner, it is also
true that it is not always simple to make things simple for everyone. There is a
need for dosing‐flexibility of antiretrovirals in relation to:

• antiviral potency/“robustness”
• toxicity management
• weight‐based dosing
• paediatric dosing
• drug interactions
• overcoming drug resistance
• need for lead‐in dosing
• renal and/or hepatic impairment.

He suggested that it may not be easy or possible to co‐formulate some of the
most desirable combination regimens, and that the most popular current FDCs
are only partially active against HIV‐2. He highlighted the need for dosing‐
flexibility in relation to toxicity management. He pointed out that rather than
having to replace a whole regimen in the case of clearly identifiable single drug
toxicity, it would be preferable to have the option to replace one of the agents. He
also noted that there is a need for dosing‐flexibility in relation to weight‐based
dosing to minimize toxicity and maximize the efficacy of some antiretrovirals.
There was also a need for dosing‐flexibility in relation to paediatrics, which
implies a need for liquid formulations in infants; and weight‐based dosing for
virtually all ARVs until adolescence.

There was also a need for dosing‐flexibility in relation to drug interactions in that
dosages of ARVs may need to be adapted in the case of co‐medication. The need
for dosing‐flexibility in overcoming drug resistance was mentioned, as was the
suggestion that drug‐resistance is not an absolute phenomenon and that
pharmacological boosting (of protease inhibitors with ritonavir) may overcome
it. Depending on the setting, it may be desirable to have available some of the PI
in non‐boosted as well as boosted form. The issue of lead‐in dosing specifically
for nevirapine, where failure to adhere to a step‐up scheme may lead to a
considerable increase in severe (life‐threatening) toxicities was highlighted as a
serious issue for FDCs containing neverapine. The problems of severe renal or
hepatic impairment requires adjustment of dosages of particular frequently used
ARVs. He mentioned possible drug interactions with herbal preparations that
patients may be taking in addition to ARVs.

He concluded that ʺone size does not fit allʺ and that even in mass treatment
programmes, where one may have to “cut corners” and allow for casualties to
save as many lives as possible, the need for the availability of various individual
drug formulations will not be negligible.

David Hoos (Columbia University, USA) spoke about the MTCT+ programme
and client’s perspective concerning dosing‐flexibility. He highlighted that blister
packs and FDCs play complementary roles. He emphasized the value of pill
15

holders and other simple adherence devices for prompting patients to take their
medicines regularly.

Bernard Pécoul (MSF) commented on MSFs experience with trying to deliver
ARVs in constrained environments. He said that MSF had organized a recent
consultation on delivery approaches in Nairobi and that he was reporting on the
consensus reached. He highlighted that the existing infrastructure is very limited
and that patient loads are high. He suggested that the ideal product would be
stable in tropical climates, not need laboratory monitoring, be low‐cost and fully
efficacious. Such a product does not yet exist but the FDC products that have
been developed come closest to the ideal. He suggested that we needed more
FDCs, particularly those containing efavirenz. He identified a need for new tools
for the future which would include new combinations, paediatric formulations,
lower dose products and a review of products that had been discarded during
the development process.

Extensive discussions followed the presentations. Leonard Sachs (FDA,USA)
expressed concern that using NNRTI FDCs could lead to broad resistance to
NNRTI. Hanne Bak‐Pedersen (UNICEF) was concerned that there were no
appropriate formulations of paediatric medicines. If FDCs could not be produced
she strongly urged that other formulations be developed. Renee Ritson (Gates
Foundation, USA) expressed concern about mothers who had previously
received NVP for MTCT prevention. Dr Pujari (India) emphasized that the first
therapy is the most important and highlighted the importance of adherence. He
pointed out that the first‐line regimen may promote resistance. He said that in
India many patients are not naïve and will need adaptation of their regimens. He
also pointed out that side effects such as dyslipidaemia and lipodystrophy were
common. David Hoos expressed support for the WHO guidelines because they
provide clear information to national programme managers as a basis for making
national policies. He agreed that infant and child regimens and formulations
were needed.

Andrew Clark (BMS) responded to concerns about the use of NNRTI regimens.
He reported that in optimum conditions good outcomes with such regimens
occurred for up to two years. He agreed that where NVP is used for MTCT
resistance does occur at significant levels. He suggested that many women will
start to receive full HAART and that they will not receive monotherapy. He
reported on the difficulty of developing formulations and undertaking clinical
trials for children. He expressed surprise at the Indian reports of lipodystrophy
and AMI.

Jos Perriens (WHO) commented on the presentations and discussions. He
reiterated all of the concerns expressed by Joep Lange but highlighted the
emphasis of the treatment committee on treating as many patients as possible. He
confirmed that the guideline committee had considered PI regimens but had
decided that the non PI regimens remained the most practical choice. He
confirmed that the committee had struggled with the issue of paediatric
formulations. The committee had agreed to organize a consultation in 2004
16

Welcome
before the next guidelines were produced. The committee had considered the
issue of NVP for the prevention of MTCT. A consultation document was posted
on the web for public comment. The durability of NNRTI regimens is a serious
concern. He commented that where programmes had good adherence levels the
outcomes were positive, and he highlighted the importance of treatment support.

Issues around treatment of co‐infection for TB and HIV were discussed. The
issues of providing FDCs containing EFZ and the need for a combined ARV FDC
with a TB 4 FDC as a co‐blister was suggested. The question as to whether NVP
was an absolute contraindication during rifampicin regimens was raised as a
research question.

Further discussion of the paediatric preparations occurred. The example of TB
experience with dispersible tablets was quoted as an example that the ARV
industry could duplicate. Bernard Pecoul suggested that clear recommendations
about formulation and type of products were needed by the industry. Warren
Kaplan highlighted the need for operational research. The question was raised as
to whether new trials would be needed for registration of these paediatric
formulations.

In further discussion of the logistics issues around the WHO model, Jos Perriens
reported that the intention was that routine treatment might be delivered by
CHWs who would monitor for common toxicities or side‐effects. Those patients
identified would be referred up the system to a health centre or district hospital.
Simple algorithms will be developed to cope with these eventualities.
Presentation and discussion of cross‐cutting issues related to logistics,
adherence and resistance with FDCs
Analysis of the impact of the introduction of FDCs on supply management and
security when compared with separate dispensing and/or co‐blistering was
presented by Jane Masiga from MEDS Kenyai (p. 113)

She identified the many advantages of FDCs from a procurement standpoint. She
suggested that selection of products and suppliers would be simplified. Drug
registration and inspection, import clearance and contract negotiation would all
be facilitated by the use of FDCs, as would distribution and storage. She
suggested that FDCs improved prescribing and dispensing and could reduce
costs to patients. She provided data to show how the uptake of ARVs had been
related to cost in Kenyan church facilities.

Cecile Mace (MSF France) highlighted the importance of including FDCs on the
national EDL and the need for paediatric formulations to be developed. She
stressed the importance of the prequalification project in helping the
procurement process. She emphasized that one obstacle to registration was the

i http://www.who.int/medicines/organization/par/FDC/MasigaFDC.ppt
17

lack of monographs. She highlighted the present short shelf‐life of FDCs, and
pointed out that the prices of FDCs have been reduced through using pooled
procurement.

There was a general discussion of the process in changing from single products
to FDCs. This has been a problem in some situations as FDCs have been very
popular and single products have not been used, risking expiry. This rapid shift
has caused problems in maintaining stocks.

Sabine Kopp (WHO/QSM) reported that WHO is working to produce
monographs and to work on developing standards and methods for ARV
products.

Review of the evidence on better compliance and treatment outcomes with
FDCs when compared with separate dispensing and/or co‐blistering was
presented by Jennie Connor from the University of Auckland, New Zealandi
(p. 119)

She reported that there were very few trials but that what evidence is available
tends to indicate the benefit of FDCs and clear instructions or packaging in
improving adherence. She confirmed that there was a need for rigorously
organized trials to evaluate the benefits of FDCs and medication promoting
measures.

Review of the evidence on effect of FDCs on the development of clinical
resistance when compared with separate dispensing and/or co‐blistering was
presented by Warren Kaplan, Boston University, USAii (p. 119)

He pointed out there are vertical (DNA changes) and horizontal (transfer of
DNA) mechanisms for generating resistance. He suggested that there were many
factors related to the development of resistance and that FDCs or co‐blistered
packs only addressed some of the factors. From his review of the literature he
reported that there were very few well conducted studies but what evidence did
exist tended to suggest that FDCs were beneficial in preventing resistance.

David Lee (MSH, USA) commented on the two papers. He pointed out the need
to focus on the two areas of adherence and AMR. He pointed out that adherence
was affected by many factors, and that factors other than the product were often
determinant. He highlighted the opportunity for natural experiments with the
distribution of ARVs. There was extensive discussion of the value of attempting
to link ARV resistance patterns with the types of ARVs provided. There was a
brief discussion as to whether medication monitors are more useful than well
organized questionnaires.

i http://www.who.int/medicines/organization/par/FDC/
Connor_revisedslidesdec18.ppt
ii http://www.who.int/medicines/organization/par/FDC/Kaplan_resistance.ppt
18

Welcome
Jane Kangeya Kanyondo spoke about the work that she was doing in regard to
co‐blistering and the delivery of antimalarial products.i She emphasized that co‐
blistering and unit dosing could use FDCs to improve outcomes. She suggested
that two systems are likely to run in parallel, and said that blistering does not
add substantially to the cost of medications. She pointed out that liquid
preparations for children were associated with under‐dosing and over‐dosing
and that paediatric blister packs achieved more reliable results.

David Hoos (Columbia University, USA) demonstrated a simple blister packing
system that was being used within the MTCT programme. He pointed out that
this system was flexible, blistering could be carried out locally and allowed for
dosage changes. Participants expressed concerns about quality assurance issues
and about the stability of the materials used.
Procurement experiences
Hanne Bak Pedersen (UNICEF, Copenhagen) presented the experiences of

UNICEF in procuring ARV products. She emphasized the need for joint
procurement plans involving nationals and donors. She suggested that more
work is needed on the area of forecasting. It is not enough to know the number of
patients, there is a need to know the patient profile mix and the different
regimens being used. There is a problem in that some countries are not willing to
fast‐track registration of these FDC products. Concerns exist within both
innovative and generic companies about IP issues. At present LDCs are not
making full use of TRIPS safeguards, although Malawi has invoked paragraph 7
of the Doha Declaration for their procurement.

Bernard Pecoul (MSF) presented the experience of MSF in procuring ARVs. He
highlighted the problem that many national treatment programmes have not
incorporated FDCs into national treatment guidelines. He stressed that political
will at national level was critical to ensure efficient procurement. He reported
that when FDCs were available they were able to shift patients to the new
regimens and to increase the uptake. Erik Nordberg reported that the
Accelerated Access Initiative was treating large numbers of patients and that
lessons could be learned from these programmes

i http://www.who.int/medicines/organization/par/FDC/Co‐packaging‐FDC%20meeting‐
Finaldec18.ppt
19

Intellectual property and industry issues
Legal options for overcoming patent barriers of fixed‐dose combinations was
presented by Warren Kaplani (p. 155)

He reviewed the range of legal and IP issues that arise with the production of
FDCs, suggesting a range of possible approaches addressing these constraints,
with different mechanisms be useful under different circumstances and he made
a series of recommendations to the meeting.

Richard Wilder (USA) made the case that IP protection was important for
incentivizing companies to invest in research. He suggested that IP is something
to be managed rather than be seen as a barrier to overcome. Ellen ‘t Hoen (MSF)
suggested that the prime issue is political and not legal, stating that there are
many reasons to have FDCs available from a public health standpoint. She
commented that where possible voluntary licences are preferable but that
compulsory licences may be needed. She suggested that the idea of patent pools
might be useful and that WHO could be involved in defining what these patent
pools should contain. She reminded participants of the danger of regulatory
barriers from regulatory agencies only considering products for which patents
have been granted. Cecilia Oh (WHO/EDM) pointed out that as TRIPS comes into
force more widely countries will need to deal with these issues. Cynthia Cannady
(WIPO) discussed the range of options to deal with IP barriers and stressed the
importance of voluntary licences in resolving these issues. She pointed out that
considerable experience exists in other technological fields in dealing with such
issues.

Industry perspectives on FDC production
After these IP discussions industry representatives spoke of a meeting held the
previous week in Washington DC and reviewed the different technical issues in
producing FDCs. John Morris from Abbott Laboratories presented an industry
perspective on FDC issues. He started by pointing out that several aspects must
be considered for successful combination of multiple active pharmaceutical
ingredients (APIs) into a single dosage unit. This included:

• formulation development
• chemical & physical stability – compatibility
• manufacturability
• analytical methodology
• In vivo performance (bioavailability and PK parameters)
• regulatory approval.

i http://www.who.int/medicines/organization/par/FDC/Kaplan_IP.ppt
20

Welcome
He reminded participants that a co‐packaging was always an alternative. In
describing FDC formulation development he confirmed that the basic
formulation approach can vary significantly based upon API chemical and
physical properties and that in vivo performance of BCS Class I compounds (high
solubility – high permeability) is not dependent upon the formulation
composition, whereas, BCS Class IV compounds (low solubility, low
permeability) are highly dependent upon the formulation to achieve
bioavailability. This problem could be encountered in developing an FDC
product containing compounds from the various classes of therapy (PI, NRTI,
NNRTI). A combination of multiple APIs of distinctly different properties can
result in complex formulation development to target bioequivalence to
individual marketed products. In addition all APIs must be compatible with each
other and with formulation excipients, the size and number of dose units needs
to be considered and some therapeutic regimens require relatively larger doses,
resulting in multiple FDC dosage units of an acceptable size.

With regard to chemical and physical stability there must be both chemical
stability with no significant change to degradation rates or introduction of new
impurities over shelf‐life and physical stability in which the products maintain
the desired solid form or solution state of the respective APIs over the shelf‐life of
the product. Changes in solid form or physical properties may impact
bioavailability and some API’s may have limitations with respect to exposure to
air, light, humidity, or temperature. The packaged FDC dosage unit must be
chemically and physically stable over shelf‐life as studied under a wide variety of
use conditions.

A robust manufacturing process must be developed to ensure routine production
of a quality FDC product. The complexity of the formulation and levels of the
respective APIs in the dosage unit will be major factors, in addition the
uniformity of the respective APIs could represent a challenge, especially if the
APIs are present at significantly different levels in the formulation. The goal is
always to maximize production efficiency.

When addressing FDC analytical methodology there is a need to develop
analytical procedures to accurately monitor identity, strength, uniformity,
quality, and purity attributes of respective API’s in the FDC product and this will
usually present a major challenge because each API will be controlled through
appropriate specifications, the complexity of the FDC product leads to more
complex test methods and the difficulty in the determination of related
substances of a smaller API component in the presence of other API components
at much larger concentrations.

When addressing FDC in vivo performance all ADME parameters must be
considered (absorption, distribution, metabolism and excretion). Producers must
understand the importance of AUC, Cmax, Cmin, t1/2 for each API with respect to
daily dosing regimen (QD, BID, TID). They must understand the effect of food on
PK profile and there may be situations where some drugs should be taken with
food while others should not. Based upon product characteristics (solubility,
21

permeability), some APIs will require more complex formulations (reduced

particle size, stabilized amorphous systems, or solutions) to achieve acceptable
bioavailability. In some circumstances complex formulation may not be
appropriate for some API’s with very different properties – in some cases, certain
combinations may not be possible. If an API is typically dosed in an immediate
release formulation, incorporation into a modified release formulation may
significantly alter the pharmaco‐kinetic profile which could have a significant
impact on bioavailability (increased or decreased). In this situation regulatory
approval through bioequivalence becomes more challenging. In addition
interactions between API’s or formulation excipients may alter PK profile.

When dealing with FDC regulatory approval the goal is to approve FDCs
through bioequivalence to individual marketed products, as this allows bridging
to existing safety and efficacy data. If PK profiles in the FDC product are
significantly altered from the individual products, then the bioequivalence
approach may not be feasible. This would result in additional safety / efficacy
trials being required by regulators.

He suggested that a co‐packaging approach could provide a viable alternative to
an FDC approach. This would allow therapeutic agents from different classes
(different properties) to be easily combined through packaging, while avoiding
many of the development challenges. It would also allow individual drug
products to be taken under conditions that are most suitable for optimum
performance with respect to food and dosing regimen (QD, BID). This approach
would mean a substantially reduced development time, and would provide
increased flexibility to create various combination therapies and adapt to
evolution of prescription strategies
Regulatory issues
Development of FDCs; pharmaceutical considerations Susan Walters presented
her keynote paper that addressed the many issues related to the sustained
quality of products once they have been produced, stored and distributed i
(p. 169). She emphasized the importance of validation after any changes are
made in the manufacture of a product.

Vinod Arora (Ranbaxy, India) presented information on his experience with the
production of ARV FDCs.ii He made a detailed presentation of the methods used
to establish bioequivalence and to assure the quality of FDCs as compared to
originator products.

Witold Wieniawski (Polish Pharmaceutical Society) emphasized the need to
identify what products are needed before the formulators are asked to produce
the required products. Regulators will be assisted by having external validation.

i http://www.who.int/medicines/organization/par/FDC/WHOGenevaSMW1203.ppt
ii http://www.who.int/medicines/organization/par/FDC/VKAroraWHOGenevaDec.ppt
22

Welcome
In addition to the prequalification scheme, he suggested that there is also a need
for specifications and quality standards to be produced. These standards are
expensive and need to be managed in cooperation with organizations such as the
USP and European Pharmacopoiea.

János Podgorny (Hungary) reported in detail on the WHO prequalification
scheme.i He presented detailed case studies on the prequalification of the 4FDC
TB product and FDC ARVs. He concluded that there were no regulatory
obstacles to the production of quality assured FDCs.

Lembit Rago (WHO/QSM) reviewed the WHO prequalification project. ii He
emphasized that sampling for QC testing was at the post‐marketing level.

Leonard Sachs (FDA, USA) highlighted the many issues around the approval of
FDCs.iii He pointed out that assuring the quality of the product affected clinical
factors.

Roger Williams (USP, USA) discussed the issue of comparator products.iv He
pointed out that individuals may respond to drugs in different ways. He
emphasized that packaging was an important component of product quality.

Jérôme Barré (France) confirmed that for well established drug combinations, all
the regulatory authorities agree that there is no need to perform extensive
studies. Proper pharmaceutical development and a study demonstrating that the
components in the FDC are bioequivalent to the components administered in the
free combination are sufficient. In the situation where one active component
should be administered with food and the others without food, the food effect on
the FDC has to be investigated. He pointed out that the regulatory requirements
for new drug combinations with which we lack experience were not addressed in
this session. In this situation things are much more complex, especially with
regard to toxicology and safety pharmacology requirements. Unfortunately these
points are often overlooked although safety problems are at stake.

He commented that Roger Williams had presented a very comprehensive review
on comparator products stressing the importance of a good choice for
comparator. Formulations of brand products which are used as reference drugs
can vary slightly from one country to another. In Susan Waltersʹ presentation, she
mentioned some of the reasons for these variations including new source of
excipients, new manufacturing equipment, new site of manufacture etc. These
variations may produce different in vitro dissolution profiles. In some cases, these
changes in dissolution profiles do not translate into different bioavailability while
in other cases they do and with confidence intervals beyond the usually accepted

i http://www.who.int/medicines/organization/par/FDC/
Janos_FDCFPPs_Experience_LaingRv1.ppt
ii http://www.who.int/medicines/organization/par/FDC/Lembit‐FDC2003adec18.ppt
iii http://www.who.int/medicines/organization/par/FDC/WHOSacksFDCs.ppt
iv http://www.who.int/medicines/organization/par/FDC/19‐comparatorproduct‐
williamsdec18.ppt
23

ranges, as regulatory authorities have sometimes noted. For some

pharmaceutical products there are publications reporting substantial differences
in bioavailability of the same brand product sold in various countries and
showing slight variations in the formulation. This is why there is a need to be
very stringent when choosing the reference drugs to be administered in loose
combination to demonstrate the bioequivalence with the test FDC. The reference
drugs should originate from the country in which the clinical trials were
performed to evaluate the efficacy of the free drug combination. This will avoid
having FDCs with sub‐optimal efficacy.
Concluding session
At the end of the meeting there was a general discussion of a draft of an
executive summary document that had been prepared by the secretariat. This
session allowed meeting participants to highlight important issues discussed at
the meeting. Many of the comments have been incorporated into the final version
of the executive summary.

Ramesh Panchangnula (NIPER, India) urged that a single drug comparator be
used for quality control of FDCs. He called on WHO to develop a rapid protocol
for testing, as had occurred for bioequivalence testing of TB FDCs and he
suggested that surrogate markers for FDCs should be developed and agreed. He
called for operational research (OR) on all aspects of the use of FDCs.

Roger Webber (USP, USA) highlighted the need for bioequivalence testing to be
an integral part of the approval process. He suggested that under some
circumstances new product studies might be necessary.

Bernard Pécoul (MSF, France) stressed that from an operational standpoint there
was a clear hierarchy of needs. The first priority was for FDC products, the
second priority was for co‐blistered products and the third priority was to have
single products. In discussion the point was made that there may be a need to co‐
blister FDCs to deal with different therapeutic eventualities, such as
simultaneous treatment of TB and AIDS. Jeff Sturchio (Merck‐USA) pointed out
that to achieve WHOʹs 3 by 5 goals many routes were needed and a range of
different approaches would have to be tried. He stressed that the innovative
pharmaceutical industry could contribute their expertise once it was clear what
they were being asked to do. He stressed as Professor Joep Lange had previously
stated that ʺIt is not simple to make things simple!ʺ

Hemadri Sen (Lupin, India) focused his comments on practical technical issues.
He agreed with prior comments that the comparator product should have been
used for validating clinical products. He stressed that formulation and packaging
were an important part of quality and could facilitate effective dispensing. He
mentioned the need for storage conditions to be defined so that manufacturers
can produce products suitable for the expected markets. Hanne Bak‐Pedersen
(UNICEF, Copenhagen) expressed concern at the lack of emphasis on
24

Welcome
procurement issues in the meeting and executive summary. She pointed out that
with the limited number of prequalified producers there were difficulties in
procuring all the products that were requested, particularly for malaria and TB.

Renee Ritson (Gates Foundation, USA) suggested that many different approaches
would be needed for effective treatment programmes, and many different
options would need to be considered. Operational research (OR) was required on
topics such as MTCT and treatment, dealing with women in treatment
programmes, co‐infection with TB in child bearing women, rifampicin and
neverapine interactions. She stressed the need for pharmacovigilance to be built
into any programme to proactively collect information on drug reactions or
treatment failures. Leonard Sachs (FDA, USA) expressed doubts that
combination therapy was always required for malaria. He stressed that in the
same way that there was a need to test the quality of products there was also a
need to monitor the quality of programmes.

William Haddad (Cipla, USA) stressed the need for an adverse event report
system that would allow early recognition of problems. He called for an
agreement on a first line regimen, and for a statement of support for the WHO
prequalification scheme. He mentioned his concern about the effect of Hepatitis B
co‐infection with HIV and the use of lamivudine causing possible fatal
interactions. David Stanton (Department of State, USA) suggested a need for OR
on the interaction between contraception and AIDS therapy. Jaideep Gogtay
(Cipla, India) urged that existing FDCs should be used more widely. Ellen tʹHoen
(MSF, France) called on participants to remember the background to the meeting.
The 3 by 5 Programme aims to dramatically increase the number of AIDS
patients under treatment. At present, very few of these patients are on ARV
treatment and the widespread provision of FDC ARVs is a critical component of
treatment expansion.

The meeting ended with thanks extended to participants by the co‐chairs (David
Hoos and Jonathan Quick). They expressed appreciation for the constructive
atmosphere created by the willingness of everyone to interact in a frank,
respectful manner. Participants agreed to continue work on the topics discussed.
25

Background documents
Background
documents
The following documents were prepared by the named authors as background
resources for the meeting. The authors are solely responsible for the content of
the papers.
27

28
formulation and regulatory perspective
Fixed-dose combinations for

tuberculosis: lessons learned from a
clinical, formulation and regulatory
perspective
Ramesh Panchagnula1*, Shrutidevi
Agrawal1, Yasvant Ashokraj1,
Manthena Varma1, Khandavilli
Sateesh1, Vivekanand Bhardwaj1,
Sonia Bedi1, Inder Gulati1, Jitendra
Parmar1, Chaman Lal Kaul1, Bjorn
Blomberg2, Bernard Fourie3, Giorgio
Roscigno4, Robert Wire5, Richard
Laing6, Peter Evans7and
Thomas Moore8

1 Department of Pharmaceutics
National Institute of Pharmaceutical Education and Research (NIPER)
Sector‐67, SAS Nagar‐160 062 (Punjab), India.
2 Department of Medicine/Centre for International Health
Haukeland University Hospital, 5021 Bergen, Norway.
3 Director, Lead Programme for Tuberculosis Research
Medical Research Council, Private Bag X385, Pretoria 0001,
South Africa.
4 Executive Director, Foundation for Innovative New Diagnostics
71 Avenue Louis Casai, P.O. Box 93, CH‐1218, Geneva, Switzerland.
5 Berkenboog 24, 5386 GC Geffen, The Netherlands.
6 Essential Drugs and Medicines Policy, World Health Organization
CH‐1211 Geneva 27, Switzerland.
7 Global Drug Facility, StopTB Secretariat, World Health Organization
CH‐1211 Geneva 27, Switzerland.
8 Principal Program Associate, Management Sciences for Health,
Washington, USA.

* Address for correspondence
Prof. Ramesh Panchagnula, Ph.D. FRSC, Head, Department of
Pharmaceutics
National Institute of Pharmaceutical Education and Research (NIPER)
Sector‐67, SAS Nagar‐160 062 (Punjab), India.
e‐mail [email protected]

29

Abstract
Worldwide, tuberculosis (TB) remains one of the most important communicable
diseases in terms of morbidity and mortality. Its control requires multi‐drug
therapy for at least six months and this tends to lead to patient non‐compliance,
and thus failure of therapy and ultimately emergence of drug resistance. Anti‐TB
therapy, given in the form of fixed‐dose combinations (FDCs) reduces the
number of tablets to be consumed and thereby increases patient compliance with
recommended treatment regimens. Thus, FDCs play a significant role in
preventing the emergence of drug resistance. However, the quality of FDCs and
their registration requirements are major hurdles to their implementation in
national programmes. There is also concern about the bioavailability of
rifampicin.

To increase use of FDCs, their quality and registration needs to be addressed
systematically. It is anticipated that a large global market for FDCs will
encourage large‐scale production and increased competition, which in turn will
result in FDCs at affordable prices. The ‘Global TB Drug Facility’, established by
WHO and its Stop TB partners, aims to ensure universal uninterrupted access to
quality TB drugs for implementation of directly observed treatment short‐course
(DOTS) in resource‐poor countries. In this programme, four‐drug FDCs were
accepted as the drugs of first choice because of their obvious advantages in
controlling TB.

Current knowledge on anti‐TB FDCs, their dosage, combinations, available
clinical studies and the experiences with TB therapy should serve as lessons for
selection of appropriate FDCs for other diseases such as malaria and AIDS.
Tuberculosis in the world of today
The extent of problem
Even a century after Koch’s discovery of the tubercle bacillus and decades after
the discovery of powerful drugs, tuberculosis (TB) remains a leading cause of
death in the developing world. More than one quarter of preventable adult
deaths in developing countries are due to TB and it is the leading infectious cause
of female death, killing more women every year than all cases of maternal
morbidity combined1. In view of the severity and spread of the disease, in 1993,
WHO declared TB to be a ‘global emergency’ with more than 1 900 million
people infected2. Each year there are 9‐10 million new infections worldwide and
it is feared that by 2020, another 200 million individuals will become sick, and 70
million will die, most of them in developing countries3. It is estimated that India
accounts for one fourth of the global TB burden, with an estimated 14 million
cases to which about 2 million are added every year, and an annual death toll of
500 000 people.
30
Today, the situation is exacerbated by the dual epidemic of TB and human
immunodeficiency virus (HIV) and spread of multi‐drug resistant TB (MDR‐TB).
The deadly synergy between TB and HIV has led to a quadrupling of TB cases in
several African and Asian countries, while treating MDR‐TB costs up to 100
times the standard treatment cost and threatens to make TB incurable in the
future4.

To achieve WHO’s TB control targets, the 22 high burden countries which
collectively account for approximately 80% of the world’s TB cases require about
$1 billion per year during the period 2001 to 2005. A further $0.2 billion per year
is needed for other low and lower‐middle income countries.

Table 1: History of chemotherapy for the treatment of tuberculosis

Treatment Specifications Year of Comments
mode introduction
Separate Streptomycin 1944 Tested in human
formulations p‐amino salicylic acid (PAS) 1946 subject
Isoniazid (INH) 1951 Found slightly potent
Pyrazinamide (PYZ) 1954 Isoniazid first used
Ethambutol (ETH) 1962
Rifampicin (RIF) 1970
Combination Streptomycin+PAS 1948 Combination decreases
drugs (SCC) INH+PAS 1952‐1955 resistance
INH+Streptomycin 1952‐1955
DOT Directly observed treatment 1958 onwards Policy of full
supervision of
chemotherapy
2‐drug (Thiacetazone+INH) Early 1980s
Fixed‐dose (ETH+INH)
combinations (RIF+INH)
(FDCs) 3 drug 1950s‐1970s Official in USP41
RIF+ INH+PYZ
Directly observed treatment, Early 1990s
short course
4 drug FDC 1993 (available Official in USP42
DOTS
RIF+INH+ETH +PYZ in market)
1999 (in WHO
EDL)
Paediatric RIF+ INH 1999 (in WHO
FDC EDL)
RIF+ INH+PYZ 13th WHO EDL

SCC- short course chemotherapy; DOT-directly observed treatment; DOTS-directly
observed treatment, short course; FDC- fixed-dose combination; USP-United States
Pharmacopoeia; EDL Essential Drugs List
31

Development of TB treatment
Following sanatorium treatment, collapse therapy, and the development of BCG
(bacille Calmette Guérin) vaccine, the era of chemotherapy for TB dawned with
the discovery of streptomycin in 1943 by Selman Waksman. The British Medical
Research Council’s Tuberculosis Research Unit contributed to the development
of current anti‐TB chemotherapy by conducting controlled clinical trials with
various regimens. The first clinical study started when streptomycin became
available for therapy and was followed by the finding that a combined regimen
with p‐amino salicylic acid (PAS) reduced the emergence of bacterial resistance
compared to that seen when either of the two drugs was given alone. After the
introduction of isoniazid, studies combining isoniazid with PAS and
streptomycin showed that these three drugs together were more effective than
any two‐drug combination in preventing the emergence of resistance early in the
course of treatment when the viable bacterial population was high. A significant
breakthrough came in 1956 with the comparative study at the Tuberculosis
Chemotherapy Centre, Madras, India (presently known as Tuberculosis Research
Centre, Chennai, India), which provided scientific justification for the domiciliary
treatment of TB, and hence made effective chemotherapy available for even the
poorest of developing countries. Further development of chemotherapy for
tuberculosis and the history of treatment are well reviewed5 6 7 8 and hence are
summarized (Table 1) but not discussed in detail.

Patient compliance has been greatly improved by reducing the period of
treatment from 12 to 6 months. This 6‐month treatment period is well‐tolerated,
guarantees cure of patients and has acceptable relapse rates under normal
programme conditions. The present day short‐course chemotherapy (SCC)
regimens consist of four first‐line anti‐TB drugs namely, rifampicin, isoniazid,
pyrazinamide and ethambutol, used in an initial intensive treatment phase of
two months and a continuation phase usually lasting 4‐6 months. Treatment
duration and numbers of drugs used for different categories of TB patients are
given in Table 29 10

32
Table 2: Treatment regimens for various categories of TB patients

TB TB treatment regimens
treatment TB patients Continuation
Initial phase
category phase
I New smear‐positive PTB; 2 EHRZ (SHRZ) 6 HE
new smear‐negative PTB 2 EHRZ (SHRZ 4 HR
with extensive parenchymal 2 EHRZ (SHRZ) 4 H3R3
involvement;
new cases of severe forms of
extra‐pulmonary TB
II Sputum smear‐positive 2 SHRZE/1 HRZE 5 H3R3E3
relapse; 2 SHRZE/1 HRZE 5 HRE
treatment failure;
treatment after interruption
III New smear‐negative PTB 2 HRZ 6 HE
(other than category I); 2 HRZ 4 HR
new less severe forms of 2 HRZ 4 H3R3
extra‐pulmonary TB
IV Chronic (still sputum smear‐ Not applicable
positive after supervised re‐ (Refer to WHO guidelines for use of
treatment) second‐line drugs in specialized centres)
The TB treatment regimens given above have standard codes.

PTB: pulmonary tuberculosis; E: Ethambutol hydrochloride; H: Isoniazid; Z:
Pyrazinamide; R: Rifampicin; S: Streptomycin.
A regimen consists of two phases. The number before a phase is the duration of
that phase in months. A number after a letter is the number of doses of that drug
per week. If there is no number after a letter, then treatment with that drug is
daily. An alternative drug (or drugs) appears as a letter (or letters) in
parentheses.

The recommended daily doses of first‐line anti‐TB drugs are: isoniazid 5 mg/kg,
rifampicin 10 mg/kg, pyrazinamide 25 mg/kg, ethambutol hydrochloride 15
mg/kg and streptomycin 15 mg/kg.
Directly observed treatment short‐course (DOTS) – an effective

tool for management of TB
The lack of organization of services to ensure widespread detection and cure of
patients has resulted in the current toll of TB and the emergence of drug
resistance. However, there is a proven, cost‐effective management package
known as directly‐observed treatment short‐course (DOTS) that ensures effective
delivery of health services to TB patients11 12. DOTS has five key components:

• Government commitment to sustained TB control activities;
• Case detection by sputum smear microscopy among symptomatic
patients self‐reporting to health services;
33

• Standardized treatment regimen of six to eight months for at least all
confirmed sputum smear‐positive cases, with directly‐observed treatment
for at least the initial two months;
• Regular and uninterrupted supply of all essential anti‐TB drugs;
• A standardized recording and reporting system that allows assessment of
treatment results for each patient and of the TB control programme
overall.

DOTS is one of the most tangible health interventions available, contributing to
social and economic development. For the past decade it has provided a means
to realize the potential of antibiotics that were discovered half a century ago.

In addition, to manage the problem of drug resistance more effectively, WHO has
launched ‘DOTS‐plus’ in the regions with high incidence rates of MDR‐TB.
DOTS‐plus includes the five tenets of DOTS strategy and, in addition, specific
issues that need to be addressed to control MDR‐TB12 13. With the Amsterdam
declaration in 20001 and the Washington commitment in 2001 to Stop TB, WHO
and partners have finally secured the political will and operational mechanisms
needed to combat TB.
Challenges in the management of TB
To combat and prevent further spread of TB, developing countries need new
drugs for the following reasons:

• to shorten the duration of therapy;
• to reduce the number of TB cases, by curing latent infections;
• to solve the major problem of MDR in TB therapy;
• to replace expensive second line drugs with cost‐effective new drugs.
Although, the term ‘short course’ is used with the current standard anti‐TB
regimens, it is very difficult for patients to adhere to treatment for such a long
period. Furthermore, the patient has to consume a large number of tablets and
capsules every day; a common cause of patient noncompliance. As treatment
given in the form of separate formulations is fixed, there exists every possibility
for overdosing or under‐dosing, as there is no flexibility in the calculation of
dosage according to a patient’s requirement. Thus, the implementation of SCC
regimens remains a challenge14.

The drugs available for treating mycobacterial infection are losing the battle
against the disease as the bacillus continues to build up resistance to them.
Although, the cost involved in development of new drugs is enormous, it will be
far outweighed by the reduction in cost of managing TB with less expensive
drugs and shorter treatment durations. To achieve this goal, a public‐private
partnership, the ‘Global Alliance for TB Drug Development’15, has taken up the
challenge of accelerating discovery and development of new anti‐TB drugs and
has a mission to register a new molecule by 2007 and another by 2010. In this
regard, partners in the Alliance have already identified promising agents with
34
novel mechanisms of action such as PA‐824, isocitrate‐lyase inhibitors,

oxazolidinones, etc., for further development16.

There are greater prospects for identification of new targets for drug
development, and for the development of an effective vaccine, as knowledge of
the tubercle bacillus and its interaction with human host expands, particularly
with the publication of complete genome sequence of Mycobacterium tuberculosis
H37RV 17 . However, the drug discovery process is very time‐consuming and
uncertain, and it will take another 5‐10 years for a new molecule to reach the
market. Hence the only currently‐available option to control the recent
insurgence of TB is to use the available drugs widely and wisely.
Combination therapy and fixed‐dose combination (FDC) formulations in
the management of TB
FDCs have a long history of development, starting with combination therapy.
Combination therapy refers to treatment with two or more active drugs,
administered at one time in their individual formulations. Combination therapy
has proven successful in the treatment of cancer, infectious diseases,
hypertension and neurological disorders18. The use of combination therapy in a
standardized regimen is the fundamental strategy of WHO and International
Union against Tuberculosis and Lung Disease (IUATLD) for treatment of TB.
However, increasing the number of drugs to be taken increases the problem of
patient compliance. “Combo‐packs” for TB treatment (in which all the pills to be
taken at one time are packed together to reduce the chances of a patient missing
doses) were introduced in an attempt to solve this problem. However, even
using combo‐packs, patients can fail to take the drugs by choosing some and
leaving out others. Combo‐packs have an additional problem when component
drugs are provided by different companies and the blister‐packing itself by
another company, making it unclear whose responsibility it is to guarantee the
quality of the overall product. Despite the development of calendar packs, the
problem of patient compliance has persisted6. The concept of FDCs came as a
further step in the solution of this problem.
Rationale for FDCs
One of the best ways of ensuring compliance with multi‐drug regimens is to
combine the requisite drugs physically into one preparation – a FDC product.
FDCs are available for treatment of diseases in a number of classes such as
cardiovascular, infectious, gastrointestinal, etc. At the beginning of the 1970s,
FDCs accounted for over half of the pharmaceutical products and for 40 % of the
best‐selling drugs in the United States of America. Since then, there has been
much controversy surrounding their use. In a study carried out by Cohen and
colleagues18, it was found that globally a significant number of drugs are
available as FDCs although the percentage may vary between countries (15%,
25% and 20%, respectively for Israel, UK and USA) and different disease classes
35

(Figure 1). The use of anti‐infective drugs in the form of FDCs was limited due to
the desire to use antibiotic treatment with as narrow spectrum as possible.
Figure 1. Percentage of FDCs in the USA for different therapeutic classes

(including or not over-the-counter (OTC) drugs)(taken from 18)

45
40
35
30
Percentage
25
20
15
10
5
0
Cardiovascular Anti-infective Gastrointestinal Dermal
Dermat Total

Percentage of FDC drugs not including OTC drugs
Percentage of FDC drugs including OTC drugs

The rationale for using FDCs for TB stems from the fact that TB always requires
multi‐drug therapy19. The development of FDCs as a single formulation was
facilitated by the fact that the component drugs were generic and their safety and
efficacy had already been proven. Anti‐TB FDC formulations combine two or
more first‐line anti‐TB drugs (namely rifampicin, isoniazid, pyrazinamide and
ethambutol) in a fixed proportion in a single dosage form. The potential
advantages associated with the use of FDCs are:

z Safety and efficacy;
z Simplified treatment;
z Dosage adjustment according to individual need;
z Better management of DOTS;
z Simplified drug supply management, shipping and distribution;
z Reduced risk of emergence of drug‐resistant strains.

WHO and IUATLD recommend the use of FDC formulations as routine practice
in the treatment of TB and FDCs are included in the WHO Model List of Essential
Drugs8 14 20 21.
Safety and efficacy
FDCs can be regarded as the generic equivalents of the separate preparations of
anti‐TB drugs requiring in‐vivo bioequivalence studies for registration. Once the
bioequivalence of a FDC to separate formulations is proved, it may be registered
and used21. In cohort studies conducted to compare results of treatment, side
effects, and complaints with FDCs and with regimens using the drugs in separate
formulations, treatment results were excellent both for regimens based on loose,
single‐drug formulations and those based on FDCs. Furthermore, FDC‐based
regimens were associated with fewer side effects and were more acceptable to the
patients22 23 24.
36
Simplified treatment
The use of FDCs as a routine therapeutic regimen simplifies TB treatment and
increases patients’ adherence to therapy. This can be appreciated from Table 3,
which shows that patients on FDC treatment need to take only three tablets per
day in contrast to 9‐16 tablets per day for those using separate formulations8 14.

Table 3. Number of tablets to be taken daily in the intensive phase of TB
treatment*
Single‐drug tablets FDC tablets
Composition No. of tablets Composition No. of tablets
R: 150mg 3 RHZE 3
H: 300 mg (100 mg) 1 (3) 150 mg + 75 mg + 400
Z: 400 mg 3 mg + 275 mg
E: 400 mg (100 mg) 2 (7)
Total 9 (16) 3
* For a 50 kg patient
Figures in parentheses refer to alternative dose formulations and related number of
tablets.
E: ethambutol; H: isoniazid; R: rifampicin; Z: pyrazinamide.

With the use of separate formulations, prescription errors can be anticipated, as a
number of formulations with varying dosage strengths are available on the
market. In a survey conducted in Mumbai, India, it was found that among 100
private doctors 80 different regimens were prescribed; most of which were
inappropriate and expensive25 26. The use of FDC formulations is particularly
helpful in the private sector where national guidelines are not readily available
and leads to a reduction in the use of inadequate regimens25 26. In general, FDCs
simplify prescribing, prevent indiscriminate selection of drugs and limit the
errors associated with choice and calculation of dosages.
Dosage adjustment according to individual patient need
With FDCs, it is possible to satisfy the dosage requirements for each drug in
terms of mg/kg body weight. In the WHO‐recommended FDCs (Table 4), the
strength of each constituent is carefully balanced in such a manner that adequate
doses of all four drugs can be achieved for all patients by altering the number of
tablets to be ingested per day according to body weight (Table 5).
37


Table 4. WHO‐recommended strengths of FDCs of first‐line anti‐TB drugs
(adapted from 19 and 44)
Rifampicin Isoniazid Pyrazinamide Ethambutol Thioacetazone# Streptomycin
(R) (H) (Z) (E) (T) (S)
Mode of action Bactericidal Bactericidal Bactericidal Bacteriostatic Bacteriostatic Bactericidal
Daily use Single 10(8‐12)* 5(4‐6)* 25(20‐30)* 15(15‐20)* 2.5* 15(12‐18)*
formulations
FDCs (Tablets)
R+H+Z+E 150 75 400 275 ‐ ‐
R+H+Z 150 75 400 ‐ ‐ ‐
R+H+Z 60 30 150 ‐ ‐ ‐
(Paediatric)
R+H 150 150 ‐ ‐ ‐ ‐
R+H 150 75 ‐ ‐ ‐ ‐
R+H 60 30 ‐ ‐ ‐ ‐
(Paediatric)
H+E ‐ 150 ‐ 400 ‐ ‐
H+T ‐ 100 ‐ ‐ 50 ‐
H+T ‐ 300 ‐ ‐ 150 ‐
Inter‐ Single 10(8‐12)* 10(8‐12)* 35(30‐40)* 30(25‐35)* Not 15(12‐18)*
mittent formulations applicable
use FDCs (Tablets)
(3 times R+H+Z 150 150 500 ‐ ‐ ‐
weekly) R+H 150 150 ‐ ‐ ‐ ‐
R+H 60 60 ‐ ‐ ‐ ‐
(Paediatric)

# WHO discourages the use of thioacetazone because of the risk of severe toxicity, in
particularly in HIV‐infected individuals. It should be replaced by E especially in area
where HIV infection is common. Thioacetazone may be used in combination with H in
the continuation phase in areas with low prevalence of HIV infection, when financial
circumstances preclude the use of E

WHO recommended doses in mg/kg body weight. The figures in parentheses denote
range.

38
Figure 2. Plots demonstrating the design of anti‐tuberculosis four‐drug FDC
containing rifampicin (150mg), isoniazid (75 mg), pyrazinamide (400 mg) and
ethambutol (275 mg).

Rifampicin 150 mg Isoniazid 75 mg
Upper/lower dose limits Ideal dose FDC dose Upper/Lower dose limits Ideal Dose FDC dose
Dose
Dose (mg) (mg)
1000 500
800 400
600 300
400 200
200 100
0 0
30 35 40 45 50 55 60 65 70 30 35 40 45 50 55 60 65 70
kg kg

Pyrazinamide 400 mg Ethambutol 275 mg
Upper dose limit Lower dose limit & Ideal dose

Upper/lower dose limits Ideal dose FDC dose Dose
FDC dose
Dose (mg) (mg)

1600
2500
1400
2000 1200
1000
1500
800
1000 600
400
500
200
0 0
30 35 40 45 50 55 60 65 70 30 35 40 45 50 55 60 65 70
kg kg

These charts demonstrate that as body weight increases, higher dosages are required.
Deciding the exact dosages to allow easy patient management is important. In this
example, a cut‐off of 50 kg is used to change from a dosage of three to four tablets

39

Table 5. Dosage schedules of FDCs of WHO‐recommended strengths*
Patient Intensive Phase Continuation Phase

body weight
(kg)
2 months 4 months
RHZ RH RH
Children
(no. of tablets (no. of tablets daily) (no. of tablets thrice
daily) weekly)
≤7 1 1 1
8‐9 1.5 1.5 1.5
10‐14 2 2 2
15‐19 3 3 3
20‐24 4** 4 4
25‐29 5** 5 5
2 months 4 months 6 months
RHZE RHZ RH HE
Adults
(daily) (daily) (daily and thrice (daily)
weekly)
30‐39 2 2 2 1.5
40‐54 3 3 3 2
55‐70 4 4 4 3
≥ 70 5 5 5 3

Table adapted from19 and modified according to43

*This dosage schedule applicable only for category I patients (see Table I); additional
drugs to be administered for category II patients.
**Additionally one tablet of ethambutol hydrochloride should be added to the
recommended regimen during intensive phase for the patients in the body weight ranges
20‐24 and 25‐29 kg.

The use of FDCs decreases both the risk of overdosing individual drugs (which
may thus reduce the risk of dose‐related adverse effects) and the risk of under‐
dosing (which may help to prevent selection of resistant strains of tubercle
bacillus). With separate formulations, patients are given the same dose over a
wide range of body weight. Thus, the patients with lower body weight receive
more drugs than is required while the heavier patients tend to be under‐dosed.
Since most of the patients in Asia are of low body weight, there is a potential for
serious large‐scale overdosing with consequent adverse effects, and wastage of
valuable drugs that could be used for treatment of other patients. FDCs, with
their accuracy of dosages for all three or four active agents, overcome these
problems20 (Figure 2).
Better management of DOTS using FDCs
FDCs can simplify the procedures involved in the DOTS strategy to a great extent
and thereby aid in its effective implementation. This can be appreciated from the
fact that after diagnosis of TB, FDCs ensure that the drugs required are available
in the correct proportions in a single dosage form. In addition, FDCs reduce the
burden on health‐care professionals in terms of monitoring the DOTS strategy14.
40
Simplifying drug supply management
With separate formulations, out‐of‐stock situations occur for three main reasons;
lack of buffer stock, delays in receipt of orders, and expiration of stocks without
replacements being available. With FDC tablets there are fewer drug
formulations to consider, thus making it easier to calculate the drug needs.
Because there are fewer formulations to order, ship and distribute, there is less
strain on staff in the national TB programmes. In addition, use of FDC tablets
minimizes the risk of theft and misuse of rifampicin for conditions other than
TB19.
Reduced risk of emergence of drug‐resistant strains
Although multi‐drug therapy is prescribed for TB, in reality, patients tend to take
fewer drugs or only one (monotherapy). The reasons for monotherapy include: a
temporary lack of supply of one or more drug; dispensing errors; decisions by
the patient to purchase only one medication to save money or to take only one
drug because of perceived or real adverse effects associated with the other
drugs27. Poor compliance and multiple interruptions in treatment are associated
with the development of drug resistance in M. tuberculosis.

The management and control of TB is complicated by the emergence of drug‐
resistant strains. The results of a sentinel survey conducted in South Africa shows
that the rate of MDR‐TB among smear‐positive patients increased six‐fold
between 1994 and 1996. In some parts of the world, the prevalence of acquired
drug resistance has increased dramatically with some centres registering an
incidence as high as 51.5% of smear‐positive patients. Acquired drug resistance
is mainly associated with monotherapy suggesting a need for appropriate
treatment regimens and increased supervision28

The usual measures recommended to control emerging resistance are: (a)
increased supervision of patients’ treatment, as in DOTS, to eliminate or reduce
the interruptions in treatment, and (b) multi‐drug therapy in the initial phase of
treatment. As a FDC combines the most effective drugs in one formulation, the
use of FDCs makes it impossible for patients to receive monotherapy. By
ensuring that the patient receives all the component drugs, and by facilitating the
dosing of these drugs in the correct proportions, FDCs may contribute to
containing or preventing the selection of resistant strains. It is important that
FDC tablets are given under supervision (as in DOTS) since lack of supervision
may lead to interruptions in treatment and consequently to the emergence of
drug resistance8.

In the UK, which has low rates of drug resistance, 73 to 79% of rifampicin is sold
as FDCs, while in the USA, which has a higher rate of TB drug resistance, only 15
to 18% of rifampicin is utilized in the form of FDCs. These data suggest that the
low use of FDCs in the USA could be part of the reason for high rates of drug
resistance19. Similarly, low rates of resistance have been recorded in other
countries, such as Brazil, which have used quality FDCs for a sustained period of
time. This circumstantial evidence, together with the fact that treatment with
41

FDCs precludes monotherapy, forms a persuasive argument for using these

formulations for treating TB whenever possible.
Issues associated with FDCs
Although, the transition from single drug formulations to FDC formulations has
been underway for many years, only an estimated 23.8% of the total number of
notified TB cases is treated with two‐ and/or three‐drug FDCs globally in the
public sector29. Uncertainties regarding the quality of FDC formulations and
their registration, and barriers to effective implementation in national
programmes, have limited the widespread use of FDCs21. The variable
bioavailability of rifampicin from solid oral dosage forms is reported whereas
bioavailability problems with the isoniazid, pyrazinamide and ethambutol
components of FDCs have not been encountered, presumably because of the
much greater water solubility and more rapid rates of absorption of these
drugs30. As evident from Table 1, rifampicin is an important component of anti‐
TB therapy to be used for treatment of all categories of patients both in intensive
and continuation phases. Hence, using FDC tablets with poor rifampicin
bioavailability could lead directly to treatment failure and may encourage drug
resistance. Furthermore, clinical and bacteriological investigations have revealed
that the anti‐mycobacterial activity of rifampicin is dose‐dependent 31 . In
addition, rifampicin’s therapeutic ratio was shown to be only approximately four
as compared with sixteen for isoniazid 32 . Thus its potency will be severely
affected by using formulations with poor bioavailability. Therefore, a good
quality FDC tablet with demonstrated bioavailability of rifampicin is an absolute
requirement for successful treatment outcomes in programmes utilizing FDC‐
based regimens. However, before an optimized product can be formulated, the
problem of rifampicin bioavailability needs to be understood.
Variable bioavailability of rifampicin from solid oral dosage forms
Possible reasons for the variable bioavailability of rifampicin vary from raw
material to in‐vivo absorption. However, no single mechanism has been proven
to explain the anomalous behavior of the formulations. A summary of the
extensive body of research into the problem and a comprehensive review of
bioequivalence studies with formulations of rifampicin can be found in the
Annex to this paper.

Rifampicin bioavailability is multifactorial and hence requires integrated
research of the three principles of drug/product development namely,
pharmaceutic, biopharmaceutic and pharmacokinetic, to solve the issue of
quality of rifampicin‐containing dosage forms. The factors associated with
altered bioavailability of rifampicin are summarized in Figure 3 and classified
according to the LADMER system described by Ritschel and Kearns33. Figure 3
also depicts the factors responsible for the liberation and absorption of rifampicin
from the dosage form and their correlation with in‐vitro dissolution
(physicochemical parameters and formulation variables) and in‐vivo performance
(physiological variables) of rifampicin‐containing dosage forms. A thorough
understanding of these factors, along with the pharmaceutical factors
summarized in Table 6, will provide an opportunity to unravel the reasons for
42
variable bioavailability of rifampicin from FDCs. In addition, in‐vitro dissolution
can be used as a surrogate for in‐vivo bioequivalence studies, to judge the quality
of FDC formulations.

Rate of in
vivo
Formulation variables
Liberation
Solubility
Physico-chemical parameters
Absorptio
Variable
bioavailabilit Physiologic variables*
y of
Permeability
Distributio • Diffusion coefficient

Healthy
Metabolis subjects with
NO EFFECT ON RIFAMPICIN
ideal body
BIOAVAILABILITY
Eliminatio weight to
height ratio,
Response normal liver
Figure 3. Probable reasons for variable bioavailability of rifampicin from either separate dosage forms or from FDC formula
anti-TB drugs (based on Panchagnula and Agrawal45)
*Physiological variables such as food, gastric emptying time, age, phenotype, gender, nutritional status, disease, etc., are not
considered as these variables are minimized in the bioequivalence trial with a cross-over design.
43


Table 6. Pharmaceutics of first‐line anti‐TB drugs in FDCs for peroral
administration

Rifampicin (R) Isoniazid Pyrazinamide Ethambutol
(H) (Z) hydrochloride
(E)
$BCS class Class II Class I Class I Class I
Stability
i) Solid state i) Chemically stable for Slowly Stable Hygroscopic
ii) Solution state 5 years affected by
ii) Unstable in low pH air and
conditions light
Dosage forms Capsules, dispersible Tablets, Tablet, Tablet
i) Alone tablets, film coated dispersible dispersible
tablets, sugar coated tablets, tablet, syrup
tablets, syrup, liquid
suspension
ii) FDCs R+H tablet, dispersible # ‐ ‐
tablet, capsule,
‐ E+H tablet ‐ #
R+H+E tablet # ‐ #
R+H+Z tablet, # # ‐
dispersible tablet, # # #
capsule,
R+H+Z+E tablet, caplets
Formulation factors ‐
i) Processing i) Sensitive to high High dose Sensitive to high
conditions temperature and limits the humidity
humidity conditions amount of conditions
ii) drug‐excipient excipients
ii) Interacts with glidents
interaction
(e.g., bentonite)

@ Packaging Coloured blister pack, Blister ‐ Packaging has to
strip packing, high‐ packs are ensure that the
density polyethylene coloured to drug is protected
bottles, glass bottles protect from moisture
(syrups and from light.
suspensions).
$ – According to the Biopharmaceutic Classification System, solubility limits are set on the basis of the
largest dose of drug soluble in 250 ml of buffer solutions in the pH range 1‐8 and at a temperature of
37ºC. Permeability limits are based on the criterion of whether or not more than 90% of drug is absorbed.
# – Component of FDC
@ – The packaging should contribute to the effective implementation of DOTS without loss of activity
during the claimed shelf life

Guidelines for establishing bioavailability of rifampicin
FDC formulations will be efficacious only if all the components of FDC are
available in therapeutically‐effective concentrations at the infected tissue site34.
WHO and IUATLD issued a joint statement in 1994 advising that only FDC
tablets of good quality and proven bioavailability of rifampicin should be used in
the treatment of TB. However until 1996, when WHO published guidelines on
registration requirements to establish the interchangeability of generic
pharmaceutical formulations, the accurate assessment of rifampicin
bioavailability was questionable. Since the involvement of human volunteers in
44
bioavailability studies is costly, WHO and IUATLD developed a simplified,

cheaper and effective protocol. Compared with the conventional requirement of
about 13 samples over a 24‐hour period, this protocol utilizes six blood sampling
time points over an eight‐hour period without affecting the precision of
estimation35 36. WHO has nominated the National Institute of Pharmaceutical
Education and Research (NIPER), India, and the Medical Research Center at the
University of Cape Town (MRC/UCT), South Africa, as reference centres for
assessing the bioavailability of rifampicin‐containing FDC tablets. At NIPER, the
WHO/IUATLD‐recommended simplified protocol has been further validated for
determination of rifampicin bioequivalence from all types of FDCs (2‐, 3‐ or 4‐
drug) available on the market37.

It is of note that national regulatory guidelines are not consistent with regard to
the number of human volunteers required for bioequivalence studies. Lack of
uniformity in the sample size in bioequivalence trials for rifampicin‐containing
products may affect the precision and result of the estimation, as rifampicin
shows high inter‐subject variation.

In summary, concern about the quality of rifampicin in some FDC formulations
has prevented their wide‐scale use. As they are not being widely purchased,
there is a limited production, resulting in prices that many countries cannot
afford. However, as the demand for FDCs increases, large‐scale production and
increased competition are expected to result in reduced prices38.
Registration requirements for rifampicin‐containing FDC formulations
An important hurdle in the development of FDCs is the fact that in most
developing countries the regulatory authorities are prone to register, rather
‘blindly’, only those formulations which have been already registered by their
European or American counterparts. In addition, concerns of manufacturers
over the regulatory process arise from varying registration requirements across
different countries. There has been a constant debate between manufacturers
and regulatory authorities regarding the use of FDCs. Regulatory authorities
have banned many of the FDCs from time to time39 and have yet to provide any
clear‐cut guidelines regarding the use and evaluation of these dosage forms.

Various fundamental requirements for the registration of FDC products
mentioned by various regulatory authorities include the following40:

• Each component must make a contribution to the claimed effect;
• The dosage of each component must be such that the combination is safe
and effective for use;
• As a special application of the first requirement, a component may be
added, either to enhance the safety or effectiveness of the principle
active ingredient or to minimize the potential for abuse of this
ingredient;
• The duration of action of drugs should not differ significantly;
45

• Drugs should not have narrow therapeutic index or critical dosage
range.

The high registration fee in some of countries is also a barrier to the entry of
FDCs into market. Therefore, time constraints, costs of clinical trials and
regulatory problems are strong disincentives for manufacturers to produce FDC
tablets21. On the contrary, the FDC formulations available on the market are
characterized by a large variety of different dosage ratios of the drugs. This
plethora of different formulations and different dosages has created considerable
confusion impacting the application of standardized therapeutic regimens.
Hence, there is a need for uniformity of dosage on the part of manufacturers to
avoid confusing prescribers.

In short, several factors hinder the introduction of FDCs and the expansion of
their use including: higher prices, particularly for three‐ and four‐drug FDCs;
lack of proof of bioavailability of rifampicin in some formulations; protectionist
measures on the part of certain national drug regulatory authorities that favor
locally‐produced single tablets over imported FDCs; and availability of
inappropriate FDC formulations in the local or international market as compared
to the international standardized regimens for TB29.
Conclusions
The combination of two or more drugs into a single formulation offers many
advantages and FDCs have become the most effective and indispensable tools for
implementing the management strategies for certain diseases like TB, addressing
issues such as patient compliance and emergence of resistance. A thorough
understanding of the biopharmaceutics and pharmacokinetics of FDCs for TB
will help to address their unique problems such as dose adjustment,
bioavailability and development of a surrogate marker for bioequivalence.

Although the concept of FDCs of drugs is very popular for TB it can also be
extended to other diseases, such as HIV/AIDS and malaria, because of the
obvious advantages of greater patient compliance and prevention of drug
resistance emergence. However, the knowledge available for the combination
therapy of these diseases is not as great as in case of anti‐TB drugs. Furthermore,
the issues concerned with adjustment of dosage regimens in a patient, and the
cost, which is going to add to an already expensive therapeutic regimen, should
be considered. Ethical issues such as the life‐prolonging as compared to the life‐
saving nature of therapy, and regulatory issues such as conducting
bioequivalence studies in patients, should also not be overlooked. A solution for
the latter would be the development of an in‐vitro surrogate for in‐vivo
bioequivalence testing which could act as an economical and regular quality
control tool for the formulations developed.
46
Acknowledgments
Dr. Panchagnula and his research team are deeply grateful to the late Dr. Gordon
A Ellard for his indispensable support and encouragement. The valuable
assistance provided by Inderjit Singh, Kanwaljit Kaur and Shantaram Bhade
during bioequivalence trials conducted at NIPER is acknowledged. The authors
acknowledge with thanks the Global Drug Facility for providing an opportunity
to compile this article.
47

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50
Annex: Bioavailability of rifampicin, the Biopharmaceutic Classification
System and the 4D approach to disease management
Issues associated with the bioavailability of rifampicin
One of the key issues which has hindered the widespread use of fixed‐dose
combinations (FDCs) for the treatment of tuberculosis (TB) is the concern about
the bioavailability of rifampicin. Bioavailability problems have not been
encountered with isoniazid, pyrazinamide and ethambutol, probably because of
their much greater solubility in water and their more rapid rates of absorption.
The bioequivalence trials of rifampicin solid oral formulations reported since
1970 are summarized in Figure A1. Details of the studies are given in Table A1. It
is very clearly evident that good quality FDCs are produced with proven
bioavailability (22 out of 34 FDC formulations were bioequivalent when
compared to separate formulations). It is pertinent to note that bioavailability of
some FDCs when compared with rifampicin alone was not negatively affected (5
out of 12 FDCs) while in some cases, comparisons with separate formulations at
the same dose levels showed reduced bioavailability (11 out of 34 FDCs).
Interestingly, some of the trials report increased relative bioavailability of
rifampicin from FDC formulations when compared to separate combinations, as
well as rifampicin‐alone products. In addition, generic formulations of rifampicin
(rifampicin‐alone) have also shown variable bioavailability. This indicates that
FDCs of good as well as bad quality formulations, with reduced or increased
relative rifampicin bioavailability, are possible. Therefore, it is difficult to make
any generalization regarding the bioavailability of rifampicin either from FDCs
or rifampicin‐alone generic formulations as variability has been found in both.
51

Figure A1. Bioequivalence trials of rifampicin‐containing formulations
reported in literature
Bioequivalence trials of RIF [61]
FDC Vs separate formulations [34] FDC Vs RIF alone [12] RIF generic [15]
BE [22] Not BE [12] BE [5] Not BE [7] BE [6] Not BE [9]

2-FDC [5] 2-FDC [4]
3-FDC [12] 3-FDC [1]
4-FDC [5]
Below limits [11] Above limits [1] Below limits [5] Above limits [2]
2-FDC [5] 4-FDC [1] 2-FDC [2] 2-FDC [1]
3-FDC [4] 3-FDC [3] 3-FDC [1]
4-FDC [2]

Figures in parentheses indicate number of bioequivalence trials in a particular
category whereas prefix before each FDC indicates type of FDC formulation.

Note: This figure summarizes all the bioequivalence trials reported since 1970
and published in journals listed in MEDLINE. Figures in parentheses indicate the
number of rifampicin formulations for which bioequivalence has been tested in
human volunteers. The number of published papers does not match with these
figures as some of the papers report bioequivalence tests of more than one
rifampicin product. Care has been taken to avoid the repeated inclusion of trials
from the papers that report re‐analysis of data based on earlier published trials.

BE‐ bioequivalent, FDC‐ fixed‐dose combination, RIF‐ rifampicin

52
Table A1: Review of bioequivalence trials of rifampicin‐containing solid oral
dosage forms

No.
S. of Formulations used in No. of
Results/c results/comments Ref
No. trial the study subjects
s
1 2 4‐FDC tablets ‐ Bioavailability of rifampicin was 30
prepared with improved when FDCs were
improved process of prepared by 3 or 4 step process
manufacturing and compared to 2 step granulation
with or without process
addition of surfactant Addition of a surfactant like
sodium lauryl sulfate had a
negative effect on rifampicin
bioavailability.
2 1 3‐FDC vs* separate 16 Patterns of absorption, plasma 31
formulations levels and pharmacokinetic
parameters of all the three drugs
were very similar in free and
fixed combinations
3 1 Four ‘rifampicin‐only’ Total 118 Two generic formulations 13
formulations and one showed very low blood levels.
2‐FDC formulation
(along with other anti‐
TB drugs)
4 1 4‐FDC vs separate 12 FDC was bioequivalent to 32
formulations separate formulations for
rifampicin, isoniazid and
pyrazinamide
5 1 4‐FDC vs separate 13 FDC was bioequivalent to 33
formulations separate formulations for
rifampicin, isoniazid and
pyrazinamide
6 1 2‐FDC vs rifampicin‐ 6 Significant decrease in 8
alone bioavailability (32% rifampicin
and 28% desacetyl rifampicin)
from FDC.
7 1 4‐FDC vs separate 22 4‐drug FDC and separate 34
formulations formulations were bioequivalent
for rifampicin
8 2 Two rifampicin ‐ Cmax of combined (7.6 mg/l) was 35
capsules greater than rifampicin alone (6.1
2‐FDC vs rifampicin mg/l); no difference in AUC
alone
9 1 3‐FDC vs separate 20 No statistical difference between 36
formulations formulations for rifampicin

53

No.
s
10 3 Two 4‐FDC and one 3‐ 24 All the drugs from FDC 37
FDC vs separate 23 formulations were bioequivalent
formulations 19 to separate formulations in all
the three studies
Sampling points were up to 48 h.
This study was done to develop
a standardized screening
protocol for assessment of
rifampicin bioavailability
11 10 FDC (marketed 18 7 marketed FDC formulations 38
products) vs separate were not bioequivalent
formulations 3 formulations (One 2‐FDC and
(Three 2‐FDC, five 3‐ two 3‐FDC) were bioequivalent
FDC and two 4‐FDC) Lowest confidence interval
reported (58‐80% with ratio of
AUC = 68%)
12 1 Two generic 19 Generic formulations were 39
rifampicin bioequivalent to Rimactane
preparations vs
Rimactane
13 2 Two 2‐FDC 12 One FDC formulation was 40
formulations vs bioequivalent; the other was not.
separate formulations
14 1 3‐FDC vs separate 18 Absence of any negative 41
formulations interaction in combined
formulation for all the three
drugs
15 1 2‐FDC vs separate 14 FDC formulation was 42
formulations bioequivalent for rifampicin
16 2 Two 4‐FDC vs 12 each One FDC was below the lower 23
separate formulations limit of bioequivalence while
other was above the limit
17 1 2‐FDC vs separate 16 FDC formulation was 43
formulations bioequivalent to separate
formulations for rifampicin
18 1 3‐FDC vs three drugs 16 The pattern of absorption, 44
given alone (In 3 plasma concentration and
successive sessions pharmacokinetic parameters for
two weeks apart, all the drugs were very similar
volunteers received (9.4 5μg/ml rifampicin‐alone and
three drugs 9.39 μg/ml rifampicin from FDC)
individually and then
in 3‐FDC)
19 1 3‐FDC (RHE) vs R 20 Test preparation was 45
capsule and H+E bioequivalent to reference
tablet formulations with respect to both
rate and extent of absorption of
rifampicin and isoniazid
54
No.
s
20 1 Rifampicin generic 12 No difference between two 46
(300 mg) capsule vs brands of rifampicin
branded (300 mg)
capsule
21 1 Rifampicin capsules 12 There was no significant effect 47
containing different (3 groups on bioavailability when particle
sieve fractions of of 4 size was changed from 450 μm to
different particle sizes volunteer 112.5 μm but significantly
(450 μm, 112.5 μm and s) decreased when particle size was
10 μm) changed to 10 μm, probably due
to the presence of electrostatic
charges, causing aggregate
formation
22 1 3‐FDC vs separate 6 No negative interaction 48
formulations
23 1 Two rifampicin 8 Comparable rate and extent of 49
branded formulations bioavailability from both
at both single dose preparations
and steady state
conditions
24 1 3‐FDC vs separate ‐ Formulations were bioequivalent 50
formulations
25 4 Three 3‐FDCs vs ‐ Serum levels of rifampicin,
Research Center [quoted in 1,2]
separate formulations isoniazid and pyrazinamide after
Unpublished data of Lepetit
giving two 3‐FDC formulations
were closely similar to those
achieved when the same
quantities were given as separate
formulations
Marked reduction in absorption
of rifampicin from one FDC
(reason: order in which 3 drugs
were mixed was altered)
26 14 Rifampicin alone 45 (6 in Marked influence of particle size 3,4
stud formulations each of rifampicin on bioavailability
ies ‐Two formulations study) Change in excipient caused
over with different particle lower serum levels
a sizes Manufacturing procedure alone
peri ‐Four formulations did not affect peak levels
od with change in
of 3 excipient and
year manufacturing
s procedure
55

No.
s
27 5 Three 2‐FDC and Total 18 For rifampicin present in 10
three 3‐FDC vs (6 per individual formulations, plasma
rifampicin alone study) concentration were similar to
reference formulation
From 3 double combinations of
rifampicin and isoniazid, one
was associated with very low
levels of rifampicin (two of the
three 2‐FDC produced similar
profile to rifampicin‐alone)
For 3‐FDC, 2 formulations were
found to be much lower than
reference compound
28 1 3‐FDC vs separate 10 Absence of negative 51
formulations pharmacokinetic interaction
between drugs when
administered in both free and
fixed combination
29 3 ‐3 drugs alone 12 Pattern of absorption and 52
‐3 drugs in free metabolism after administration
combination of each drug alone did not differ
‐3 drugs in fixed from that of administration of
combination drugs in free and fixed
combinations
Cmax of rifampicin alone: 5.5
μg/ml; in loose combination: 7.5
μg/ml; and fixed combination: 10
μg/ml
30 1 Rifampicin capsules ‐ Capsules differed in the level 12
manufactured by 5 and rate of antibiotic absorption
different companies
31 9 Nine rifampicin 10 Absorption of syrup was twice 17
preparations (3 that of best capsule
capsules, 2 syrup, 4 One capsule formulation
tablets) vs rifampicin absorbed more slowly than
capsule others
Absorption of one of the tablets
was very poor and resulted in
very low peak serum levels
32 1 2‐FDC vs rifampicin ‐ No formulation‐related 53
alone and isoniazid differences in either rate or
alone extent of bioavailability were
found after administration of
each formulation
56
No.
s
33 5 Rifampicin alone 69 No effect on serum concentration 54
Isoniazid alone patients or half life of rifampicin and
Rifampicin + PAS isoniazid were found after
PAS alone simultaneous oral administration
Rifampicin + Isoniazid of 2 drugs compared to drugs
given alone
In case of PAS, peak serum levels
of rifampicin were delayed from
2 to 4 h and reduced from 8 to
3.8μg/ml

This table summarizes bioequivalence trials of rifampicin containing solid oral dosage forms
published since 1970, in peer‐reviewed journals.
Bioequivalence trials of oral modified release formulations of anti‐TB drugs are not listed in this
table.
The reported bioequivalence trials are arranged in descending chronological order.
Unless otherwise stated, 2‐FDC, 3‐FDC and 4‐FDC are the combinations of RH, RHZ and RHZE,
respectively.
R: Rifampicin, H: Isoniazid, Z: Pyrazinamide, E: Ethambutol, FDC: Fixed‐dose combination, PAS:
p‐amino salicylic acid, TB: tuberculosis
*vs: versus

Since the 1980s, combinations of isoniazid with p‐amino salicylic acid (PAS),
thioacetazone, ethambutol and rifampicin have been marketed for convenient
administration and to avoid monotherapy with isoniazid which was a tempting
choice for patients because of its small bulk. Rifampicin‐containing FDC
preparations in combination with isoniazid and pyrazinamide were first
developed at the Lepetit Research Center, Italy, and the plasma concentrations of
the three initial combination preparations (Rifater 1, 2 and 3) were found to be
closely similar to the corresponding separate formulations. The problem of
rifampicin bioavailability as a consequence of the manufacturing process was
identified in the early 1980s when, in a further Lepetit preparation (Rifater 4), the
order of mixing of the three component drugs was changed, resulting in an
alarming reduction in the absorption of rifampicin1,2. Since then altered
bioavailability of rifampicin from various preparations has been reported and
efforts made in both industry and academia to elucidate the underlying causes of
this problem. However, the studies were hindered by lack of information in
public domain regarding the changes made in the formulations and their effects
on rifampicin bioavailability.

It is apparent from the excellent reviews by Fox1,2 that much of the information
regarding the development of FDCs and rifampicin bioavailability has not been
published. Complete information regarding the excipients used, the change in
the manufacturing process, etc., was not disclosed3,4 and remained in the
company’s drug master files. This lack of information has delayed progress in
industry as well as academia with regard to understanding and addressing the
problem of rifampicin‐bioavailability in FDCs.
57

Even four decades after the discovery of rifampicin, the cause of altered
bioavailability of rifampicin from some of the formulations is not yet clear and
the reasons are only speculative. Hypotheses put forward in the literature
include raw material characteristics4, changes in the crystalline habit of
rifampicin5,6, excipients7, manufacturing and/or process variables3, degradation in
gastro‐intestinal (GI) tract8,9, inherent variability in absorption10 and
metabolism11, as well as others. As mentioned earlier, there is evidence that
particle size, excipients and manufacturing process are causative factors for
reduced bioavailability; however, complete information regarding these variables
is not reported in the literature4. Rifampicin being the only water‐insoluble
component, formulation and manufacture of rifampicin‐containing FDCs with
the other highly water‐soluble component drugs is the most critical process.
Hence, it is necessary to address the issue of variable bioavailability of rifampicin
from the perspective of raw material characterization and the manufacturing
process. In this regard, further studies are necessary to identify/specify optimum
particle size range, physicochemical properties, excipients that may interact with
rifampicin and the critical manufacturing variables which have an effect on
rifampicin bioavailability. Once these parameters are optimized, good
manufacturing practices (GMP) should produce batch‐to‐batch uniformity and
reproducibility to ensure acceptable bioavailability.

It was considered that the variable bioavailability of rifampicin was largely
confined to FDC formulations; however, reduced plasma concentrations
following administration of rifampicin‐only formulations were also reported by
Zak and colleagues12 as early as 1981. In recent years, the problem of
bioavailability associated with generic formulations of rifampicin was again
highlighted by McIlleron et al. 13, who found that two rifampicin capsule
formulations showed reduced blood concentrations and were responsible for the
failure of TB treatment. In this regard, reduced blood concentrations from the
capsule ‘rifampicin‐only’ formulations indicate that apart from the
manufacturing variables, the raw material also needs to be optimized.

Polymorphism of rifampicin is always regarded as a probable reason for the
variable bioavailability of rifampicin from solid oral dosage forms. Based on the
first report of rifampicin polymorphism14, it was assumed that impaired
bioavailability may result from changes in the rifampicin crystalline form during
the tableting process5. The biopharmaceutic and clinical relevance of
polymorphism is important only when the solubility of physical forms differs
significantly15. Although in the original report it was stated that the crystalline
form of rifampicin is affected by grinding, the effects on solubility were not
studied for the different physical forms and requires further investigation.

In a few of the recent reports, it was found that in‐vitro degradation of rifampicin
is catalyzed by isoniazid in acidic medium and hence this was considered as the
reason for poor bioavailability from FDCs9,16. Although this might explain the
reduced bioavailability of rifampicin in the presence of isoniazid when compared
to rifampicin alone8, this mechanism does not provide justification for reduced,
or increased, bioavailability of rifampicin from FDCs when compared to the
58
individual drugs given in combination at the same dose levels. In addition, as
evident from Figure A1, similar or increased bioavailability of rifampicin in the
presence of isoniazid compared to that of rifampicin alone remains unanswered
by this mechanism. Thus, degradation of rifampicin in presence of isoniazid
does not explain the anomalous behaviour of rifampicin from solid oral dosage
forms.

The other probable reasons such as inherent variation in the absorption of
rifampicin and extent of metabolism11, in our opinion may not be the
contributory factors for the altered bioavailability of rifampicin when determined
by controlled bioequivalence trials. In the randomized, two‐way crossover study
design, which is adopted for most of the trials listed in Figure A1, every
volunteer acts as their own control and hence, gastric emptying time, pH of the
stomach, rate of metabolism and other individual variations have only a minor
role. However, in order to explain the variations in absorption from the different
dosage forms (syrup > capsules > tablet)17, it is necessary to determine the effect
of pH on the solubility and subsequently on absorption of rifampicin from the
different segments of the GI tract. In other words, detailed information about the
biopharmaceutic properties of rifampicin and in‐vitro/in‐vivo variables affecting
its solubility and permeability is necessary in order to understand the in‐vivo
behaviour of rifampicin‐containing dosage forms.

On the other hand, in‐vitro dissolution tests do not guarantee in‐vivo
bioavailability of rifampicin. It is reported that formulations showing poor
dissolution had good bioavailability and vice versa 18. However, this report does
not mention the medium, pH and dissolution conditions used. As rifampicin is a
zwitterion, it might be possible that dissolution of rifampicin from either FDCs or
separate formulations is a function of pH and hence selection of a discriminatory
dissolution medium is important. In addition, with the increased understanding
of the complex absorption procedure and the factors affecting it, in present
context, it may be possible to develop a dissolution test as a surrogate for costly
bioequivalence trials using appropriate dissolution medium, pH and
hydrodynamic conditions 19.
Rationale for biopharmaceutic and pharmacokinetic studies of

rifampicin in FDC product development
One of the most significant tools developed to facilitate product development in
recent years has been the Biopharmaceutic Classification System (BCS), which is
based on the two fundamental tenets of drug absorption, i.e. solubility and
permeability20. According to BCS, drug molecules are divided into four
categories based on their high or low solubility and permeability. Realization of
these important properties has resulted in number of guidelines to reduce the
regulatory burden and to hasten the product registration process 21. In BCS,
solubility limits are set on the basis of the largest dose of the drug soluble in 250
ml of buffer solutions in the pH range of 1‐8 and at a temperature of 37oC. On the
other hand, permeability limits are based on the criterion that more or less than
90% of drug is absorbed. Thus, bioavailability of a compound is a function of
59

absorption, dissolution and dose, described by Absorption number (An),

Dissolution number (Dn) and Dose number (Do). The anti‐TB drugs like
isoniazid, pyrazinamide and ethambutol, by virtue of their high solubility and
bioavailability, may be considered as BCS class I drugs and hence do not possess
any bioavailability problem. However, the BCS class of rifampicin cannot be
judged from the literature because of its zwitterionic nature and variable
bioavailability. Better appreciation of the biopharmaceutic and pharmacokinetic
properties of rifampicin alone and in combination with other anti‐TB drugs will
help to predict the physicochemical, pharmaceutic, manufacturing and
physiologic variables which affect the absorption of rifampicin from various
dosage forms22. In addition, by understanding the relationship between the
drug’s absorption, solubility and dissolution characteristics, it is possible to
define the dissolution conditions to use as a surrogate for in‐vivo bioequivalence
assessments19. Rifampicin, a zwitterionic molecule with two pKa values (1.7 and
7.9), shows a highly pH‐dependent solubility and lipophilicity profile, especially
in the pH range that exists across the GI tract (pH 1.2 to 7.4). Further, rifampicin
absorption may be complicated because of its high molecular weight and
hydrogen bonding capacities. These fundamental physicochemical properties
that determine the intestinal absorption are complex for rifampicin and
understanding of these may help in reducing the variability in bioavailability.
Recent findings23, using in‐vitro, in‐situ and in‐vivo absorption models, indicated
that permeability of rifampicin is not a rate‐limiting step. In these studies, it was
clearly demonstrated that the rate and extent of drug release from the
formulations is ultimately deciding the overall bioavailability. However,
simulation of in‐vivo dissolution conditions and their applicability to predict
bioavailability is difficult for rifampicin, leading to poor in‐vitro/in‐vivo
correlations. Thus in the process of developing a dissolution test as a surrogate
marker for bioavailability of FDCs, we proposed a decision tree that can predict
the bioavailability.

To address the issue of minimum registration requirements in terms of sample
size and sampling time for bioequivalence estimations of rifampicin‐containing
products, a thorough understanding of pharmacokinetics of rifampicin is
necessary. The number and frequency of samples taken during bioavailability
studies is determined by pharmacokinetic parameters such as absorption rate
constant (ka) and elimination rate constant (kel) which ultimately affect Cmax, Tmax
and blood concentration‐time profile. In addition, the minimum sample size to
acquire statistically significant results is determined by variability in these
pharmacokinetic measures24. Thus, better understanding of the
biopharmaceutics and pharmacokinetics of rifampicin will help in elucidating the
rifampicin bioavailability problem and will provide the scientific evidence to
recommend and implement FDCs in TB programmes.
60
The 4D approach, BCS and tuberculosis
All through evolutionary history to the present, unraveling the mysteries of the
genome on one side and the vastness of the universe on the other, man has been
kept engaged in a seemingly never‐ending fight by the tiny co‐inhabitants of this
planet ‐ those causing diseases like tuberculosis, malaria and AIDS. As we
change the weapon in the form of more potent and effective drugs, the enemy
changes shape, countering with the phenomenon of drug resistance. The
successful eradication of smallpox has proved that the correct strategy, based on
sound scientific principles, properly implemented, can help us to emerge
conquerors in this battle.

The 4D approach25 of disease management proposes such a strategy to envisage a
world free from such infections. The first D, denoting disease, may be acute like
malaria or chronic like TB and may or may not have a cure, the therapy only
serving the purpose of prolonging the life of the patient as in the case of AIDS.
First and second line anti‐TB drugs constitute the second D, the latter being
reserved for cases of resistance and toxicity associated with the former. The
delivery system/mode forms the third D and has to ensure that the drugs are
available, at their optimally‐effective concentrations at the desired site(s) of
action or the “destination”, comprising the fourth D.

This link between the drug, delivery and destination is provided by the BCS
(Figure A2). Today BCS finds an integral role in every stage of the life cycle of a
drug molecule, beginning with judging the drug candidate’s suitability for a
purpose, proposing techniques for development and deliverability26 and its
ultimate evaluation based on clinical and regulatory standards27,28. In cases
where more than one drug is available for the same indication, it helps to decide
upon the drug candidate to take forward to the delivery state and the approach
to be employed. For TB, WHO and IUATLD have proposed the use of a cocktail
of drugs to be incorporated into FDCs to increase patient compliance and prevent
the emergence of resistance. These FDCs, though simple in idea, represent a very
effective delivery system in order to overcome the emergence of drug resistant‐
strains, and improve patient compliance. To date, biowaivers are granted only
for class I drugs, but extension of this umbrella to include other classes of drugs,
especially when they do not deviate greatly from class I inclusion criteria, is a
very promising and desirable possibility29. The applicability of BCS to many
drugs simultaneously when they are a part of FDCs, and especially when they
belong to different classes, is a challenging task. Nevertheless, once
accomplished, this approach will have far‐reaching consequences on the
regulatory front. Regulatory agencies have shown concern about the quality of
FDCs, mostly regarding the bioavailability of rifampicin from these formulations.
The BCS, provides an opportunity to develop and adopt a surrogate marker for
bioavailability assessment of these FDCs, so that with the aid of a resulting
biowaiver21, the quantum of monetary, human and material effort can be
channeled towards the implementation of DOTS and related policies for an
assured and speedy eradication of TB from the globe. This amalgamation of BCS
61

with the 4D approach can similarly be applied as a platform for uprooting or
controlling other infectious diseases like malaria and AIDS which are being
addressed by FDCs.

Figure A2. BCS and 4D approach for disease management

oach

Solubility
Bioavailability Permeability
Solubility
Permeability

Delivery is dependent on the nature of the drug, the disease and the destination
(the route). The drug may be required to be localized at a specific site, or to be
delivered into the systemic circulation, as determined by the disease condition. In
some cases existing technologies may be readily used for delivering molecules.
However, in many cases it is necessary to develop a delivery system in order to
meet the destination. The rate and extent to which the drug is absorbed from the
drug product and reaches its destination is governed by two tenets of
biopharmaceutics. These two properties, solubility and permeability, are of
profound importance in drug development and delivery and form the basis for
determining bioequivalence of oral immediate‐release drug products. Drugs
other than class I, when evaluated in vitro may not correlate to the in‐vivo
performance because of highly complex and multi‐faceted cascade phenomena.
This may be further complicated when a formulation contains a combination of
drugs. The true understanding of solubility, permeability, dissolution and
pharmacokinetics of a drug product is needed to define dissolution test
specifications that can predict the in‐vivo performance. Use of such surrogate
dissolution would help in product evaluation for number of drugs, especially
drugs for AIDS and cancer, where performing in‐vivo biostudies in normal
healthy volunteers is not possible.
62
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225

66
dispensing and or co‐blistering of antituberculosis drugs
Product costs of fixed-dose combination

tablets in comparison with separate
dispensing and or co-blistering of
antituberculosis drugs

Robert Bwire
Introduction
Current recommendations for the treatment of tuberculosis emphasize the use of
short‐course multidrug chemotherapy under proper supervision. Since the mid‐
1990s the World Health Organization (WHO) has promoted directly observed
treatment short‐course (DOTS) as the global strategy of treating tuberculosis (1).
The DOTS strategy has been shown to increase cure rates, reduce the risk of
emergence of drug resistance and prevent relapse (2,3).

In resource‐poor countries there is often freqent and serious lack of adequate
funding of the national tuberculosis program, which hampers the
implementation or expansion of DOTS. The impact of poor drug supply in
diseases such as tuberculosis and HIV does have far‐reaching public health
consequences. Drugs are essential to prevent and cure tuberculosis. The
inadequate and irregular supply of antituberculosis drugs could fuel the
emergence of multidrug resistance. Patients treated for tuberculosis need to take
a large number of tablets every day for long periods of time, which carries the
risk of patients becoming non‐compliant. Blister packing in tuberculosis control
has been promoted as a way of facilitating patient compliance (4). Also fixed‐
dose compounds (FDCs) as an integral part of the DOTS strategy provide
additional patient management options for tuberculosis by decreasing the
number of tablets a patient takes and increasing chances of completing treatment.
In 1994 the WHO and the International Union Against Tuberculosis and Lung
Disease (IUATLD) recommended the use of FDC tablets for treatment of
tuberculosis (5,6). In 1999 the WHO Model List of Essential Drugs was updated
to include a four‐drug FDC in the recommended formulation (7). One advantage
of the 4‐drug FDC is the greater reliability with which tuberculosis programs can
deliver short‐course multidrug treatment (8).
67

An earlier study showed that the international prices of antituberculosis drugs
had over the years remained fairly stable or declined (9). Although some
suppliers sell the two‐drug FDC with rifampicin and isoniazid at a price lower
than the individual single‐drug the high price of the four‐drug FDCs has been
cited as one of the drawbacks of this formulation (10). Quantification of the costs
involved in choosing an intervention is important for the proper planning of
allocation of the often meager resources available to national tuberculosis
programs. The aim of this study is to compare the prices of four‐fixed‐dose
combinations and single entity drugs as loose tablets or packed in blisters for the
treatment of tuberculosis.
Method
For estimating the acquisition costs of anti‐tuberculosis drugs information on
pricing in the period 1998 to 2002 was obtained from the Management Sciences
for Health (MSH) International Drug Price Indicator Guide (11). The MSH guide
provides price quotations from drug suppliers and procurement agencies, and
for this study data based on the listings from suppliers was used. Prices quoted
by agencies were only used when information on pricing was absent from
sources listed in the guide as suppliers. Pricing information for the loose four‐
drug FDC tablets was not available from the MSH guide, and data on acquisition
costs over the years (period 1999 to 2002) was obtained from the Medical Export
Group (MEG), a supplier of antituberculosis drugs. The price of four‐drug FDC
in blister packs was obtained from the Global TB Drug Facility (GDF).
Selection of anti‐tuberculosis drugs:
The antituberculosis drugs (with the exception of the four‐drug FDC) were
selected from the MSH Drug Price Indicator based on the WHO‐recommended
formulations of essential antituberculosis drugs for daily use (7). To allow for
uniform comparison only strengths used for treating adult patients were
selected. Because price quotations from the different sources varied substantially
with extreme outliers, the median prices rather than the mean prices were used.
The median unit costs were calculated separately for loose tablets, blister packs,
and four‐drug FDC.
Total acquisition costs for intensive phase treatment:
Total acquisition costs of intensive phase anti‐tuberculosis treatment were
calculated for an adult tuberculosis patient of body weight band 40‐54 kilogram
receiving:
a) daily treatment based on standard short course loose single‐drug regimen
with rifampicin, isoniazid, pyrazinamide and ethambutol
b) daily treatment based on standard short course single‐drug regimen with
rifampicin, isoniazid, pyrazinamide and ethambutol in blister packs
c) daily treatment based on short course loose four‐drug FDC (rifampicin,
isoniazid and pyrazinamide)
d) daily treatment based on short course four‐drug FDC (rifampicin, isoniazid
and pyrazinamide) in blister packs
68
Because it is recommended that a patient in the body weight band 40‐54 kilogram
be given 450 mg daily of rifampicin, the 150 mg rifampicin strength has been
chosen for calculating the total acquisition costs of a full course of treatment with
anti‐tuberculosis drugs in the intensive phase. Blister pack prices were only
available for 2002. No data could be obtained from the MSH guide on 150 mg
rifampicin in blister packs. However, information on the 300 mg in blister packs
was available from a source listed in the MSH guide as an agency. To get an
insight into the costs based on a fully blister pack strategy the agency price of 300
mg rifampicin is used in this study.

All calculations are based on 28 doses per month with a 2‐month intensive phase
i.e. a total of 56 doses. To calculate the acquisition costs during the intensive
phase the following formula was used:

Number of tablets per day X median unit price X 56.
For the single‐drug regimen with loose or blister pack tablets the sum of the
individual costs for each drug in the regimen EHRZ gave the total cost.

The acquisition costs for treatment in the continuation phase should be similar
between patients receiving the four‐FDC and those on single drug formulations
in the intensive phase since most national tuberculosis programs employ a 2‐FDC
regimen in the continuation phase. Because of this consideration no comparisons
have been made between the two groups during the continuation phase.
Results
Between 1998 to 2000 the unit median acquisition price of rifampicin (150 and 300
mg) decreased but rose thereafter to slightly above the 1998 level in 2002. The
unit median price of the other single‐dose formulations showed slight fluctuation
and remained almost stable. There was a remarkable decline in the unit median
price of the four‐drug FDC, a decline of about fifty‐percent in 2001 and 2002
compared to the 1999 price (figure 1). Blister pack prices for single‐drug or four‐
drug FDC were only available for 2002, and these are excluded from figure 1.

The unit price and number of tablets required in the intensive phase for a patient
in the 40‐54 kilogram band weight on a 4‐FDC or single‐drug (loose tablets or
blister pack) based treatment in 2002 is given in the table. The unit prices of loose
tablets of isoniazid and ethambutol are higher than tablets in blister packs. There
is hardly a price difference between loose pyrazinamide and blister pack drug.
However, blister packs of 300 mg rifampicin are more expensive than loose
tablets.
Treating the intensive phase with loose single‐drug formulations and loose four‐
drug FDC
A comparison of the total acquisition costs for treating a patient in the 40‐54
kilogram weight band during the intensive phase with the four loose single‐drug
formulations and the four‐drug FDC is shown in figure 2. The costs were less for
69

the four‐drug FDC‐based treatment and these substantially declined in 2001 and
2002; 5.1 US$ in both years compared to 12.4 US$ and 13.9 US$ for single‐drug
formulation in 2001 and 2002 respectively.
Blister pack, loose drugs and the 4‐drug FDC for intensive phase:
The total acquisition costs of antituberculosis drugs in the intensive phase
treatment of a patient in the weight band 40‐54 kilograms were graphically
plotted for the single‐drug treatment based on loose tablets or blister packs and
the four‐drug FDC as loose or blister pack tablets (figure 3).

Blister pack prices of rifampicin were only available for the 300 mg strength.
Therefore to allow for uniform comparison the price of the loose tablets of
300 mg rifampicin have been used in calculating the total acquisition costs for a
fully blister pack based intensive phase treatment versus loose tablets. A fully
blister pack based regimen with single drugs cost 10 US$ compared to 11 US$ for
loose single drugs, a difference of 1 US$.

The acquisition costs for treating the intensive phase with the 4‐drug FDC either
in blister packs or as loose tablets was about half the price of single drugs in
blister packs (5.5 US$ and 5.1 US$ compared to 10 US$).
Discussion
The results of this study show that the international prices of some single‐drug
formulations have declined or remained fairly stable over the last years, a trend
that was observed earlier (9). Remarkable, however, is the substantial decline in
the price of the 4‐drug FDC. In 1999 the unit price of a 4‐FDC tablet was
0.065 US$, falling to 0.03 US$, which is a decline of about 50 percent. These
results also show that in 2002 acquisition costs of single‐drug formulations of
antituberculosis drugs in blister packs were less than loose tablets, which might
be explained by the fact that the blister packs were from a supplier whose prices
tended to be less than that of other suppliers. On the other hand the price of 4‐
drug FDC in blister packs was slightly higher than the loose tablets. Of particular
importance is the finding that acquisition costs of antituberculosis drugs for
treating patients in the intensive phase are substantially lower for regimens
relying entirely on the four‐drug FDC compared to the total cost of individual
single drugs either as loose tablets or in blister packs. The cost savings when
using 4‐drug FDC were about 50 percent compared to single‐drug formulations.
This finding represents a substantial cost saving on acquisition costs for national
programs. In 2001 over 1.18 million smear positive tuberculosis cases were
notified to the WHO under DOTS (12). Of these patients 60 percent (over 700,000)
were estimated to represent newly diagnosed pulmonary smear positive disease.
If it were assumed that 80 percent of these newly diagnosed patients were within
the 40‐54 kilogram weight band then a fully four‐drug FDC based intensive
phase with loose tablets instead of the loose four drugs as individual
formulations would save over 4 million US$.

70
Besides the savings on acquisition costs the WHO recommended four‐drug FDCs
carries more advantages that translate into net savings to the national
tuberculosis program and the community. FDCs are given according to a
simplified schedule based on body weight and in such a manner that adequate
doses of the antituberculosis drugs included in FDC tablets are within the
therapeutic margin (10). Thus the risk of administering low‐doses of the drugs
and selection of resistant strains is minimized (13). Also the use of the four‐drug
FDC in the intensive phase greatly reduces the patientʹs daily ʺpill burdenʺ. For a
patient in the weight band 40‐54 kilogram this means three instead of nine tablets
per day (see table). In a study of 312 patients prescribed FDC only 1%
complained about the number of tablets they had to swallow compared with 5%
of 308 patients on single drug formulations (14). Thus by reducing the number of
tablets a patient needs to swallow, FDCs make treatment more acceptable, which
promotes compliance and reduces chances of emergence of multidrug‐resistant
tuberculosis (MDR‐TB) (10). However, poor compliance with FDCs may result in
development of resistant tuberculosis bacteria (15). To improve compliance it is
recommended that FDCs be given as directly observed treatment (10). Therefore
FDCs should be considered as additional tools in the reliable delivery of
treatment within the broader context of DOTS (13).

The use of fixed‐dose combinations is associated with additional advantages for
the national program such as simplification of drug quantification, procurement,
handling and supply (13,16).

There have been concerns about the management of serious adverse reactions
when using FDCs since this requires discontinuing all drugs and carefully
reintroducing single‐drug formulations (17). Studies done in an era before the
human immunodeficiency virus (HIV) began having an impact on the clinical
and epidemiological profile of tuberculosis suggested that adverse reactions
severe enough to lead to the withdrawal of FDCs are relatively rare (18‐21).
Apart from thiacetazone, a two‐drug FDC that has been associated with severe
cutaneous hypersensitivity reactions in HIV‐infected tuberculosis patients (22‐
24), it appears that administration of FDCs do not lead to more adverse events
compared to single‐drug formulations. A recent study showed that patients
receiving the four‐drug FDC regimen had less frequent complaints compared to
those on single‐drug regimen (25). Nonetheless it is recommended that programs
relying on fully FDC‐based regimens should establish a limited number of health
facilities where it is possible to manage adverse drug reactions using single‐drug
formulations (13).

In spite of the relative advantages of four‐drug FDC over single‐drug
formulations there has been a slow implementation of this strategy. Unpublished
data from a 2002 Global TB Drug Facility (GDF) survey in 64 countries indicated
that only 7 (11%) countries used four‐drug FDCs. Reasons suggested for this
slow uptake include concerns about quality, reluctance by programs to change
treatment policies, and lack of advocacy from TB bodies (13). The current study
has demonstrated that cost of the four‐drug FDC should not be an issue
anymore.
71

There are drawbacks to making conclusions based on acquisition costs alone.
These prices are not adjusted for possible differences in efficacy. However this is
unlikely to impact negatively on the advantage of four‐drug FDC over single‐
drug formulations. The four‐FDC regimen has been shown to be highly effective
in treating smear‐positive patients with sputum conversion rate at 2‐months
treatment of 94 percent compared to 89 percent among patients on single‐drug
formulations (25). Given the low cost of four‐drug FDC, simplification of
treatment and the advantages of improved drug management national
tuberculosis programs should consider replacing single‐drug formulations with
fully FDC‐based regimens for intensive phase of tuberculosis treatment.

Table: Number of tablets per day using the standard single drug regime and
the 4‐drug fixed‐dose combination tablet in the intensive phase treatment of a
patient 40‐54 kilograms
Drug Strength 2002 unit price No. of tablets

(US$) per day
Single drug short‐
course regimen
isoniazid (H) 300 mg 0.00855 (loose) 1
0.0058 (blister)
rifampicin (R) 150 mg 0.0416 (loose) 3
300 mg 0.06285 (loose)
300 mg 0.0685 (blister) 1.5
pyrazinamide (Z) 400 mg 0.0151 (loose) 3
0.0150 (blister)
ethambutol (E) 400 mg 0.0232 (loose) 2
0.0133 (blister)
4‐drug fixed‐dose
regimen
Isoniazid + 75 mg + 150 mg + 400 0.0305 (loose) 3
rifampicin + mg + 275 mg 0.0327 (blister)
pyrazinamide +
ethambutol (HRZE)

72
Figure 1: Pricing trends for single drug and 4-FDC antituberculosis drugs
0.07
0.06
0.05
Median cost U S
0.04
0.03
0.02
0.01
0
1998 1999 2000 2001 2002
Year
H 300 R 150 R 300 Z 400 E 400
73

Figure 2: Pricing trend for intensive phase treatment w ith single-drug

formulations or 4-drug FD C
16
14
12
10
Median cost US$
0
1999 2000 2001 2002
Year
Single-drug 4-drug FDC
Figure 3: Total acquisition price for intensive phase with single entity drugs and
four-drug FDC - loose or blister packed tablets
12
10
8
Median cost US$
0
Single-drug (loose) Single-drug (blister pack) 4-drug FDC (loose) 4-drug FDC (blister pack)
74
References
1. World Health Organization. Framework for effective tuberculosis control.
WHO/TB/94.179. 1994.
2. Kamolratanakul P, Sawert H, Lertmaharit S et al. Randomized controlled trial of
directly observed treatment (DOT) for patients with pulmonary tuberculosis in
Thailand. Trans R Soc Trop Med Hyg 1999;93: 552‐557.
3. Weis SE, Slocum PC, Blais FX et al. The effect of directly observed therapy on the
rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:1179‐1184.
4. World Health Organization. Treatment of tuberculosis: guidelines for national
programmes. Third edition WHO/CDS/TB/2003.313. 2003.
5. World Health Organization, International Union Against Tuberculosis and Lung
Disease. The promise and reality of fixed‐dose combinations with rifampicin. A joint
statement of the International Union Against Tuberculosis and Lung Disease and the
Tuberculosis Programme of the World Health Organization. Tuber Lung Dis
1994;75:180‐181.
6. World Health Organization, International Union Against Tuberculosis and Lung
Disease. Assuring bioavailability of fixed‐dose combinations of anti‐tuberculosis
medications. A joint statement of the International Union Against Tuberculosis and
Lung Diseases and the World Health Organization. Int J Tuberc Lung Dis 1999; 3:
S282‐S283.
7. World Health Organization. Essential Drugs. WHO Model List (revised December
1999). WHO Drug Information 1999;13:249‐262.
8. Norval PY, Blomberg B, Kitler ME, Dye C, Spinaci S. Estimate of the global market
for rifampicin‐containing fixed‐dose combination tablets. Int J Tuberc Lung Dis
1999;3: S292‐S300.
9. Laing RO, McGoldrick KM. Tuberculosis drug issues: prices, fixed‐dose combination
products and second‐line drugs. Int J Tuberc Lung Dis 2000; 4: S194‐S207.
10. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed‐dose
combination tablets for treatment of tuberculosis. Bull World Health Organ 2001;79:
61‐68.
11. Management Sciences for Health. International Drug Price Indicator Guide. accessed
on October 13, 2003 at http//erc.msh.org/dmpguide
12. World Health Organization. Global Tuberculosis Control: Surveillance, Planning,
Financing. WHO Report 2003. Geneva, Switzerland, WHO/CDS/TB/2003.316.
13. Blomberg B, Evans P, Phanouvong S et al. Informal consultation on 4‐drug fixed‐dose
combinations compliant with the WHO Model List of Essential Drugs, Geneva,
Switzerland, 15‐17 August 2001. Geneva: UNDP, World Bank, WHO Special
Programme for Research & Training in Tropical Diseases (TDR); 2002. Report No.:
TDR/TB/02.1, WHO/CDS/TB/2002.99.
14. Hong Kong Chest Service/British Medical Research Council. Acceptability,
compliance, and adverse reactions when isoniazid, rifampin, and pyrazinamide are
given as combined formulation or separately during three‐times‐weekly
antituberculosis chemotherapy. Am Rev Resp Dis 1989; 140:1618‐1622.
15. Mitchison DA. How drug resistance emerges as a result of poor compliance during
short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 1998; 2:10‐15.
16. Blomberg B, Fourie B. Fixed‐dose combination drugs for tuberculosis: application in
standardised treatment regimens. Drugs 2003; 63: 535‐553.
17. Moulding T, Dutt AK, Reichman LB. Fixed‐dose combinations of antituberculous
medications to prevent drug resistance. Ann Intern Med 1995; 122: 951‐954
75

18. Snider DE, Graczyk J, Bek E, Rogowski J. Supervised six‐months treatment of newly
diagnosed pulmonary tuberculosis using isoniazid, rifampin, and pyrazinamide with
and without streptomycin. Am Rev Respir Dis 1984;130: 1091‐1094.
19. East African and British Medical Research Councils. Controlled clinical trial of five
short‐course (4‐month) chemotherapy regimens in pulmonary tuberculosis. First
report of 4th study. East African and British Medical Research Councils. Lancet
1978;2:8085 334‐338.
20. Singapore Tuberculosis Service/British Medical Research Council. Clinical trial of six‐
month and four‐month regimens of chemotherapy in the treatment of pulmonary
tuberculosis. Am Rev Respir Dis 1979;119: 579‐585.
21. British Thoracic Association. A controlled trial of six months chemotherapy in
pulmonary tuberculosis. First Report: results during chemotherapy. British Thoracic
Association. Br J Dis Chest 1981;75:141‐153.
22. Nunn P, Kibuga D, Gathua S et al. Cutaneous hypersensitivity reactions due to
thiacetazone in HIV‐1 seropositive patients treated for tuberculosis. Lancet 1991;16:
627‐30.
23. Pozniak AL, MacLeod GA et al. The influence of HIV status on single and multiple
drug reactions to antituberculous therapy in Africa. AIDS 1992;6:809‐814.
24. Chintu C, Luo C, Bhat G et al. Cutaneous hypersensitivity reactions due to
thiacetazone in the treatment of tuberculosis in Zambian children infected with HIV‐
I. Arch Dis Child 1993;68: 665‐668.
25. Gravendeel JM, Asapa AS, Becx‐Bleumink M, Vrakking HA. Preliminary results of an
operational field study to compare side‐effects, complaints and treatment results of a
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regimen in South Sulawesi, Republic of Indonesia. Tuberculosis 2003;83: 183‐186.

76
Fixed‐dose combinations:
artemisinin‐based combination therapies for malaria treatment
Fixed-dose combinations:
artemisinin-based combination
therapies for malaria treatment
Authors
Dr Kamini Mendis, APET/RBM
Dr Andrea Bosman, APET/RBM
Dr Wilson Were, APET/RBM
Dr Pascal Ringwald, APET/RBM
Dr Peter Olumese, APET/RBM
Dr Clive Ondari, PAR/EDM

APET = Access to Prompt and Effective Treatment for Malaria
Introduction
There are at least 300 million acute cases of malaria each year globallyi, resulting
in more than a million deaths. round 90% of these deaths occur in Africa, mostly
in young children. Malaria is Africaʹs leading cause of under‐five mortality (20%)
and constitutes 10% of the continentʹs overall disease burden. It accounts for 40%
of public health expenditure, 30‐50% of inpatient admissions, and up to 50% of
outpatient visits in areas with high malaria transmission

There are several reasons why Africa bears an overwhelming proportion of the
malaria burden. Most malaria infections in Africa south of the Sahara are caused
by Plasmodium falciparum, the most severe and life‐threatening form of the
disease. This region is also home to the most efficient, and therefore deadly,
species of the mosquitoes which transmit the disease. Moreover, many countries
in Africa lacked the infrastructures and resources necessary to mount sustainable
campaigns against malaria and as a result few benefited from historical efforts to
eradicate malaria.

In Africa today, malaria is understood to be both a disease of poverty and a cause
of poverty. Annual economic growth in countries with high malaria
transmission has historically been lower than in countries without malaria.
Economists believe that malaria is responsible for a growth penalty of up to
1.3%% per year in some African countries. When compounded over the years,
this penalty leads to substantial differences in GDP between countries with and
without malaria and severely restrains the economic growth of the entire region.
Malaria also has a direct impact on Africaʹs human resources. Not only does

i http://www.rbm.who.int/cmc_upload/0/000/015/372/RBMInfosheet_1.htm
77

malaria result in lost life and lost productivity due to illness and premature
death, but malaria also hampers childrenʹs schooling and social development
through both absenteeism and permanent neurological and other damage
associated with severe episodes of the disease.

One of the greatest challenges facing Africa in the fight against malaria is drug
resistance. Resistance to chloroquine, the cheapest and most widely used
antimalarial, is common throughout Africa (particularly in southern and eastern
parts of the continent). Resistance to sulfadoxine‐pyrimethamine (SP), often seen
as the first and least expensive alternative to chloroquine, is also increasing in
east, central and southern Africa. As a result of these trends, many countries are
having to change their treatment policies and use drugs which are more
expensive, including fixed‐dose combinations of drugs, which it is hoped will
slow the development of resistance.

This paper outlines the critical issues that underpin the selection, distribution
and use of antimalarial medicines. It also highlights the major key milestones
that have been reached in moving towards ensuring access to safe, effective and
good quality fixed‐dose combination antimalarial products.
Background
Antimalarial drug resistance
Resistance of P. falciparum to chloroquine appeared almost simultaneously in
Colombia in 1960 and on the frontier between Thailand and Cambodia. In Asia,
chloroquine‐resistance was confined to Indochina until the 1970s, when it
extended to the west and towards the neighbouring islands to the south and east.
Today, only few countries in Central America north of the Panama Canal,
including Haiti and Dominican Republic, do not report chloroquine‐resistant
falciparum malaria. Amodiaquine remains useful in areas where there is a
moderate resistance to chloroquine, in spite of the results of some studies that
suggest its low efficacy, perhaps because insufficient dosages were involved1.

The sulfadoxine‐pyrimethamine (S/P) fixed‐dose combination i was used to
replace chloroquine. At the beginning of the 1980s, that combination became
almost totally ineffective in Thailand and neighbouring countries. Resistance to
the drug combination spread rapidly in Central America. South Africa was the
first country to replace chloroquine with SP in one Province and later Malawi
was the first country to change its policy to sulfadoxine‐pyrimethamine as the
first line drug. Other African countries followed that example, but because of
massive use of this product, resistance is already high in many parts of East
Africa.

i SP is a synergistic fixed‐dose combination, in which both components synergistically act on
the the antifolate methabolic pathway of the parasite. Operationally, however, they are
considered a single product in that neither of the individual components in itself can be
given alone for antimalarial therapy.
78
Resistance to quinine and mefloquine is found mostly in Thailand and
Cambodia. Sporadic cases of prophylactic failure of mefloquine in travellers and
therapeutic failure with amino‐alcohols have been reported in Africa, South
America, and in other Asian countries. Several studies have noted a diminution
in in vitro sensitivity to quinine throughout the world, and in West Africa, in vitro
studies have shown strains presenting decreased sensitivity to mefloquine even
before its therapeutic use.

The description of chloroquine‐resistant P. vivax is more recent. In 1989, the first
cases appeared in Papua New Guinea. Other cases of resistance or decreased
sensitivity were reported from Irian Jaya and other Indonesian islands,
Myanmar, the Solomon Islands, India and, more recently, Brazil and Guyana.
The main problem in the evaluation of the sensitivity of P. vivax is the distinction
between reappearance and relapse caused by the hypnozoites. As with P.
falciparum, the measurement of the blood chloroquine level can give an
individual confirmation that an effective concentration of the drug has been
achieved. Chloroquine‐resistant P. vivax infection could become a serious
therapeutic problem since the sulfadoxine‐pyrimethamine combination is not
fully effective against this species.

So far, no resistance to artemisinin or artemisinin derivative has been reported,
although some decrease in in vitro sensitivity has been reported in China.
However, sensitivity testing as guided by WHO protocols2 continues to be of
paramount importance.
The effects of resistance
The appearance of resistance to antimalarials has increased the global cost of the
disease. Therapeutic failure means that patients continue to consult health
facilities for further diagnosis and treatment resulting in a loss of working days
for adults and absence from school for children. Studies in East Africa have
shown that ineffective treatment causes malaria‐realted anaemia, which renders
children’s health more fragile. In Central Africa, the appearance of chloroquine
resistance led to an increase in hospital admissions because of the severe attacks
of malaria. Other studies have shown increase in malaria case fatality rates and
increasing mortality trends at the community level due to chloroquine resistance.
The impact of drug resistance can also be illustrated by the changes in the
proportion of P. falciparum relative to other species of malaria. For example, in
India, P. falciparum now accounts for about 40% of the malaria cases after the
advent of drug resistance, instead of the previously reported 15%3.
Use of antimalarials
Where are antimalarial medicines bought by the public?
A major proportion of cases is treated outside the formal health delivery system
in many Sub‐Saharan African countries. Self‐treatment of malaria has been
documented to range from a low of 19% in Guinea to a high of 94% in rural
Ghana; the average of reviewed studies being about 66%. A review of 2 urban
and 8 studies of paediatric cases of malaria in rural areas in African countries
found a median of only 38% of malaria case being seen in government health
79

centres. In Togo, 83% of reported fevers were treated at home with an
antimalarial drug. In Kenya 60% of surveyed episodes of febrile illness were
treated at home with locally purchased herbal remedies or medicines, and only
18% went for treatment to a health centre or hospital. A household survey in
Burkina Faso concluded that only 13% of mild episodes and 54% of severe cases
of fever were treated by ‘professional services’. Self‐treatment with drugs from
ordinary shops was commonly reported in a survey in Uganda4 5 6;
Appropriateness of self‐medication with antimalarials
Appropriateness of self‐administered treatments is often low. In Togo, the
dosage of 70% of the treatments administered at home was found to be
inadequate. A large fraction (24.6%) of caretakers in a Nigerian study used sub‐
curative doses of chloroquine to treat their children. Only 38% of adults in a
Zambian study knew the correct dosage of malaria treatment for adults, and only
25% could state the correct dosage for children. A survey in Kenya estimated
that only 4% of children given shop‐bought chloroquine had received an
adequate total dose, while fewer (2%) received chloroquine over the
recommended 3‐day period. These data demonstrate that self‐medication
practices have been severely inappropriate with the current antimalarials, and
are likely to be inappropriate with future antimalarials, unless action is taken.
The provision of FDCs may reduce this inappropriate use7 8 9, by improving
adherence to treatment and standardization of regimens.
The quality of antimalarial drugs in developing countries
An issue of serious concern is the high prevalence of substandard and counterfeit
antimalarial products circulating in developing countries. Quality of antimalarial
drugs differs greatly among countries, both in content and dissolution. Hence,
an important cause of treatment failures may be actually due to drug quality
problems.

Anti‐infective products of poor quality may contribute to the emergence of
resistance, as treatment with poor quality drugs may result in low bioavailability,
which may result in drug under‐dosage. This, in turn, may promote the selection
and spread of resistance. Quality of antimalarials is rarely independently verified
in most countries and local capacity for independent drug quality assurance is
poorest where the disease burden is highest. Although malaria‐endemic
countries carry out drug resistance monitoring as per WHO protocols, the data
are not linked to the overall proportion of treatment failures, which is due to
many factors, including product quality.
80
Figure 1: The quality of anti-malarial products differs greatly among countries - both content and dissolution are
problems
Cholorquine Tabs - % failure * Sul phdoxi ne/pyri methami ne Tabs - % fai l ure*
100 100
80
80
60
60
40
40
20
20 0
e
e
n
na
li
bw
u
da
0
ny
Ma
bi q
a
ba
Su
Gh
Ke
e
ue
n
li
a
za m
a
n
bw
Z im
bo
an
Ma
ny
da
b iq
ba
Ga
Gh
Mo
Ke
Su
zam
Zim
Mo
Content Dissolution(pyrimethamine)
Content Dissolution
* Samples were judged to have “failed” if

content was < 93% or >107%, and dissolution * Samples were judged to have “failed” if
<80% in 45 minutes content was <90% or >110%, and dissolution
<65% in 30 minutes
In a recent survey of the quality of antimalarial drug products in eight African
countries, significant quality problems were detected 10 . The study evaluated
samples of chloroquine syrup, chloroquine tables and
suphadoxine/pyrimethamine tablets. Findings included:

• active ingredient content failure rates averaged 57% for chloroquine syrup,
and ranged from a high of 66%, to a low of 25%;
• active ingredient content failure for chloroquine tablets was very significant
with highest levels being 66% and the lowest levels being 20%; and
• failure rates for SP tablets were most serious with regard to the dissolution of
the pyrimethamine component. Average failure rates were 91.1%, and ranged
between 75% to 100%.

It is recommended that definite action be taken at the country level to address
this problem. Measures should include: promoting good procurement practices
in the public sector; monitoring and supporting GMP compliance of
manufacturers and suppliers; supporting the implementation of sound and
effective drug quality control programmes within drug regulatory authorities to
ensure safe use of good quality antimalarial products.
81

Implementation issues
Changing of antimalarial treatment policy
A change of policy on the first‐line drug for malaria is a major challenge to
endemic countries, malaria being a ‘high‐burden’ disease, and particularly, as in
the case of chloroquine or S/P, when it entails changing from a low cost, and
easy‐to‐administer drug with a known safety prophile. This was evident in the
all too delayed response from countries all over the world in replacing
chloroquine and S/P, often at the cost of a high morbidity and mortality.

Although several indicators i may signal the need for a policy review, failing
therapeutic efficacy of the first‐line antimalarial drug is the single most important
guide to drug policy review. Currently, countries are advised to be on high alert
for policy review when clinical failure ratesii exceeds 6%, and to change the
antimalarial treatment when failure rates reach 15%.
Delivering antimalarials to the community
Health facilities are most often not able to meet all treatment needs especially in
remote and rural areas and among marginalised populations, ethnic minorities
and forest dwellers in Africa, Asia and Latin America. This coupled with scarce
transport facilities make the likelihood of reaching a functional health facility in
time very low. These constraints can only be surmounted by making treatment
available as near the home as possible, be that in the community or in the home
itself. This strategy is referred to as “Home Management of Malaria”.

Malaria treatment requires accessing effective treatment within 24 hours of the
onset of illness especially for non‐immune persons and this is critical to saving
child lives in Africa and for reducing child and adult mortality in other endemic
regions of the world. Therefore, one of the most important strategies to reduce
child mortality due to malaria is home management of malaria. The strategy
entails educating mothers, community health workers, volunteers and/or drug
vendors to recognise symptoms suggestive of malaria and deliver appropriate
preferably pre‐packed antimalarial drugs. Home management of malaria is very
much embodied within the principles of primary health care (PHC) to improve
access to care and to ensure equity, and it widely implemented in the Indian sub‐
continent. Providing FDC antimalarial products could simplify the home
management of malaria.

i Framework for developing, implementing and updating national treatment policy: a guide
for country malaria control programmes. Brazzaville, WHO Regional Office for Africa, 2002
ii As defined by the ʺWHO Protocol for Assessment and Monitoring of Antimalarial Drug
Efficacy for the Treatment of Uncomplicated Falciparum Malariaʺ. WHO unpublished
document. WHO/HTM/RBM/2003.50
82
Delivering antimalarials through public sector
Home management of malaria involves engaging communities, changing
treatment seeking behaviour, educating mothers and training community health
workers, pre‐packaging drugs and putting in place supervisory and simple
monitoring systems. It requires intensive support from the public health
services, particularly from the peripheral health facilities. The most important
components are the Community Owned Resource Persons , be they community
volunteers, shop keepers or mother co‐ordinators who frequently function on a
voluntary basis. Governments need to consider how these persons can be
remunerated to prevent the currently high attrition of trained personnel within
these programmes.

In many Asian countries village level workers, such asmidwives and public
health inspectors (in Sri Lanka) and multi‐purpose community health workers (in
India) are on a government payroll. In Africa, community health nurses in
Ghana show the importance of government investment in the community level of
health care. In Uganda, the government is promoting community drug
distributors to ensure access to pre‐packed antimalarial drugs (chloroquine plus
S/P) within the communities. A similar programme is under way in Madagascar.
Delivering antimalarials through the private sector
In endemic countries where malaria is a major health problem today, the private
sector plays a significant role in delivering antimalarial treatment, and in some
affected communities it may be the sole provider of life‐saving medicines. When
governments have been slow to review national treatment policy and replace
failing drugs with effective ones, populations have turned to this poorly
regulated private sector market in order to buy newer drugs that are perceived to
be effective. While their motive is profit, they may offer the best option for
accessing treatment to those communities who would otherwise have to travel
long distances to reach health facilities only to find them functioning poorly,
often being out‐of‐stock of antimalarial drugs and offering no more than a
clinical diagnosis before referring them back to the drug sellers for purchasing
treatment.

However, the informal private sector is also a source of major challenges in
malaria treatment delivery. This sector ir represented inmany countries by a
network of small‐scale traders, unregulated and unregistered peddlers or drug
sellers that sells a variety of goods from food to household items and drugs with
questionable quality, including counterfeits. More importantly, regulation of
drug quality and price is difficult to impose leaving a chaotic antimalarial drug
market.

It is imperative to engage and train local drug vendors in the basics of disease
recognition as well as proper prescription and referral practices, which form an
integral component of home management of malaria in Africa today.
Experiences in Kenya, Nigeria and Uganda have shown that training of
shopkeepers and chemical sellers may lead to significant improvement in
treatment practives with antimalarial drugs. Investment in their training would
83

need to be continued as new traders continuously enter the market. The public
sector’s stewardship role is critically important to ensure the quality of drugs
sold and proper patient counselling delivered in the informal private sector.
Delivering antimalarial through partnership with NGOs
In many malaria endemic countries, non‐governmental organizations (NGOs) are
governments’ most reliable partners in the delivery of health care in hard to
reach populations. National and district level health administrations working
with these organisations should actively be encouraged by principal financing
sources such as bilateral agencies and the Global Fund to Fight AIDS,
Tuberculosis and Malaria (GFATM). NGOs are usually at the grass root and
committed workforce that is able to function efficiently without the constraints of
bureaucratic organizations

Given the findings presented above, it can be concluded that:

• The majority of “malaria” cases is being treated at home, with home remedies
or drugs bought directly from the informal private sector. Distance to,
frequent stock‐outs, and poor services are the main reasons for non‐use of
public health facilities for malaria treatment;
• In many countries there is a common practice to consider and treat all cases
of fever as being ʺmalariaʺ;
• Malaria treatment practices are frequently inappropriate, especially in the
private sector, and this may contribute significantly to the problems of drug
resistance;
• There are serious quality problems with antimalarial products circulating in
countries;
• Costs of malaria treatment for households are considerable, and may be a
major contributor to poverty in some countries. Cost of malaria drugs affect
disproportionately poor households. Costs of new ACTs may significantly
add to this.
• Poor practices with malaria treatment may be continued with the use of new
FDC ACT preparations, especially if prices to the consumers of these drugs
will be high. New and effective approaches will be necessary to promote the
appropriate deployment of ACTs.
84
Process leading to the development of guidelines on the use of
artemisinin‐based combination therapies (ACTs)
Consultations
In 2000, WHO convened an Informal Consultation on the Use of Antimalarial
Drugs (13‐17 November 2000)i to review and update recommendations on the
use of antimalarial drugs for malaria prevention and treatment of uncomplicated
malaria and to assess the implications of the latest drug developments for
national treatment policies.

A total of 41 participants, reflecting a broad range of expertise in the
development and use of antimalarial drugs, and in the implementation of
antimalarial treatment policies, made specific recommendations to national
malaria control programs after reviewing and discussing working paper
prepared by specific experts in the respective technical areas. Among the main
recommendations, the meeting highlighted the value of combination therapy as a
strategic and viable option:

“The potential value of drug combinations, notably those containing an
artemisinin derivatives, to improve efficacy, delay development and selection of
drug‐resistance parasites and thus prolog the therapeutic life of existing
antimalarial drugs is widely accepted. Combinations that do not contain an
artemisinin derivative could be a preferred option for reasons of cost and
accessibility in some countries.”

The meeting provided specific definition of antimalarial combination therapy, i.e.
simultaneous use of two or more blood schizontocidal drugs with independent
mode of action and different biochemical targets in the parasite, and listed
examples of specific multiple‐drug therapies or synergistic fixed‐dose
combinations which are not considered to be combination therapy. Examples of
fixed‐dose combinations, that strictly speaking fit the criteria of synergistic fixed‐
dose combinations, but are operationally considered as single products, include,
in addition to S/P, chlorproguanil/dapsone and atovaquone/ proguanil (for these
drugs neither of the individual components can be given alone for antimalarial
therapy).

In April 2001, WHO convened a Technical Consultation on Antimalarial
Combination Therapy (4‐5 April 2001) to undertake a systematic review of
existing data on combination therapy for malaria and to identify appropriate
combinations for use, particularly in African countries. The technical
consultation took the form of presentations based on working papers and
plenary discussions, on the basis of which specific conclusions and

i WHO (2000) The Use of Antimalarial Drugs Report of a WHO Informal Consultation. WHO
unpublished report WHO/CDS/RBM/2001.33.
85

recommendations were agreed. The proceedings of the meeting and working
papers formed the basis of a WHO report. i

The conclusions of Technical Consultation was based on the following:

• in‐depth reviews of existing non‐artemisinin FDCs [chloroquine plus
sulfadoxine/pyrimethamine (SP), amodiaquine plus SP, mefloquine‐SP and
quinine plus tetracycline or doxycycline];
• an independent review of artemether/lumefantrine (Coartem®), the only
existing fixed‐dose artemisinin‐based combination therapy, i.e.;
• the results of individual patient data meta‐analysis of clinical efficacy and
safety of artemisinin combinations coordinated by the International
Artemisinin Group (ACTs available as multiple drug therapies: chloroquine
plus artesunate; SP plus artesunate; amodiaquine plus artesunate and
mefloquine plus artesunate);
• Expert reviews of artemisinin‐based combination therapies FDCs under
development, i.e. piperaquine/dihydroartemisinin/trimethoprim,
pyronaridine/artesunate, chlorproguanil/dapsone/artesunate and
naphthoquine/dihydroartemisinin.

The Technical Consultation strongly endorsed the potential of combination
therapy for use in Africa. On the basis of the available safety and efficacy data, it
recommended 4 therapeutic options with potential for deployment (in prioritized
order) if costs were not an issue:

1. artemether/lumenfantrine (Coartem®);
2. artesunate (3 days) plus amodiaquine as FDC;
3. artesunate (3 days) plus SP as FDC, in areas where SP efficacy is high;
4. amodiaquine plus SP as FDC, in areas where efficacy of both drugs
remains high.

The consultation recognized that increased funding would be required to
facilitate the appropriate exploration of use and purchase of optimal antimalarial
drugs. Failure to assure funding for antimalarial drugs will provide a major
obstacle for many countries in Africa in moving to combination therapy.

i WHO (2001) Antimalarial Drug Combination Therapy Report of a WHO Technical
Consultation, WHO unpublished report, WHO/CDS/RBM/2001.35.
86
Support to countries in the implementation of ACTs
Prequalification of artemisinin based products and suppliers
WHO and other partners have started a prequalification project for artemisinin‐
based antimalarial productsi. Dossiers submitted for review by manufacturers
who have expressed interest to participate in this process are evaluated for
compliance with WHO recommendations and guidelines regarding the
assessment of Multi‐source products (WHO 1998). Manufacturing sites are
inspected to assess compliance with Good Manufacturing Practices (GMP).

Products and manufacturing sites that meet the standards are included in a list of
suppliers whose products are considered to be acceptable in principle for
procurement by UN Agencies. The list will be reviewed and updated at regular
intervals. Currently, only one ACT, artemether + lumefantrine (Coartem®) is
pre‐qualified. A number of products and manufacturers are awaiting
clarification(s) onproof of efficacy, and compliance to good manufacturing
practices (GMP). A major challenge facing the pre‐qualification exercise is the
difficulty of establishing the comparator ʺreferenceʺ products for purposes of
determining bio‐equivalence. Although many of the recommended ACTs have
been in use on a programmatic level, especially in South East Asia for several
years , they remain largely ʺnovelʺ products as much of their safety and efficacy
data are not in the public domain. Secondly, very few of regulatory authorities
have experience in the review of the applications for the registration of these
products.
Negotiated prices and centralised procurement through WHO
Given the potential of artemether/lumefantrine (Coartem®) as a fixed‐dose

combination therapy, WHO has established an agreement with Novartis to
supply this drug at cost for use in the public sector of disease endemic
developing countries. The cost varies from US $2.40 for an adult dose to US $
0.90 for the youngest age dose. The price of the same brand in different
packaging for the private sector varies between US $12.00 and US $7.00 in the
endemic countries, and is around US $40.00 in non‐endemic countries. The low
prices are available to buyers who procure the product through WHO ensuring a
broad and equitable access to the product. This arrangement also offers the
advantages of the company not negotiating with independent buyers, and relies
on WHO to forecast the expected demand to adapt its manaproduction capacity
and supply chain management accordingly. Course‐of‐therapy packs have been
developed to improve adherence to treatment with the 6‐dose regimen, as well as
educational support material for patients and health workers. A study in Uganda
has showed 90% adherence to treatment with the improved packaging and
support material.

i http://www.who.int/medicines/organization/qsm/activities/pilotproc/malaria/procmal.shtml
87

While the prequalification and sourcing project for artemisinin‐based

antimalarials is ongoing, it has been necessary for WHO and other RBM partners
to support countries who are in immediate need to procure artesunate and
amodiaquine to be used as a co‐packaged product or to be co‐administered.
Currently, there are no fixed‐dose combination products of these two drugs.
WHO and UNICEF have issued joint tenders for the procurement of artesunate
and amodiaquine as separate blister packs. This tender process is supported by a
technical review team and assessment of GMP compliance by the participating
manufacturers.
WHO technical support for pharmacovigilance
Currenlty, there are limited data on: Phase IV studies on ACTs, deployment and
use of ACTs, efficacy and safety data on vulnerable groups (young infants and
pregnant women); information on the efficacy and safety in patients with
malnutrition or HIV/AIDS; information on the interaction of ACTs with other
drugs. WHO is supporting the implementation of pharmacovigilance of ACTs in
six Afican countries. Guidelines are also being developed to guide
pharmacovigilance of ACTs in resource‐limited settings.
Challenges/way forward
1. RBM partners plan to create a forum for dialogue with the manufacturers of
ACTs. Such a forum is key in facilitating the sharing of information on needs
and capacities as well as bottlenecks in ensuring access to these vital
products.
2. WHO should coordinate the forecasting of needs for ACTs, due to the
implications for manufacturers in sourcing APIs and requirements for raw
materials to be extracted from natural sources, linked with agricultural
production plans.
3. Manufacturers of ACTs should be encouraged to extend their stability testing
protocols to include evaluation of products under tropical conditions
(Climatic Zone IV ‐ as described under WHO guidelines for GMP).
4. The pre‐qualification of antimalarials should be extended to include the
sources of active pharmaceutical ingredients (API) for artemisinin derivatives
and their recommended partner drugs.
5. Safety and efficacy data on the WHO recommended ACTs should be collated
and disseminated to national regulatory authorities to facilitate the review
and registration of these products.
6. Comparator products for bio‐equivalence studies with the ACTs should be
established. A process for this activity is established in WHO/EDM and
funding now needs to be identified.
88
Recommendations for further research
1. Mechanisms for enhancing ACT product stability in the distribution
channels need to be identified. Currently available formulations are
generally stable for limited periods of up to 2 years.
2. Approaches of optimising the use of non‐public sector distribution
channels for antimalarials need to developed. This is crucial as the
majority of malaria cases are treated outside the public sector facilities.
Conclusion
Roll Back Malaria is committed to promoting FDC antimalarial products
particularly ACTs in areas where resistance is a significant problem. RBM
recognises the complex problems that are faced by manufacturers in producing
such products, national malaria control programmes in making a change to the
new FDC products, and for regulators in ensuring the quality of these products.
RBM partnership is committed to working to resolve these problems.
89

References

1 World Health Organization Drug resitance in malaria Geneva, World Health
Organization, 2001 (WHO/CDS/CSR/DRS/2001.4).
2 World Health Organization Assessment and monitoring of antimalarial drug
efficacy for the treatment of uncomplicated malaria Geneva, World Health
Organization, 2003. (WHO/HTM/RBM/2003.50).
3 Brinkmann U., Brinkmann A. Malaria and health in Africa: the present situation and
epidemiological trends Tropical Medicine and Parasitology, 1991, 42(3):204‐213.
4 Deming MS., Gayibor A., Murphy K., Jones TS., Karsa T. Bulleting of the World
Health Organization, 1989, 67(6):695‐700.
5 Ruebush TK. et al. Self‐treatment of malaria in a rural area of Western Kenya Bulleting
of the World Health Organization, 73(2):229‐236.
6 Ndyomugyenyi R., Neema S., Magnussen P. The use of formal and informal services
for antenetal care and malaria treatment in rual Uganda Health Policy and Planning,
1998, 1:94‐102.
7 Ejezie GC., Ezedinachi EN., Usanga EA., Gemede EL., Ikpatt NW., Alaribe AA.
Malaria and its treatment in rural villages of Aboh Mbaise, Imo State, Nigeria Acta
Tropica, 1990, 48(1):17‐24.
8 Makubalo EL. Malaria and chloroquine use in Northen Zambia, PhD thesis, 1991,
London School of Hygiene and Tropical Medicine, University of London.
9 Kirigia JM., Snow RW., Fox‐Rushby J., Mills A. The cost of treating paediatric
malaria admissions and the potential impact of insecticide treated mosquito nets on
hospital expenditure Tropical Medicine and International Health, 1998, 3:145‐150.
10 World Health Organization The quality of antimalarials: A study in selected African
countries Geneva, World Health Organization, 2003. (WHO/EDM/PAR/2003.4).
90
Developing combinations of drugs for malaria
examination of critical issues and lessons learnt
Developing combinations of drugs for

malaria examination of critical issues
and lessons learnt
P.L. Olliaro, W.R.J. Taylor,
WHO/TDR/PRD
Background
The malaria burden
Malaria is one of the major infectious diseases facing modern man. Estimates of
the global burden vary but a figure of 400 to 600 million cases per year seems
reasonable.1 2 The vast majority of cases are in African children under five.
Despite the focus and burden of malaria in Africa, malaria is still an important
public health problem in other tropical areas e.g. Indonesia, India, Papua New
Guinea, and the Amazon area of Latin America. Whilst there are four species of
human malaria, Plasmodium falciparum is the form that causes substantial
morbidity and almost all of the mortality.
Points of intervention in the malaria cycle for control
Malaria control aims to reduce the burden of disease. Current strategies include
integrated vector control, the use of impregnated bed nets, reducing parasitaemia
and anaemia in pregnant women through intermittent presumptive treatment,
and rapid access to reliable diagnosis and effective treatment. Chemotherapy is,
therefore, a major element of malaria control.
The strategy – rapid access to effective antimalarial drug treatment
This has now been adopted by WHO as a key element for controlling malaria
and is seen as a sustainable and realistic approach. The aim is to reduce the
malaria mortality in African children by half by the year 2010. 3 This is an
ambitious target that could be achieved provided certain criteria are met. These
include:

• evidence of drug efficacy and safety
• availability of sufficient quantities of drugs to meet the need
• affordability
• political commitment on the part of Governments to change drug policy
• a well thought out strategy to make the change in drug policy.
91

Parasite resistance to antimalarial drugs: a major impediment to effective
control
The longevity of antimalarial drugs – the role of resistance
Drug resistance erodes drug efficacy. Resistance by P. falciparum to several
classes of drugs is widespread and well established.4 Chloroquine resistant P.
vivax has emerged to become a significant problem in focal areas, and, more
recently, chloroquine resistant P. malariae has been described in Indonesia.5 6 The
stark reality is that drug resistance is now causing increased morbidity and
mortality. This is well documented in Africa but doubtless occurs in many other
areas.7 The prime mechanism of resistance is the naturally occurring genetic
mutations in the malaria parasite that confer a survival advantage. These
mutations result in a decline in drug sensitivity that depends on the class of
antimalarial drug.8 Inadequate treatment (e.g. sub therapeutic dose, sub optimal
drug) of a high biomass infection will not kill mutant parasites and is the main
selective pressure for resistance. Resistant parasites are then transmitted to other
individuals by mosquitoes. In addition, drugs with long half‐lives are more
likely to select for resistance because low drug concentrations linger and are only
able to kill sensitive parasites.9
Strategies to overcome resistance
The theory of combination therapy
Experience from other infections and cancer chemotherapy have shown that cure
rates can be sustained by using combinations of drugs and that this strategy
protects drugs in a mutual fashion. The use of single drugs that are easily prone
to resistance limits therapeutic choice and can have serious deleterious effects on
disease management. This is particularly so for infectious diseases like malaria,
leprosy, TB, and HIV/AIDS for which a limited number of drugs are available.
Contrast this with the abundant choice of drugs for resistant hypertension.

For malaria treatment, the number of drugs is limited mainly to chloroquine,
amodiaquine sulphadoxine/pyrimethamine (SP), mefloquine, artesunate,
dihydroartemisinin, the recently registered chlorproguanuil/dapsone (LapDap),
atovaquone/proguanil, dihydroartemisinin‐piperaquin and artemether/
lumefantrine. Appreciable resistance exists against chloroquine, amodiaquine,
and SP. Well documented studies from Thailand have shown graphically the
rapid demise of SP and mefloquine within some five years of use.10

The idea that drug combinations could be used to delay antimalarial drug
resistance came from Peters.11 An early attempt failed when a combination of
mefloquine and SP were used in Thailand at a time when there was already
widespread resistance to SP. The next attempt also came from Thailand when
mefloquine, which was originally highly efficacious at the dose of 15mg/kg
against drug resistant falciparum malaria, began to fail. An increment in the
mefloquine dose (25mg/kg) lead to a transient and modest increase in efficacy.
92
Then artesunate for three days was added which resulted in a high cure rates
(– 95%).12 Longitudinal data from western Thailand have shown remarkably
that these high cure rates have been sustained, transmission has been reduced,
and the in vitro sensitivity of malaria parasites to mefloquine has increased. 13

The underlying science behind the therapeutic effect is that the artesunate kills
rapidly and substantially most of the parasites; those that remain are then killed
by high concentration of the companion drug.14 The efficacy and short half life
(≤1 hour) of the artemisinins offer protection against resistance.15 The long half
life companion drug is needed to act for long enough in order to kill the residual
parasites. In this way, the probability that mutant parasites survive and emerge
from these two drugs is low. The question of matching pharmacokinetic profiles
is still being debated. Some contend that a long tail of lingering drug levels of
unprotected drug (as is the case in all artemisinin‐containing regimens) will
continue to provide selective pressure which will encourage resistance.

It is believed that the key to success is to use combination drugs to which
parasites are still sensitive. In vivo resistance to the artemisinins has not been
described but it can be induced in the laboratory.16 There is ample evidence as to
the comparative ease at which resistance develops to standard antimalarial drugs
when used alone.17
Evidence – the key to sensible recommendations
In these days of evidence based medicine, both international and national public
health bodies cannot make recommendations and expect them to be widely
endorsed and taken up without data.
Organising international clinical trials – management, choosing the drugs, data
analysis
In 1998, it was agreed by WHO/TDR, with USAID funding, and the Wellcome
Trust, to commence a series of clinical trials to assess the efficacy and tolerability
of artesunate combined with three standard antimalarial drugs (chloroquine,
amodiaquine or SP) in Africa (11 trials in 8 countries) and Latin America. 18
WHO/TDR was to be the co‐ordinating body. The aim was to use these drugs in
countries where their efficacy was deemed to be no less than 75%. Chloroquine
was used only in West Africa; the other two drugs were used across Africa. In
Latin America, amodiaquine was used in Colombia (trial on going) and SP in
Peru. The sites were also selected in order to have a blend of established and
emerging centres, where relevant clinical trial capacities were to be built.

These were randomised, double blind, placebo controlled trials that were
conducted under Good Clinical Practices (GCP). Common clinical protocols and
one analytical plan were used. The latter was designed so that an individual
patient data (IPD) meta‐analysis could be done. Such an analysis is considered
the optimal way to present evidence of an intervention. The protocol and the
analytical plan were prepared via an iterative process that involved WHO/TDR,
93

experts and investigators. Collectively, these trials represent the largest series of
antimalarial drug trials ever conducted in Africa. The primary efficacy end
points were parasitological cure at Days 14 and 28. Secondary efficacy
parameters were parasite and fever clearance, and gametocyte carriage rates.
Studies included molecular genotyping to distinguish between recrudescent
infections and re‐infections, and PCR for mutations conferring drug resistance,
and population pharmacokinetic assessments. Artesunate‐placebo was provided
by Sanofi/Guilin, amodiaquine by Warner‐Lambert/Parke‐Davis (now Pfizer),
and SP by IDA.

All the SP studies had three arms: SP alone, and two dosing regimens of
artesunate which was administered once daily for one or three days at
4mg/kg/day. The chloroquine and amodiaquine studies used three days of
artesunate. Several studies have been published, others are in press, as is the IPD
meta‐analysis. 19 20 The meta‐analysis includes also eligible artesunate +
mefloquine studies conducted in Thailand by the Wellcome Trust and Mahidol
University.21

This was a labour intensive undertaking with many challenges. The key factors
that led to its successful execution included:

• pressing on despite the opposition (see below)
• efficient management of operations, co‐ordination of several centers, despite
sub‐optimal funding and limited human resources
• a well informed and supportive Task Force consisting of committed experts
• a centrally written common protocol and analytical plan
• good logistics e.g. drug supply through good interaction with manufacturers
• selecting drugs on the basis of resistance patterns
• communicating results regularly to policy makers and publishing within a
reasonable time frame.
Translating research into action
The clinical trials that were conducted under the auspices of TDR had the force of
numbers behind them. The results were clear: adding artesunate (an artemisinin
derivative) had a profound positive effect when added to a standard antimalarial
drug without adding to toxicity. This proved a key principle. Two steps were
taken from this juncture. Further studies were organised to deploy artemisinin‐
based combination treatments (ACTs) in several African countries with the aim
of collecting more data (efficacy, safety, transmission, and economic benefits) on
greater numbers. In parallel, RBM organised a meeting in April 2001 that
endorsed fully the use of artemisinin based combinations for treating falciparum
malaria.22
Another form of resistance: wrestling with resistance to change
It would be an understatement to say there was opposition to the concept of
using artemisinin‐based combinations. At some point a divide was apparent
between scientists23 and control people. Happily, with the emergence of more
data some critics were silenced, others were convinced, and but a vocal minority
still believe in monotherapy even in the face of resistance. More work needs to
94
be done. It is hoped that now data are generated and collated during the
deployment and implementation phases, including data on pharmacovigilance
and effectiveness under field conditions.
Further work on the artemisinins
We need to broaden the basis and increase access to ACTs. This will require
working at various levels.
Increased access to ACTs
We need to increase our knowledge of ACTs and convince resource poor nations
and funding agencies that investing in the artemisinin based combinations is
worthwhile. Such work includes:

• determine how to efficiently deploy artemisinin combinations on a large scale
and project/measure the consequences for health and antimalarial drug
resistance
• examine the feasibility and sustainability of implementation of ACTs
• identify the elements of success and challenges
• study optimal drug presentation e.g. blister packs, fixed‐dose co‐formulations
• key factors of the drug chain from production to patient consumption
• the economic costs and benefits
• the safety of ACTs, including accidental exposure during pregnancy.
Better products
Today, there is only one fixed‐dose ACT, artemether‐lumefantrine (Coartem®)
registered internationally. The artemisinin‐components of non‐fixed formulations
have not yet received international accreditation. In general, non‐fixed
formulations may be a short‐term solution but are unlikely to be the definitive
answer to the problem, because of anticipated sub‐optimal adherence. Therefore,
fixed‐dose combinations should be developed.

This represents additional challenges. For well established drug combinations,
there is no need to perform extensive studies. A proper pharmaceutical
development and proof of bio‐equivalence should suffice to register these fixed‐
dose combinations, as is the case for other diseases.

Regarding artesunate combinations with either amodiaquine or mefloquine, the
situation was, unfortunately, different. We have been obliged to perform the
whole set of pre‐clinical and clinical studies. The reasons were:

• For artesunate‐mefloquine ample data exist on the current standard
treatment (artesunate 4mg/kg on days 1‐3, mefloquine 15mg/kg on day 2 and
10mg/kg on day 3). However, this schedule cannot be used in a fixed‐dose
combination. A new regimen was proposed, keeping the current dose of
artesunate but using 8 mg/kg /day of mefloquine. While preliminary data
95

exist on its efficacy and safety (using loose tablets), the new fixed‐dose
regimen must be tried properly in phase III trials .
• The artesunate‐amodiaquine combination has been studied in relatively small
numbers of patients and additional data are needed with the fixed‐dose
combination.
• For both the pharmaceutical development work is being conducted with the
aim of producing a cheap, stable formulation to withstand tropical climates
(current artesunate products have relatively short shelf‐lives because of their
sensitivity to heat and humidity).
• For both there were no pre‐clinical data on drug‐drug interaction and
potential toxicities.
Recommendations & outstanding challenges
RBM is now fully behind the use of ACTs to treat drug resistant falciparum
malaria. Evidence was needed before this could be done. It was a challenging
task. By contrast, combination chemotherapy for HIV/AIDS has been established
for several years and appears to have had a less painful birth. The common
challenges for malarial and HIV/AIDS are many and include:

• choosing the optimal combination for a given clinical indication
• having a suitable alternative when the first line choice is ineffective or causes
unacceptable toxicity
• on going research on efficacy and safety
• ensuring drugs are affordable
• ensuring drugs get to the people who need them in the public sector
• continuing the development of new drugs and those with new modes of
action
• assessing the economic benefits of using these combinations
• continuing of surveillance of drug resistance
• continual advocacy at international level.

There is considerable overlap in the geographical distribution of malaria,
HIV/AIDS and TB. The strategy for controlling these three diseases is converging
and lessons can be learnt from each other. Closer co‐operation between the
relevant departments within WHO and between WHO and other like‐minded
agencies is needed.
96
References

1 World Health Organisation. World malaria situation in 1994. Weekly
Epidemiology Record 1997;72: 269‐276.
2 Snow RN, Craig M, Deichmann U, Marsh K. Estimating mortality, morbidity and
disability due to malaria among Africaʹs non‐pregnant population. Bull World
Health Organization 1999;77: 624‐640.
3 Remme JH, Binka F, Nabarro D. Toward a framework and indicators for
monitoring Roll Back Malaria. Am J Trop Med Hyg 2001;64(1‐2 Suppl): 76‐84.
4 Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of
drug‐resistant malaria. Lancet Infect Dis 2002;2: 209‐18.
5 Taylor WR, Widjaja H, Richie TL, Basri H, Ohrt C, Tjitra, Taufik E, Jones TR, Kain
KC, Hoffman SL. Chloroquine/doxycycline combination versus chloroquine alone,
and doxycycline alone for the treatment of Plasmodium falciparum and
Plasmodium vivax malaria in northeastern Irian Jaya, Indonesia. Am J Trop Med
Hyg 2001;64: 223‐8.
6 Maguire JD, Sumawinata IW, Masbar S, Laksana B, Prodjodipuro P, Susanti I,
Sismadi P, Mahmud N, Bangs MJ, Baird JK. Chloroquine‐resistant Plasmodium
malariae in south Sumatra, Indonesia. Lancet 2002;360: 58‐60.
7 Trape JF, Pison G, Preziosi MP, Enel C, Desgrées du Lou A, Dlaunay V, Samb B,
Lagarde E, Molez JF, Simondon F. Impact of chloroquine resistance on malaria
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98
Safety and long‐term effectiveness of generic fixed‐dose formulations of nevirapine‐based
HAART amongst antiretroviral‐naïve HIV‐infected patients in India
Safety and long-term effectiveness of

generic fixed-dose formulations of
nevirapine-based HAART amongst
antiretroviral-naïve HIV-infected
patients in India
Pujari S1, Patel A2, Patel K2, Dravid A1,
Patel J2, Mane A1and Bhagat S1

1. Department of HIV Medicine, Ruby Hall
Clinic, Pune India
2. Infectious diseases Unit, Sterling Hospital,
Ahmedabad

Abstract
Efforts should be directed at developing fixed‐dose combinations (FDCs) of
antiretroviral drugs for treatment of HIV infection. FDCs improve adherence to
therapy because of their convenience. Generic companies in the developing
world have developed certain FDC formulations for drugs used as highly active
antiretroviral therapy (HAART), some of which are not available through
international companies. Bioequivalence studies have shown equivalence
between some of these formulations and the patented products. It is essential to
document the long‐term effectiveness of these generic formulations in clinical
settings.

We report here the safety and long‐term clinical and immunological effectiveness
of generic FDC formulations (AZT/3TC/NVP and d4T/3TC/NVP) amongst
antiretroviral naïve HIV‐1 infected patients in India. Carried out at two private
tertiary referral centres, this observational study recruited 1253 patients with
minimum three months of follow up, thus making it the largest study from India.
Safety was assessed clinically and by laboratory markers and immunologic
effectiveness was assessed by serial CD4 counts. Clinical events were
documented during follow up.

There was a significant improvement in the mean CD4 counts over time. Most
improvement occurred within 3‐6 months of initiation of HAART and was
sustained for up to 2 years. Rash and hepatitis were documented in 6.9% (95% CI
5.5‐8.3) and 3.2% (CI 2.3‐4.8) respectively of patients initiating therapy. Only
female gender was associated with higher risk of development of any adverse
event. All adverse events occurred within 1‐12 weeks of initiating therapy.
99


The incidence of mortality and morbidity on HAART was 5.2 and 28.1 per 100
person years of follow up respectively. Tuberculosis was the commonest cause
of death and overall clinical events in the cohort. Only baseline CD4 counts were
significantly associated with increased risk of development of clinical events.

Thus HAART delivered as FDCs has shown potent and durable effect amongst
HIV‐infected patients in this clinical study. Programmes intending to scale up
antiretroviral therapy in the developing world should consider FDCs containing
nevirapine‐based HAART as a first line regimen.
Introduction
Highly active antiretroviral therapy (HAART) has changed dramatically the

morbidity and mortality profile of the HIV epidemic in the developed world [1].
Over the last few years, prolonged survival of HIV‐infected individuals has been
attributed to the widespread use of HAART, and has been reported even in a
developing country situation [2].

HAART normally consists of a combination of three or more antiretroviral (ARV)
drugs taken together. The goal of therapy is to maximize viral suppression, thus
limiting and reversing immune damage, leading to decline in opportunistic
infections. The durability of response depends on viral‐, drug‐ and patient‐
related factors. Viral factors include the genetic barrier to resistance
development, the capacity to remain latent in reservoirs, and on‐going
replication in sanctuary sites like the nervous system, genital tissue and kidneys.
Drug‐related factors include the potency, tolerability and convenience of a
regimen and pharmacologic barriers to resistance as a function of trough
concentrations achieved by these drugs. The most important patient‐related
factor is adherence, but toxicities, quality of life, and psychosocial issues also
need to be addressed to ensure success of therapy.

Several studies have documented the efficacy and safety of nevirapine (NVP)‐
based HAART in ARV‐naïve HIV‐infected patients [3,4,5]. NVP‐based HAART
has been found to be superior to a combination of two nucleosides alone and also
had similar efficacy to a protease‐inhibitor or efavirenz‐based regimen. In a
randomized controlled trial of NVP versus efavirenz with a backbone of
stavudine(d4T)/lamivudine(3TC), NVP was found to have similar efficacy, but
was associated with more hepatitis and rash [6]. Hence in terms of potency, NVP‐
based HAART is as effective as a protease‐inhibitor or efavirenz‐based HAART.
100
Adherence
Adherence is critical for success of HAART. Numerous studies have documented
that a high level of adherence is needed to ensure maximal and durable
suppression of the virus [7]. Various factors influence adherence: Drug
combinations, which are difficult to take because of pill burden or due to food
restrictions [8]; treatment costs, in situations where patients have to pay for their
own treatment; and difficulties in accessing care, and unavailability of drugs in
remote places, may all contribute.

Since eradication of HIV is unlikely with currently‐available HAART and since
the evidence for structured treatment interruption seems disappointing [9], HIV
therapy needs to be life‐long. Coupled with high levels of adherence needed to
ensure response, this is a demanding task for HIV‐infected patients. Studies have
shown that adherence to prescribed drugs over long treatment periods is
generally poor [8]. Non‐adherence to HAART can lead to rebound in viral
replication and, in presence of sub‐optimal drug concentrations, rapid
development of drug resistance. The development of drug resistance can be
disastrous because of the complexity and cost associated with second‐line
regimens and the potential for transmission of drug‐resistant virus in the
community.
Fixed‐dose combinations (FDCs)
The cost of antiretroviral drugs has been reduced dramatically because of generic
manufacturing in some countries across the world. This has contributed
significantly to improving access to ARV drugs. Apart from lowering drug costs,
generic manufacturing has also led to development of FDCs and once daily
combo‐packs of ARVs. FDCs have been available for treatment of other diseases
and have long been regarded as a standardized, simpler and potentially more
reliable way of treating tuberculosis (TB). Guidelines from WHO and many
other international bodies recommend the use of FDC formulations as a step to
facilitate the optimal treatment of TB [10]. However, unlike TB treatment, HIV
therapy, being life‐long, is more demanding. Hence, the use of FDCs to treat HIV
infection for long periods of time is crucial.
Development of FDCs
Development of FDCs has not been possible in countries where the component
drugs are under patent because different companies manufacture the drugs used
in these formulations. The only patented FDC formulation available is trizivir, a
single pill combining zidovudine (ZDV)/3TC/abacavir (ABC). Generic
companies have been successful in developing two three‐drug FDC formulations
for use in HIV infection: ZDV/3TC/NVP and d4T/3TC/NVP (Table 1).
101

Formulation of FDCs
Developments of FDC formulations essentially concentrate on ensuring the
physico‐chemical compatibility of drugs in combination. Furthermore, the in‐
vitro dissolution profile of individual drugs and the formulation should be
similar to the patented products. Drug compatibility studies [pers comm] have
shown physical incompatibility for 3TC with d4T, and NVP with d4T. However,
3TC and NVP were compatible. Hence the formulation of d4T/3TC/NVP is a bi‐
layered tablet, where d4T is one layer and 3TC and NVP another layer and thus
the physical incompatibility has been minimized. Excipient compatibility
studies, carried out with the chosen excipients from the individual formulated
drugs, did not reveal any interactions with any of the excipients, indicating
compatibility with the drug combination
A similar approach has been used for manufacturing a FDC of AZT/3TC/NVP.
However, in this case no incompatibility was observed between any of the
individual drugs. Therefore all drugs can be combined into a single pill.

Table 1: Anti‐HIV FDC formulations available in India

Formulation Form and Manufacturers Dose
strength (mg)
zidovudine/lamivudine/nevirapine tablet Cipla 1 tab orally
300/150/200 Genix (Hetero) twice daily
Immunus–
Aurbindo

stavudine/lamivudine/nevirapine (30) tablet Cipla 1 tab orally
30/150/200 Immunus– twice daily
stavudine/lamivudine/nevirapine (40) Aurbindo (wt< 60 kg)
tablet Ranbaxy 1 tab orally
40/150/200 twice daily
(wt>60 kg)
zidovudine/lamivudine tablet Cipla 1 tab orally
300/150 Genix (Hetero) twice daily
Immunus–
Aurbindo
Ranbaxy
stavudine/lamivudine (30) tablet Cipla 1 tab orally
30/150 Genix (Hetero) twice daily
Immunus– (wt<60 kg)
stavudine/lamivudine (40) tablet Aurbindo 1 tab orally
40/150 Ranbaxy twice daily
(wt>60 kg)

102
Safety, efficacy and quality of FDCs
There are limited data on the safety and efficacy of FDC formulations in
treatment of HIV disease. Although there have been anecdotal reports of lack of
active ingredients in some generic antimicrobials [11], in one study of NVP in
generic formulations, drug content in both individual tablets and in
combinations was found to be satisfactory [12]. In a clinico‐pharmacological
study from India [Gogaty et al. unpublished], FDC formulations were found to be
bioequivalent to the reference loose drugs given in similar doses. Many of the
generic drugs are listed in WHO’s supplier’s and formulary list.

The quality of FDC formulations available in India has also been evaluated in
pharmacokinetic studies. In a randomized, two‐treatment, two‐period, two‐
sequence, single dose, crossover bioavailability study in healthy volunteers, the
FDC formulation was compared with the individual reference drugs. The FDC
formulation met all the requisite criteria for proving bioequivalence with regards
to rate and extent of absorption. The ratios of AUC 0‐t and AUC 0‐x for the three
drugs ranged from 96.6% to 104.8% [Gogaty; unpublished].
Advantages and disadvantages of FDCs
There are distinct advantages and some disadvantages associated with the use of
FDC formulations for treatment of HIV infection. An obvious advantage is the
convenience associated with taking these formulations, as patients prefer taking
one pill twice a day as compared to three pills twice a day. Convenience
increases adherence, which will lead to durable response to therapy.

Another advantage is easier delivery of treatment with FDCs. Using FDCs
simplifies the physician’s job, leading to reduction in prescription errors.

FDCs also reduce the risk of giving the wrong dose (high or low) of individual
drugs. While high doses can lead to development of serious adverse events, low
doses can lead to sub‐optimal drug concentrations and development of drug
resistance. Ingestion of proper dosages through FDC formulation can help
prevent development of drug resistance; missing a dose of a FDC tablet maybe
more “forgiving” than erratic missing of doses of the individual drugs when
taken separately. However, sufficiently irregular intake of FDCs can also lead to
drug resistance; in an NVP‐based regime, drug resistance may easily develop
because of NVP’s long half life. Any missing dose in this context can lead to
persistence of NVP in the plasma beyond that of the backbone nucleosides,
rendering it as monotherapy.

There are also some disadvantages associated with the use of FDCs, particularly
for NVP‐based HAART. Many physicians may initiate these regimes without the
lead‐in dose, thus increasing the risk of development of adverse events like rash
and hepatitis.
103

This study
The efficacy of FDCs can be assessed by determining virological, immunological
and clinical responses amongst HIV‐infected patients. A randomized controlled
trial comparing FDCs with treatment regimens based on loose drugs has not
been carried out and may not be required if bioequivalence studies show
comparable plasma concentrations. Here, we report the results of the largest
study carried out to date to assess the clinical and immunological effectiveness
and the safety of NVP‐based FDCs in ARV‐naïve HIV‐1‐infected patients in
India.
Methods
Setting
This was an observational study carried out at two private tertiary level HIV
clinics in Pune and Ahmedabad, both in Western India. Patients paid for their
own treatment and laboratory investigations.
Patients
From April 2000, patients starting ARV therapy were recruited consecutively.
Patients were offered therapy only after careful screening and intense
counselling.
Drugs
Patients were initiated on NVP‐based HAART with one of two backbone
nucleoside combinations, either d4T/3TC or AZT/3TC. Since AZT/3TC was
expensive, a larger number of patients preferred to take d4T/3TC. If adverse
events occurred, patients were switched from the AZT combination to the d4T
one, or vice versa. NVP was given in a lead‐in dose of 200 mg orally once a day
followed by 200 mg twice a day, as part of the FDC; d4T was dosed according to
body weight of the patient. During the lead‐in dose phase of NVP, AZT/3TC and
d4T/3TC were given as two‐drug FDCs and then shifted over in the continuation
phase to the standard three‐drug FDC formulation.

Adherence to treatment was assessed at each follow‐up visit by self‐report. To
promote adherence patients were counselled intensively by treating physicians.
Patients were considered to be lost to follow‐up if they failed to visit the clinic for
more than a year. Tracing of patients lost to follow up was not undertaken.
104
Monitoring
Patients were followed up monthly. CD4 counts were recommended to be done
every three months although, on account of the cost, patients did miss these tests
and they were performed only once a year in some patients. CD4 counts were
estimated by FACSCount. Viral loads were done only in those patients who
could afford the test and since their numbers were very small, these results have
not been included as an outcome in the analysis.

Diagnosis of various infections and malignancies during follow‐up was
performed using standard clinical and laboratory methods. An immune
reconstitution disorder (IRD) was defined as a clinical event, usually infection,
occurring within 2‐12 weeks of initiation of ARV therapy, and which was
associated with improvement in the CD4 count.

Toxicity of NVP was assessed by clinical examination for rash and liver function
tests for hepatitis. Liver function tests were only done when patients complained
of nausea or vomiting, with or without yellowish discoloration of urine/sclera.
Grading of adverse events for rash and hepatitis was done according to the
National Cancer Institute grading system and was judged to be definitely,
probably or possibly related to NVP by the investigators. Adverse events were
managed according to standard protocols. Drugs were discontinued in case of
development of Grade 3 or 4 events. We have not reported the prevalence of
adverse events associated with the backbone nucleosides in this study.
Statistical analysis
All results reported here are from an on‐treatment analysis. Prevalence of
adverse events was summarized. Logistic regression analysis was used to assess
the risk of development of adverse events (rash and hepatitis) with age, gender,
and baseline CD4 counts and concomitant co‐trimoxazole (TMP‐SMX) or
antituberculous therapy (ATT) as independent variables. Mean and median CD4
counts were determined at each follow‐up visit and confidence intervals
calculated. The difference in mean CD4 counts at 12 and 24 months was assessed
by the Mann‐Whitney test.

We calculated the incidence of occurrence of clinical events as person‐years of
follow up and frequencies were determined. Logistic regression analysis was
used to determine the risk of death or development of clinical events with age,
gender and baseline CD4 counts as independent variables. Analyses were done
using SPSS sigmastat 3.0.
105

Results
Patients and follow up
A total of 1253 patients with the minimum of three months of follow up were
included in the final analysis. Median duration of follow up was 18 months. The
mean age of the patients at baseline was 36.3 years (median 34.5; range 18‐70).
Other characteristics of the patients at baseline are summarized in Table 2. The
smaller number of women taking ARV therapy is a reflection of gender
discrimination prevalent in the society. About 80% of patients decided to take
d4T/3TC as their backbone nucleoside because it was much cheaper than the
AZT/3TC‐based regimen.

Table 2. Characteristics of patients at baseline

Characteristic No. (%) of patients
Gender:
Male 975 (77.8)
Female 278 (22.3)
Backbone nucleosides:
d4T/3TC 995 (79.4)
AZT/3TC 258 (20.6)
Clinical stage at baseline
CDC stage C 858 (68.4)
Baseline CD4 count (mm ) in range:
3
<50 279 (22.2)
51‐200 718 (57.3)
201‐350 194 (15.5)
>350 62 (4.9)

Almost 78% patients initiated therapy when their CD4 dropped to less than
200/mm3, an indication of patients presenting late to our clinics. Additionally, we
routinely use a CD4 count of less than 200/mm3 as an indication to offer ARV
therapy.
Adverse events
Most of the adverse events occurred within 1‐8 weeks of initiation of therapy.
Rash was documented in 6.9% (n=86, 95% CI 5.5‐8.3), clinical hepatitis in 3.2%
(n=41, CI 2.3‐4.8) and gastrointestinal disturbances such as nausea, vomiting and
diarrhoea in 15.5% (n=237, CI 13.1‐16.9) of patients. Eight patients developed
Grade 4 rash and 2 died due to the same. Most of the rashes occurred when the
patient switched from the lead‐in to full dose of NVP, while Grade 4 rashes
occurred within 2‐3 days of initiation of NVP. None of the patients had fulminant
hepatitis.

106
Female gender was associated with significantly higher risk of development of
any adverse event (see Table 3). Hepatitis virus status was not assessed for all
patients; hence the contribution of these viruses to development of hepatotoxicity
could not be evaluated.

Table 3. Risk factors for development of adverse events

Variable Odds Ratio (95% CI) P value
Age 0.99 (0.97‐1.00) 0.64
Gender 0.52 (0.3‐0.8) 0.02
CD4 count at baseline 1.00 (0.99‐1.00) 0.31
Concomitant 0.87 (0.43‐1.75) 0.70
co‐trimoxazole therapy
Concomitant 0.82 (0.35‐1.92) 0.65
antituberculous therapy
Immunological improvement
The mean CD4 count at baseline was 130.5/mm3 (SD 97.8; median 115; range 2‐
814). Twelve percent patients were lost to follow up. Patients who showed an
improvement in CD4 counts reported more than 95% adherence to their regimen.
Ninety‐three patients had a significant decline in their CD4 counts warranting
change in the treatment regimen; only seven of these reported more than 95%
adherence to their initial regimen.

Mean increases in CD4 counts during 24 months of follow up are shown in Table
4. There was a rapid improvement in the mean CD4 count in the first 3‐6 months,
which later reached a plateau (Figure 1). The difference in the mean CD4 counts
at baseline and at 12 and 24 months was significant (p<0.001).

Table 4. Improvement in CD4 counts during 24 months of treatment

Time from starting No. patients Mean increase in CD4 count
treatment (months) evaluated per mm3 (95% CI) above
baseline
3 1253 150.2 (143.4‐157)
6 835 179.4 (170.8‐188)
9 372 204.3 (189.2‐219.4)
12 499 245.7 (230.6‐260.8)
15 174 255.3 (231.2‐279.4)
18 256 280.0 (255.5‐304.5)
21 74 283.1 (237.4‐328.8)
24 113 317.3 (277.6‐357.0)

107

Figure 1: Box plot of CD4 response over time
2000
1500
1000
500
CD4-0 CD4-3 CD4-6 CD4-9 CD4-12 CD4-15 CD4-18 CD4-21 CD4-24
duration
Clinical outcomes
The incidence of deaths amongst patients was 5.2 per 100 person years of follow
up. The causes of HIV‐attributable death were disseminated TB including
tuberculous meningitis (21), cryptococcal meningitis (4), severe bacterial
pneumonia with sepsis (3), progressive multifocal leukoencephalopathy (3),
lymphoma (2), toxoplasmosis (1), Pneumocystis carinii pneumonia (1),
cryptosporidial diarrhoea with renal failure (1), cytomegalovirus pneumonia (1),
herpes simplex encephalitis (1) and not determined (2). Eight deaths were
attributed to drug toxicity. The causes of death included lactic acidosis (4), severe
skin rash (2) and pancreatitis (2). The median baseline CD4 count of patients
who died was 93/mm3.

The incidence of development of clinical events was 28.1 per 100 person years of
follow up. The frequency of occurrence of various clinical events is shown in
Table 5. Sixty‐seven percent occurred within 2‐12 weeks of initiation of therapy
and were defined as IRDs. Only baseline CD4 counts were associated with
increased risk of development of clinical events or death (OR 0.994, CI 0.990‐
0.997, p<0.001).

108
Table 5. Type and frequency of occurrence of clinical events in patients
receiving HAART

Type of clinical event Frequency (%)
Tuberculosis 77 (41.3)
Herpes zoster 25 (13.4)
Bacterial pneumonia 16 (8.6)
Cryptococcal meningitis 13 (7)
Candidiasis 24 (12.9)
Pneumocystis carinii pneumonia 10 (5.3)
Protozoal diarrhoea 7 (3.7)
Non‐Hodgkins lymphoma 8 (4.3)
Others 6 (3.2)
Total 186
Discussion
In this large study in India, NVP‐based HAART, given as a FDC formulation,
was shown to be safe, tolerable and effective amongst HIV‐1 infected patients.
Generic FDC formulations were used in all the patients in the study.
Adherence
Adherence in patients showing improvement was excellent. One of the reasons
may have been the use of FDC formulations, which are convenient to take. Many
of the FDC formulations are available as monthly packs, which ensure supplies
for patients staying away from tertiary centres and with limited access to
medications. Additionally, patients paid for their own medications. Patients were
screened carefully for their ability to pay before they were offered HAART. To
ensure they understood, we demonstrated how to take the pills especially during
the lead‐in phase. Finally, we reinforced the importance of adherence at each
follow‐up visit.
Adverse events
The frequency of acute adverse events attributable to NVP was lower than in
other reported studies [13]. The frequency of rash may have been lower because
of the high proportion of patients adhering to the lead‐in dose of NVP while
initiating therapy. Only female gender was significantly associated with higher
risk of development of adverse events, while concomitant TMP‐SMX and
baseline CD4 counts were not.

The low frequency of hepatitis reported in our study may be attributed to the fact
that screening was done only when the patients had clinical symptoms of
hepatitis. Asymptomatic elevation of liver enzymes would have been missed.
However, in spite of selective screening, we did not see any mortality due to
hepatitis in our cohort. Hence in resource‐limited settings, screening for hepatitis
109

may be done only when clinically indicated rather than as a routine. In spite of
concomitant use of ATT in some patients the incidence of hepatitis was low. This
may be due to absence of rifampicin from the ATT regimen because of its
potential drug interaction with NVP. We did not assess background prevalence
of hepatitis viruses amongst these patients and hence we could not assess their
effect on the incidence of development of hepatitis.

We have not reported the type and frequency of adverse events attributable to
backbone nucleosides in our study. We will report elsewhere the prevalence of
morphologic and metabolic abnormalities associated with long‐term use of these
regimens in our cohort.
Immunological improvement
The magnitude of the improvement of the mean CD4 cell count seen in this study
is one of the largest reported for this regimen in literature [14]. One of the reasons
may be that patients initiated HAART at lower CD4 counts than in most other
studies. There was a substantial improvement in the CD4 counts initially (after 3‐
6 months) which was subsequently sustained. The initial improvement is
postulated to be due to redistribution of memory CD4 cells from the lymph
nodes into the blood and later improvement because of the production of naïve
CD4 cells. Although a significant proportion of patients started therapy at
advanced stages of HIV infection there was still a remarkable improvement in
CD4 counts indicating the potency of this regimen and these formulations.
Viral load
Routine viral load tests to assess suppression of HIV by these regimens were not
performed. Studies have documented durable suppression of the virus to
undetectable levels (<50 copies/ml) in more than 50% of ARV‐naïve patients
initiating NVP‐based HAART. The improvement seen in CD4 counts is an
indication that the virus had been suppressed in the majority of patients in our
study.
Clinical findings
Although this was a non‐comparative study, mortality amongst patients taking

NVP‐based HAART was found to be lower than in similar stage patients in
natural history studies from India [15]. The majority of the clinical events on
HAART were defined as IRDs and occurred within 2‐12 weeks of initiation of
therapy. It is however difficult to separate IRDs from actual occurrence of
opportunistic infections since CD4 counts are still low up to 12 weeks after
initiation of HAART. In a large, international randomized study with clinical
outcomes as primary endpoints, the AZT/3TC/NVP arm was found to have fewer
110
deaths and fewer patients with progression to AIDS compared to the
AZT/3TC/placebo [16].

TB was the most common of the clinical events occurring on HAART in this
cohort. This is not surprising as TB is the commonest opportunistic infection
amongst HIV‐infected patients in India. Most TB is either new occurrence or
paradoxical worsening of existing infection. It commonly presents at an extra‐
pulmonary site with lymphadenopathy (external and internal) and tuberculous
meningitis. Other common events included herpes zoster, cryptococcal
meningitis, Pneumocystis carinii and bacterial pneumonias. However, overall it
was found that NVP‐based HAART significantly improved clinical outcomes in
patients.
Conclusions
Our study was purely observational with recruitment only of those patients who
initiated HAART. These patients can afford therapy and tend to be of middle to
higher socioeconomic status and also more literate. However, more than half of
these patients also came from rural areas indicating that such patients are capable
of adhering optimally to the regimens using FDCs.

Thus we conclude that NVP‐based HAART, delivered as FDC formulations, is
safe and showed durable clinical and immunologic benefit amongst ARV‐naïve
HIV‐infected patients in this study in India. The regimens were convenient to
take and thus easy to adhere to, potent, well‐tolerated and also reserved future
treatment options in case of drug failure. Hence NVP‐based HAART can be
positioned as a good first‐line regimen in programmes intended to deliver ARV
therapy in resource‐limited settings.
111

References
1. Kholoud P. and CASCADE collaboration Survival after introduction of HAART in
people with known duration of HIV‐1 infection Lancet, 2000; 355:1158‐1159.
2. Marins Ricardo J. et al. Dramatic improvement in survival amongst adult Brazilian
AIDS patients AIDS, 2003; 17:1675‐1682.
3. Montaner JS. et al. A randomized, double blind trial comparing combinations of
nevirapine, didanosine, and zidovudine for HIV infected patients: The INCAS trial. Italy,
Netherlands, Canada and Australia study JAMA, 1998; 279:930‐937.
4. Podzamczer D. et al. A randomized clinical trial comparing nelfinavir or nevirapine
associated to zidovudine/lamivudine in HIV infected naive subjects (the Combine study)
Antiviral Therapy, 2002; 7:81‐90.
5. Raffi F. et al. The VIRGO study: nevirapine, didanosine and stavudine combination
therapy in antiretroviral naive HIV‐1 infected adults Antiviral Therapy, 2000; 5:267‐272.
6. Leth Van F. et al. for the 2 NN study group,. Results of 2NN study, A randomized
comparative trial of first line antiretroviral therapy with regimens containing either
nevirapine alone, efavirenz alone or both drugs combined together with stavudine and
lamivudine Presented at the Xth Conference on Retroviruses and Opportunistic
Infections, Boston, USA. 2003; abstract no. 176.
7. Paterson DL. et al. Adherence to protease inhibitor therapy and outcomes in patients with
HIV infection Annals of Internal Medicine, 2000; 133:21‐30.
8. Escobar I. et al. Factors affecting patient adherence to highly active antiretroviral therapy
Annals of Pharmacotherapy, 2003;37:775‐781.
9. Jintanat A. et al. Swiss HIV Cohort Study. Failures of 1 week on, 1 week off antiretroviral
therapies in a randomized trial AIDS, 2003 ;17:F33‐F37.
10. Blomberg B., Fourie B. Fixed‐dose combinations for tuberculosis: application in
standardized treatment regimes Drugs, 2003; 63:535‐553.
11. Newton PN. et al. Murder by fake drugs BMJ, 2002; 324:800‐801.
12. Penzak S. et al. Analysis of generic nevirapine products in developing countries JAMA,
2003; 289:2648‐2649.
13. Pollard RB., Robinson P., Dransfield K. Safety profile of nevirapine, a non‐nucleoside
reverse transcriptase inhibitor for the treatment of human immunodeficiency virus
infection Clinical Therapeutics, 1998; 20:1071‐92.
14. Lange J. Efficacy and durability of nevirapine in antiretroviral drug naive patients
Journal of AIDS, 2003;34:S40‐S52.
15. Kumarasamy N. et al. Natural history of human immunodeficiency virus disease in
southern India. Clin Infect Dis, 2003;36:79‐85.
16. Pollard R. Factors predictive of durable HIV suppression in randomized double blind trial
with nevirapine, zidovudine, and lamivudine in treatment naive patients with advanced
AIDS. Presented at 7th Conference on Retroviruses and Opportunistic Infections,
San Francisco, USA. 2000; abstract no. 517.

112
experiences from the field
Effect of introduction of fixed-dose

combinations on the drug supply
chain:
Jane Masiga
Mission for Essential Drugs &
Supplies
(MEDS)
Kenya

Abstract
Management of a process in which a drug passes through from the manufacturer
or supplier to the patient, the Drug Supply Chain is important and complex.
However, this becomes even more challenging in developing countries,
especially when most drugs are imported, as the chains are characterised by
several levels of bureaucratic processes that make the delivery of drugs to
patients, slow, labour intensive and expensive. In many instances, drug
registration in the country, that may take several months to complete, is a
requirement before importation is permitted. Further, import declaration fees
may have to be paid for each product and, inspection done at the port of exit
from the country of origin or entry into the user country. Reducing the number
of products handled, which is achieved by introduction of Fixed‐dose
Combinations results in a more efficient system and reduces costs.
Intoduction
In the development of formularies, it is recommended that Fixed‐dose
Combinations (FDCs) should be avoided unless the dosage of each ingredient
meets the requirements of a defined population group. The combination should
also have a proven advantage over single compounds administrated separately
in therapeutic efficacy, safety or compliance1.

In recent times, FDCs have been strongly recommended in the management of
tuberculosis, and are now gradually gaining entry in the management of malaria
and of HIV/AIDS. In addition to the well‐accepted advantage of patient
compliance, FDCs also have a considerable effect on a drug supply chain2 3.

113

The supply chain begins when the manufacturer or supplier dispatches drugs. It
ends when drug consumption information is reported back to the procurement
unit4. The major activities of the cycle which are affected by the introduction of
FDCs are discussed below:
Procurement
The decisions made and actions taken during procurement determine the
quantities of specific drug quantities obtained, the prices paid, and the quality of
drugs received. This document focuses on those activities which are most
affected by the introduction of FDCs.
Selection of drugs
Some countries have adopted the Essential Drugs concept in which they select a
limited number of drugs considered to be essential, in order to achieve better
supply, more rational use, and lower costs5. However, in many of these countries
the Essential Drugs list is not updated regularly leaving the health worker with
no easy reference. Thus, when confronted with emerging problems such as the
development of resistance to commonly used drugs, as in case of malaria, or the
new trends in the management of HIV/AIDS, clinicians choose a variety of
combinations. This leaves the supply chain struggling to meet the varying needs
for the individual drugs.

The introduction of FDCs makes drug selection easier and thus the necessary
products can be made available in sufficient quantities in the supply chain at all
times.
Selection of suppliers
While it is essential that all suppliers are pre‐ or post‐qualified through a process
that considers product quality, service reliability and delivery time, this can take
a long time, involving inspections, reference checks with past clients and
informal information gathering. The process becomes more complex and
expensive, and many circumstances impossible, especially for country/local NGO
supply chains, when the supplier is in another country.

The introduction of FDCs should reduce the work in this area, since use of FDCs
reduces the number of products and suppliers and thus results in less work for
the supply chain.
Drug registration
In many countries, drug registration is often a major element of national drug
law. This is to ensure that the drugs used in the country are from reputable
manufacturers. The dossier submitted to Registration Authority would include
for example, the product name, name of the manufacturer, non‐proprietary
names for active substances, inactive ingredients, pharmacological action, and
114
claims made in the package insert. The cost of registration varies in different
countries; in Kenya, for example, it is US$ 1000 per formulation.

For a FCD of three drugs, instead of registering the three separate drugs, only
one registration will be required and hence only one registration fee will be paid.
Thus the introduction of FCDs should reduce drug registration costs.
Import declaration
In countries where declaration of imports is required, the supply chain manager
has to submit to the Ministry of Health for approval a separate import
declaration form for each supplier. Each declaration must be accompanied by an
import declaration fee payable to the Ministry of Finance (e.g. in Kenya this
amounts to 2.75% of total value of consignment).

The introduction of FDCs will reduce the number of suppliers, resulting in fewer
of declaration forms and less fees to pay.
Drug inspection
Inspection of the consigned drugs by authorised agents may be required either at
the point of exit or point of entry in the country. Individual items require
separate inspections, which becomes cumbersome particularly when they are
from different suppliers or different origins.

By reducing the number of different consigned drugs, introduction of FDCs will
reduce the delays associated with drug inspections.
Other aspects
Due to the reduction in number of suppliers as a result of introducing FDCs, less
time will be spent by the supply chain in drawing up contracts, monitoring the
status of orders, preparing payments to different suppliers, and receiving and
checking of orders. There will also be a reduction in costs associated with freight,
insurance and customs clearance.

Thus, overall, the introduction of FDCs can be expected to reduce time and
money spent in procurement.
Distribution
An effective drug supply chain should maintain a constant supply of drugs, keep
drugs in good condition and minimise drug losses (due to spoilage, expiry, theft,
and fraud). The maintenance of effective inventory records (computerised or
manual) for each product is essential. Physical stock counts should be carried out
for re‐ordering purposes and for determining the inventory value. This can be
done either by cyclic counting (continuous counting) or by annual stock count.4

115

FDCs will reduce the number of products stocked, making stock counts less
complex and less time‐consuming. In consequence, disruptions of the supply
system are minimised and inventory management is simplified.
Storage
Products in a supply chain should be stored so that they are easily accessible and
protected against damage. The storage facilities should provide for both bulk
storage and picking locations and may include cupboards, shelves, flour pallets
or pallet racks. FDCs will require less storage space.

The introduction of FDCs will also reduce time and distribution costs because:
• Fewer products stocked
• Less time spent in packing of orders, recording packing details (batch,
expiry date and quantity)
• Fewer personnel as the number of products is less
• Less packaging materials required
• Reduced transportation costs due to reduced volume.
Prescribing
Some countries have published guidelines for the use of antiretroviral (ARV)
therapy. In countries where this is not done, clinicians have problems in
determining appropriate combinations for the drugs used. They rely on
information provided by medical representatives or from out‐dated publications.
The use of FDCs makes prescribing decisions easier for clinicians and eliminates
the use of the wrong combinations or of inappropriate doses.
Dispensing to patients
Dispensers usually do not spend sufficient time in giving information to patients
about their drugs and how to take them. They may not even label the drugs
properly, that is indicating name of drugs, quantity, instructions on use, etc. If
the number of products to be dispensed is reduced, then the chances of giving
better patient information are increased.
Cost to patient
The cost of the drug will determine whether the patient takes that drug especially
in situations where the patient pays the whole, or part of, the cost. The
introduction of FDCs should mean reduced drug cost to the patient due to
reduced cost of production, registration, importation and customs cost, inventory
management and distribution. This reduction can be expected to lead to an
uptake in patients receiving ARV treatment as has occurred in Kenya with the
reduction in prices that has occurred for other reasons.
116

Figure 1
Patient use
FDCs will lead to simplified treatment regimens. A patient will be able to get one
product instead of three or more different products. The number of tablets to be
taken will be reduced (e.g. to as few as two tablets in a day for ARVs). Reducing
pill burden has been shown to enhance adherence to treatment6.

FDCs will also reduce the chances of patients under‐dosing because they cannot
afford all the individual drugs at the same time or because one of the drugs from
the combination is unavailable. This is usually a major problem when the
patients have to pay for their drugs.
Consumption data
Health facilities are required to send information on drug consumption to the
supply unit for use in quantifying drug needs. In case of ARVs this may also
include patient code, drug combinations and quantities dispensed to each
patient. If adequate inventory and requisition records are kept, or where the
facilities and patients are few, it is easy to analyse the data and establish useful
trends in the use of the drugs. However, when the numbers increase
substantially, extracting individual drugs from the return forms becomes a
challenge, especially since the individual drugs are distributed separately.

In some situations, data overload may lead to analyses being abandoned,
especially in the absence of appropriate computer packages and trained
personnel. The introduction of FDCs will make the gathering and analysis of
consumption data easier.
117

Conclusion
Introduction of FCDs results in fewer numbers of products being handled, thus
reducing the complexities in the Drug Supply Chain. This increases the chances
of getting the right drug, in right quantities, of recognised standards of quality
reaching the patient at the right time and at reasonable price.
References

1 WHO. The use of essential drugs: report of a WHO expert committee Tech Rep Ser
WHO no 914. Geneva World Health Organization, 2002
2 Blomberg B, Spinaci S, Fourie B, Laing R. The rationale for recommending fixed‐
dose combination tablets for treatment of tuberculosis. Bull WHO 2001; 79: 61‐79
3 Laing R, McGoldrick KM. Tuberculosis drug issues: prices, fixed‐dose combination
products and second‐line drugs. Int J Tuberc Lung Dis 2000; 4: S194‐S207
4 Quick J. et al (Eds.), Managing Drug Supply Management Sciences for Health in
collaboration with the World Health Organization. Kumarian Press, West Hartford,
USA 1997
5 Laing R. Waning B. Gray A. Ford N. ʹt Hoen E. 25 years of the WHO essential
medicines lists: progress and challenges. Lancet. 361(9370):1723‐9, 2003 May 17
6 WHO. Adherence to Long‐term Therapies Evidence for action Geneva World
Health Organization 2003

118
Effect of fixed‐dose combination (FDC) medications
on adherence and treatment outcomes
Effect of fixed-dose combination (FDC)

medications on adherence and
treatment outcomes
Dr Jennie Connor
Senior Lecturer Epidemiology, Clinical
Trials Research Unit, School of
Population Health,
University of Auckland, New Zealand
Tel: +64 (9) 373‐7999
Fax: +64 (9) 373‐7624

[email protected]

Introduction
Adherence to medication
Low adherence to prescribed self‐administered medication is well documented

and particularly problematic in the treatment of chronic or asymptomatic
conditions1 2. Even in affluent countries with well developed health care
infrastructure adherence to long‐term therapy is estimated to average only 50%3.

The implications of poor adherence are substantial at both the individual and
population level. Treatment benefits for patients are reduced, leading to both
under‐treatment of their condition and difficulties for the prescriber in assessing
efficacy and appropriate dosage. Higher doses to improve treatment response
can result in toxicity at times when adherence is high. At the population level,
non‐adherence results in increases in morbidity, mortality and secondary health
care costs, as well as medication wastage. Incompletely treated infectious
conditions can result in on‐going transmission and accelerated development of
antimicrobial resistance.

The causes of poor adherence, and therefore the potential solutions, are complex.
A framework for understanding the interacting dimensions of adherence has
been elaborated in a recent WHO report on adherence to long‐term therapies3.
An extensive review of the literature on factors contributing to level of adherence
with therapy identified the broad determinants as: the specific condition being
treated, the health care system and team delivering the intervention, the social
and economic conditions of the patient and setting, characteristics of the therapy
itself, and the contribution of the individual patient. This framework is outlined
in Table 1. While acknowledging the importance of interactions between these
dimensions, the report’s emphasis on systematic rather than individual
determinants of adherence to therapy has outlined a range of opportunities for
improving adherence.
119

The report indicated that the simplicity of the dosage regimen and side effects of
the drugs were the therapy‐related factors that most influenced adherence. The
complexity of self‐administration increases rapidly with the use of multiple
therapies for the same condition or for several conditions in the same patient,
with a resultant reduction in adherence3‐7
Potential for FDCs to improve adherence and outcomes in TB,
malaria and HIV/AIDS
Fixed‐dose combination medications therefore have the potential to address one
of the main therapy‐related factor affecting adherence to medication, the
complexity of the dosing regimen. FDCs are being designed to reduce both the
pill burden and the dosing frequency. In certain conditions, e.g. cardiovascular
disease, the synergistic effects of the medications combined in the FDC allows the
reduction in dose of individual components reducing the likelihood of side
effects. Development of FDC regimens that do not require timing of doses in
relation to food is also likely to bring adherence benefits8 9. Inadvertent
medication errors will be reduced and monotherapy due to short supply of single
components would be eliminated.

The beneficial effect of co‐blistering of medications is likely to be the same or less
than use of FDCs. This intermediate step provides a similar reduction in regimen
complexity compared with separate dispensing, but the pill burden is not
reduced. Co‐blistering provides an opportunity to gain some of the benefit of
FDCs in situations where physical combination of all the essential components is
not possible. It seems likely that although development costs would be less, the
ongoing supply of blister‐packed drugs would be substantially more expensive
than supplying FDCs. Co‐blistering may be a worthwhile adjunct to FDC use in
some groups of patients, for example in HIV/AIDS patients with TB co‐infection.

Although FDCs only address one dimension of the complex problem of
adherence, they have a special role as a relatively cheap passive intervention that
can be used in resource‐limited settings where individually tailored adherence
support is not going to be feasible or affordable. The effectiveness of more
complex behavioural interventions to improve adherence is unclear4.

Potential disadvantages of large‐scale FDC use for adherence and treatment
outcomes include the reduced ability to tailor medication to individual needs. In
particular, where lead‐in dosing is necessary starter packs will be required, and
adverse effects of a single component may lead to discontinuation of all
treatment. Also, the lack of inexpensive paediatric equivalents encourages the
splitting of adult tablets and possible under/overdosing or disproportionate
amounts of component medications being given. The impact of these
disadvantages will need to be clarified, and to be balanced against the benefits of
FDC use facilitating access to medication for so many more people than would
otherwise be possible.
120
What this paper covers
This paper reviews the available evidence about the effect of FDC medications or
unit‐of‐use packaging on adherence to medication and treatment outcomes, both
generically and in the context of TB, malaria and HIV/AIDS treatment. Future
research needs and opportunities are briefly discussed.
Evidence of effect of FDCs or unit‐of‐use packaging on adherence and
treatment outcomes
Systematic review
In response to increasing advocacy for the use of FDCs in the control of both
communicable and non‐communicable disease, we recently conducted a
systematic review of the research literature to attempt to quantify any adherence
or treatment benefit of FDCs. This review is reported in detail separately10.

The review was limited to randomised (or quasi‐randomised) controlled trials
that compared medications combined in a single pill, or medications combined
within unit‐of‐use packaging, with the same medications in their usual
presentation. “Unit‐of‐use packaging” included blister packaging of several
medications in fixed combination to be taken together (with or without calendar
labelling) and the use of devices into which customised combinations of
medications are loaded at regular intervals, to be self‐administered according to
calendar labelling. Studies of adult patients taking more than one oral self‐
administered medication, and including at least one outcome measure relating to
adherence, the pharmacological goal of medication (e.g. blood pressure control)
or cost of therapy were included.

Fourteen trials were identified which met the review criteria, but a FDC was only
used in three. Most of the remaining studies used blister packaging or medication
boxes to improve the adherence to individualised medication regimens,
particularly in the elderly or for the reduction of blood pressure.

Five of the 14 studies involved treatments for the control of communicable
diseases (tuberculosis11 12, HIV13, leprosy14, malaria15) and are described below,
including the three FDC trials.

Two trials compared FDCs of anti‐tuberculosis drugs with the same drugs given
separately over a 6‐month course. A US study conducted in 1984‐612 with 701
subjects found a significant difference in the proportion of patients with sputum
conversion at 8 weeks in favour of the FDC group, but no difference in
“compliance” with medication at 8 weeks or at 6 months (see Table 2).
Compliance in this study was assessed using a combination of self‐report, pill
counting and urine testing. The other tuberculosis trial was conducted in Taiwan
in 1997‐811 and was much smaller, with only 57 and 48 patients in the
intervention and control groups respectively. Differences in sputum conversion
121

at 8 weeks, in compliance, and in radiological improvement at 2 years all
favoured the FDC group, but none reached statistical significance. Loss to follow‐
up was so high in this trial (50%) that slight improvements in adherence amongst
those remaining were not considered clinically important.

The third FDC trial was in HIV patients in the US13, randomising 223 subjects to
having two of their three medications combined in a single tablet. Self‐reported
adherence and questionnaire scores reflecting adherence behaviours were
significantly improved in the intervention group, while clinical outcomes showed
a non‐significant trend towards improvement. Unfortunately this trial was
powered only to show non‐inferiority of the combined pill, which it did, but was
too short to adequately assess relevant clinical outcomes.

The other two communicable disease trials were conducted in developing
countries using cluster randomisation of health centres to investigate the effect of
pre‐packaging medications14 15. Clinical outcome data were not collected in either
of these studies and the clusters were not accounted for in the analyses. The
Indian trial of calendar‐blister packs (CBP) containing 3 medications for leprosy14
followed subjects for 6 months and found no differences in adherence between
groups by pill counting or urine testing. They did find significant advantages in
storage, handling and preservation of medication and that CBPs were preferred
by staff and users. Pre‐packaging of three‐day courses of medication for malaria
was trialed in Ghana15 with significant improvement in adherence in the
intervention group (82% vs 60.5%), measured by self‐report and medication
checks. There was also a 50% reduction in the total cost of treatment, and a 50%
reduction in time patients spent waiting at the clinic.

The remaining 9 trials were conducted within the health‐care systems of
developed countries; 4 assessed improvements in compliance with long‐term
therapy for chronic conditions (hypertension and diabetes) and measured
clinically relevant outcomes16‐19; 5 others aimed to reduce the complexity of self‐
administered medication amongst geriatric patients on multiple medications, and
measured only adherence6 20‐23. Details are given in the accompanying paper 10.

Despite the importance of improving adherence, we found surprisingly few
large, reliable trials of the effect of combining medications on adherence with
treatment. In all but two of fourteen trials identified there were trends to
improved clinical and/or adherence outcomes. Seven of 12 studies (58%) reported
a statistically significant improvement in medication adherence, although the
outcome measures used were heterogeneous. Four of seven studies reporting
clinical outcomes found a significant improvement in a clinically relevant
endpoint; one in sputum conversion rate in tuberculosis patients, two in blood
pressure, and one study in diabetics showed a reduction in both diastolic blood
pressure and HbA1c. However interpretation of these findings is limited by the
methodological quality of the studies. Almost all the studies were too small or
had inadequate follow‐up time, and were therefore likely to miss small to
moderate‐sized effects. Also Haynes24 has suggested that for long‐term
treatments studies with initially positive findings need to continue for at least 6
122
months because of waning adherence over time. Substantial loss to follow up
was common and intention‐to‐treat analysis was only performed in two trials13 16.
These two trials, which were the most methodologically rigorous, showed
statistically significant improvements in adherence13 and in clinically relevant
endpoints16. In the other trials bias may have resulted from assessing adherence
in only those patients sufficiently compliant to remain in this study, and may
have reduced the differences between the groups. Subjects were not blind to the
interventions and assessors rarely were.

Self‐reported and pill‐counting adherence measures may have resulted in
significant misclassification. As this is usually in the direction of overestimating
adherence it may have also contributed to underestimating of the effect of
interventions24.
Other evidence in TB, malaria and HIV/AIDS
In searching the literature several studies were identified that investigated the
adherence and treatment benefits of FDCs in TB, malaria and HIV/AIDS that did
not meet the criteria of the systematic review. These are described in the
remainder of this section and are included in Table 2, which summarises the
evidence specific to these three diseases.

No trials were identified that directly compared FDC medications with co‐blister
packaging of component medications. A number of studies were identified
where the safety and efficacy of FDC medications were compared with
separately dispensed alternative drugs. These studies do not address the effect of
physically combining the same drugs in a single “unit‐of‐use” separately from
the effect of the different medication, and so have not been included in this
summary
Tuberculosis
Studies from Singapore25 26, Hong Kong27 28 and China29 have investigated the
effect of using FDCs in place of some or all of the medications used in directly
observed therapy (DOT) for tuberculosis. As medication was taken under the
supervision of health care workers there was no adherence effect with the FDC
apart from rates of attending the appointments. In all three studies attendance at
the clinic was very high for both FDC and free combination groups.

In all three studies the FDCs were at least as effective as free combinations of
drugs in terms of culture negativity rates, and had similar experience of adverse
reactions. In the Singapore study25 there was a slightly higher relapse rate in the
FDC groups at 2 years (6% vs 1% ; p=0.04) and at 5 years (7.9% vs 2.2% ; p=0.03)
but there was no difference in the other two studies. Two of the three studies28 29
reported a positive effect of FDCs on acceptability to the patient, and one on
acceptability to physicians, pharmacists and administrators. The third study
showed no difference in acceptability.
123

Malaria
A randomized study conducted in 1994 in China30 showed that the use of blister
packs for an 8‐day course of antimalarial drugs significantly increased patients
compliance (97% vs 83% and 97% vs 81% in two phases of the study; p<000.1)
compared to usual methods of dispensing. This study included written
instructions with the blister packs in addition to the oral instructions received by
both groups. Much of the non‐compliance in the control group was due to the
deterioration or loss of the tablets dispensed in a paper envelope. No difference
in efficacy was demonstrated.

A series of studies were conducted in Myanmar to compare the efficacy of
artesunate and mefloquine with artesunate alone31. The research reported an
adherence rate of >99% in both arms of their randomized study using blister
packaging and written instructions for the 5 day treatment, and the authors drew
the comparison with an adherence rate of 28% to usual treatment without
intervention in a previous patient sample. They also reported high levels of
prescribing of incorrect dosages in usual practice that was avoided with the
blister packs.
HIV/AIDS
Numerous descriptive studies have shown that a simpler dosage regimen and
lower pill burden is associated with better average compliance to HIV/AIDS
treatments, and this was demonstrated reliably in the single HIV trial described
above13. A recent retrospective study from Spain32 illustrated a benefit to
adherence associated with a change from a free combination to FDC in HIV‐
infected adult outpatients. In a group of 76 patients there was an overall
improvement in adherence from 93.7 to 96.1% (p=0.0024). In the patients who
previously had not previously achieved >95% doses, 16 of 31 patients changed
from non‐adherent to adherent with the simplification of dosage regimen.
Research needs
There is little reliable evidence about the effect of FDC medications or blister
packaging on adherence and/or treatment outcomes in TB, malaria or HIV/AIDS,
and even less originating from the poorly resourced environments of greatest
need. Extrapolating from the weak evidence of benefit from all settings and
disease conditions, it seems likely that simplifying treatment regimens and
reducing pill numbers will improve adherence to medication. However, large
simple randomised trials to compare FDC treatment with the same doses of
separately dispensed medications are required to quantify the adherence and
treatment benefits of FDCs for each disease.

124
The critical features of such trials would be that they:

• are big enough to have sufficient power to detect important differences
• are long enough to be confident that benefits are not transitory
• use robust randomisation procedures
• minimise loss to follow‐up
• include both reliable measures of adherence and appropriate outcome
measures
• use intention to treat analysis
• have no “inactive” treatment arms

Ideally such trials would be conducted in settings relevant the intended use of
the FDC medications. At present, trials are being set up to measure adherence
and treatment benefits of FDCs for cardiovascular disease (secondary prevention
and high risk primary prevention) but the conditions under which these trials
will be conducted and the different nature of the conditions being treated may
limit the relevance of these findings to treating TB, malaria and HIV/AIDS in
resource‐limited settings. At this time, there is also a need for trials to adequately
answer questions about the effect of FDCs and blister packaging on the
emergence of antimicrobial resistance.

With the recent promotion of FDCs to facilitate the rapid scaling up treatment of
TB, malaria and HIV/AIDS, there appears to an opportunity to conduct large
simple randomised trials, in appropriate settings, as the new medications are
being introduced. These trials could combine the objectives of quantifying the
effect of FDCs (or blister packaging) on adherence, health outcomes and

There are currently no direct comparisons of FDCs vs co‐blistering of the same
medications. Quantification of the relative benefits would inform the choices of
different modes of delivery in different settings and diseases, and this
comparison could be incorporated into the same trials.

Development of inexpensive paediatric formulations that maximise adherence in
the treatment of HIV is lagging behind innovations for adults. While the splitting
of adult FDCs has been discouraged, the availability and expense of other drugs
formulated for children can be prohibitive. For example, the Mildmay centre in
Kampala, which treats 60% of Ugandan children on ARVs, is using divided FDCs
for 86% of their children, for these reasons. They report that outcomes have not
been affected33, but clearly further research is required in this area. For children
whose treatment is being supervised by their families, the matching of paediatric
formulations to standard adult regimens needs to be considered8.

There is a range of evidence suggesting that education of both healthcare
workers and patients about the disease, the taking of medication and the
management of side effects improves adherence, and that the use of clear written
instructions is synergistic with the use of FDC or unit‐of‐use packaging19 31. The
simplification of treatment with FDCs increases the likelihood that patients and
125

their families will understand the instructions, but the most cost‐effective and
culturally appropriate modes of communication must be investigated.
Conclusion
Combination pills and unit‐of‐use packaging are likely to improve adherence to
medication in TB, malaria and HIV/AIDS compared with free combinations of
drugs, especially where the pill burden is high. However, direct evidence of the
size of any benefit is weak as few trials have been carried out, and most have
significant limitations. The uncertainty about these benefits, as well as
uncertainty about the effects of specific FDCs on treatment response, adverse
effects and antimicrobial resistance, can only be reliably addressed by the
conduct of well designed trials of FDCs and/or blister packed medications
compared with free combinations of the same drugs. There is an important
opportunity to carry out this research as treatment of these diseases in resource‐
limited settings is being scaled up.
126
Table 1: Dimensions of adherence
(adapted from “Adherence to long‐term therapies: evidence for action” WHO, 20033)

Five interacting dimensions affecting adherence
A. Social and economic factors • Poverty, illiteracy, lack of social support, poor
access to services, high cost of transport,
unstable living conditions, and family
dysfunction associated with poor adherence
• Cultural beliefs
• War (adverse material and psychological
effects)
• Degree of supervision of children and elderly
patients

B. Health care team/system • Quality of patient‐provider relationship
factors • Cost of treatment
• Reliability of medication distribution systems
• Level of training and workload of healthcare
providers
• Capacity for education and follow‐up of
patients
• Monitoring of performance of system
• Ability to establish community support and
self‐management capacity

C. Condition‐related factors • Severity of symptoms
• Level of disability
• Rate of progression of disease
• Availability of effective treatments

D. Therapy‐related factors • Complexity of the medical regimen (esp. dose
frequency)
• Side‐effects
• Duration of treatment
• Previous treatment failures
• Availability of medical support

E. Patient‐related factors • Knowledge and beliefs about their illness
• Risk perception
• Information and skills for self‐management
• Motivation and self‐efficacy
• Co‐morbidities (esp. depression, alcohol and
drug abuse
127


Table 2: Studies of the effect of FDCs and blister packs on adherence and
treatment outcomes in TB, Malaria and HIV/AIDS

Trial Intervention Clinical outcomes Adherence Comments
outcomes
FDC vs free combination
Tuberculosis
Su 2002, 2 months Ritafer FDC, Sputum conversion Compliance No difference
Taiwan11 with Ethambutol + At 2 months 95.0% vs (not lost to follow‐up demonstrated
4 months Rifinah FDC, 88.9% (p>0.05) or changed treatment) between the groups.
RCT with Ethambutol (n=57) at 6 months 70.2 % vs Large loss to follow
At 6 months 100% vs 66.7% (p>0.05) up (50% by 2 years)
vs free combination 100% means that
(n=48) outcomes only
Radiological improvement measured in the
At 2 years 92.3% vs selected group
84.0% (p>0.05) remaining in the
study

Geiter 1987, 2 months Rifater FDC + Sputum conversion Urine testing Early benefit in
US12 4 months Rifamate FDC At 8 weeks 86.6 vs 77.7% Pill counting sputum conversion
(n=169) Self‐report but no long‐term
RCT Absolute difference 8.9% At 8 weeks 96.5% vs difference in
vs free combination (95% CI 1.1 to 16.7) 98.1% fully compliant compliance.
(n=532) (p<0.05) (p>0.05)
At 6 months 88.5 vs
87.3 % fully compliant
(p>0.05)
Singapore Ritafer FDC ± Acceptability assessed by Directly observed No demonstrated
Tuberculosis streptomycin (one or two spontaneous complaints: therapy benefit of FDC
Service months) followed by same in both groups High attendance in all
1991,1999,25 isoniazid and rifampicin groups Slightly higher
26 for remainder of 6 Adverse effects: similar in relapse rate at 2
months (n=155) FDC and free groups years and 5 yrs in
FDC groups
RCT vs free combination of Culture negativity
same drugs (n=155) At 1 month 74 vs 72%, 76
vs 70%, 68 vs 62%
At 2 months 100 vs 96%, 93
vs 91%, 95 vs 98%

Relapse during 18 months
from end of treatment 6%
vs 1% (p=0.04)
Relapse at 5 years 7.9% vs
2.2% (p=0.03)
128
Trial Intervention Clinical outcomes Adherence Comments

outcomes
FDC vs free combination
Hong Kong 2 months Ritafer FDC + Nausea and vomiting 38 vs Directly observed Small advantage of
Chest streptomycin (n=314) 39% therapy FDC in acceptability
Service vs free combination Problems taking pills 1% High attendance in to patients
1989, 199127 (n=313) vs 5% (p<0.05) both groups
28 Regularly brought drink to No differences
FOLLOWED BY help take pills 32% vs 45% shown in culture
(p<0.01) negativity at 1or 2
ISONIAZID,
RCT months, or in
RIFAMPICIN AND
Adverse reactions: similar relapse rate
STREPTOMYCIN ± in FDC and free groups
PYRAZINAMIDE FOR 2
MONTHS, Culture negativity
and isoniazid, rifampicin At 1 month 68 vs 58%, 65
± pyrazinamide for 2 vs 60%, 73 vs 66%, 59 vs
months 53%
At 2 months 96 vs 93%, 90
vs 86%, 92 vs 93%, 89 vs
88%

from end of treatment: 5%
vs 3.5% (p>0.05)
Zhang 1996, 2 months Ritafer FDC + Strong patient preference Directly observed Equal efficacy and
China29 4 months Rifinah FDC for FDC (p<0.01) therapy tolerability of FDCs
(n=104) Strong physician High attendance in
preference for FDC both groups Advantage in
vs free combination (105) (p<0.01) acceptability by
Strong patients, physicians,
pharmacist/administrator pharmacists and
preference for FDC administrators
(p<0.01)

Adverse reactions: 12% vs
16%

Culture negativity
At 2 months 99 vs 96%
(p>0.05)
At 6 months 99 vs 98%
(p>0.05)

from end of treatment 2%
vs 2%

129


Malaria
No trials found
HIV/AIDS
Eron 2000, Combivir FDC bd with Treatment failure (viral Self‐reported missed Powered to show
US13 an FDA approved load) doses (diary cards) only non‐inferiority
protease inhibitor 3.6 vs 7.1 % :>98% compliance for of clinical outcomes
RCT (n=110) Absolute difference = 3.5% both groups. for FDC so can’t
(‐2.4% to 9.3%) demonstrate a
vs Lamivudine 150 bd, (p=0.26) Less missed doses of benefit.
Zidovudine 200 tid with L/Z at:
an FDA approved Change in CD4+ : At 8 weeks (p=0.007) Clear improvement
protease inhibitor Treatment difference = 5.9 At 16 weeks (p= 0.046) in adherence but too
(n=113) (‐15.8 to 27.6) cells/litre short in duration to
(p=0.59) Adherence show and effect on
for 16 weeks questionnaire: adherence to long‐
Better scheduling and term treatment
(Combivir= Lamivudine timing scores
150/Zidovudine 300) At 8 weeks (p= <
0.001)
At 16 weeks (p=
0.022)
Better total scores
At 8 weeks (p=
0.002)
At 16 weeks (p=
0.020)

Rozenbaum Combivir FDC bd (n= Log 10 HIV RNA (median Abstract only
1988, 35) change from baseline) available
France34 ‐1.26 vs –1.29 copies/ml
vs free combination (n= Equivalent antiviral
RCT 40) CD4 (median change form activity and same
baseline) 34 vs 38 cells/mm3 safety profile in both
for 12 weeks groups
Tolerance: 1 vs 4 pts with
adverse events

130

Unit‐of‐use packaging vs free combinations
Tuberculosis
No trials found
Malaria
Yeboah‐ Chloroquine and Compliant for 3 days: Precision of
Antwi 2001, paracetamol pre‐ Tablets 82.0% vs 60.5% estimates not
Ghana15 packaged in unit doses Abs diff = 21.5% (11.8‐ adjusted for cluster
(n=3 health centres; 314 31) (p< 0.001) design
Cluster RCT patients)
Syrup 54.7% vs 32.6% Significant
vs same drugs in usual Abs diff = 22.1% (8.3‐ improvement in
presentation (n=3 health 36) (p< 0.001) compliance
centres; 340 patients)
Total 72.1 vs 49.8% 50% reduction in
Abs diff = 22.3% (14.1‐ cost of treatment,
31) (p< 0.001) 50% reduction in
waiting time at
clinic
Qingjun Chloroquine 4 tablets on All patients smear‐negative Phase 1: Compliance Marked
1998 day 1, 3 tablets on days 2 and symptom free 97 vs 83% (p<0.01) improvement in
China30 and 3 in blister pack + following treatment compliance with
Primiquine 3 tablets on Of 27 non‐compliant in blister packaging
RCT days 1‐8 in blister pack control group, 16 had and written
Oral and written lost the medication or instructions (as well
instructions it had dissolved or as oral instructions
(Phase 1 : n= 161, Phase 2 crumbled in the paper for both groups).
: n=138) envelope Most of the
improvement in
vs free combination in Phase 2: Compliance compliance was
paper envelope, oral 97 vs 81% (p< 0.001) related to the
instructions only (Phase preservation of the
1 : n=163, Phase 2 : medication in the
n=134) blister packs.
No difference in
efficacy shown
HIV/AIDS
No trials found
FDCs vs unit‐of‐use packaging
No trials found
Acknowledgements
Thanks to Natasha Rafter, Anthony Rodgers, Rod Jackson and Patricia Priest,
School of Population Health, University of Auckland, for contributions to the
systematic review and comments on the draft of this paper.
131

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Effect of fixed‐dose combination (FDC) drugs on development
of clinical antimicrobial resistance: a review paper
Effect of fixed-dose combination (FDC)

drugs on development of clinical
antimicrobial resistance:
a review paper
Warren Kaplan, PhD., JD, MPH
Executive summary
The emergence of previously unreported infectious diseases, the re‐emergence of
infectious disease thought to have been on the way to elimination, and the rapid
evolution of infectious pathogens exhibiting antimicrobial resistance (“AMR”)
and in particular, multiple‐drug resistance (“MDR”) have created a major clinical
and public health threat of global dimensions.

The idea that AMR can be delayed or even prevented by combining drugs with
different targets as so‐called “free” combinations or “fixed‐dose” combinations
(FDCs) has been shown in animal models of malaria and circumstantially in field
trials of tuberculosis drugs but is difficult to rigorously test in the field. Micro‐
organisms have several strategies (some used simultaneously) to resist being
killed by chemotherapeutic agents. These include lack of, or a decrease in,
transport of drugs into the cell, the operation of pumps to remove the agent from
the cell, the production of drug‐inactivating enzymes, and the mutations in the
genes encoding drug targets. Microbes may be inherently resistant to an anti‐
infective agent and can acquire resistance to anti‐infective agents. Most
antimicrobials cause the selection of preexisting mutations, not the emergence of
new mutants and acquired resistance is driven by mutation and selection ‐
sometimes referred to as vertical evolution. This is particularly important for
Mycobacterium sp., protozoans (Plasmodium sp., possibly Leishmania sp.) and
viruses (HIV).

There are several ways that the different components of free or fixed‐dose
combinations produce their antimicrobial effect. The different drugs may attack
the same biochemical target by different mechanisms (e.g., cotrimoxazole).
Alternately, combination therapy may use drugs with completely different
135

modes of action (e.g., artemether‐mefloquine for malaria) and which in theory do
not share the same resistance mechanism.

FDCs may be better than free combinations in slowing or even eliminating AMR.
Multiple interruptions when using free dose combinations of pills creates the risk
of monotherapy on some drugs and not in others. This fact, coupled with the in
vivo mutation rates of the genome, rapidly leads to drug resistance to one or
more of the free combination drugs. Fixed‐dose combinations make the
possibility of monotherapy even more remote. Effectiveness of FDCs, however,
depends on detailed knowledge of the epidemiology and microbial ecology of
the particular pathogen. Since in HIV, malaria, or TB, development of AMR
commonly occurs by rapid genetic alterations, if evolution of AMR is occurring
within a host during course of therapy (which in the case of HIV or TB is quite
long), then FDCs would theoretically be effective if more than one drug is
present in therapeutic concentration at any one time. If one in 109 microbes are
resistant to drug A and one in 1013 are resistant to drug B, and the genetic
mutations that confer resistance are not linked, only 1 in 1022 will be
simultaneously resistant to both A and B. If correctly given, combination drug
treatments should in theory retard emergence of resistance compared with
sequential use of single drugs.

The literature directed to determining if FDCs or free combinations are more
effective in slowing or eliminating the development of AMR is weak. In this
regard, we summarize our conclusions below:

• Most head to head comparisons/trials of monotherapy versus fixed
combination versus free combinations are safety and efficacy studies;
• Only relatively recently has individual resistance to anti‐TB and anti‐
malarials been measured at the molecular level;
• Responses of TB, malaria and HIV pathogens to combination drugs are very
complex, particularly for malaria and HIV and the more and different
combinations that will be used, the more complex will be the interactions;
• Free combination drugs are generally more prone than FDCs to dispensing
and patient error. No studies of which we are aware have systematically
looked at the effect of blister packs compared to FDCs and/or free
combinations with regard to development of resistant pathogens. In this
regard there seem few studies on health outcomes generally;
• Some studies suggest that decreasing overall antibiotic use may reverse
bacterial resistance in human populations. One cannot assume from this that
combination therapy will have the same effect. It is thus critical to know if
using FDCs will prevent the appearance of drug resistance and/or reverse
existing rates of drug resistance at both individual and population levels.
The primary difficulty in assessing the evidence will be to actually measure
developing/ongoing antimicrobial resistance in populations in field
situations;
• Recent uses of molecular biology techniques might allow for easier tracking
of clinical resistance markers although this genotyping must be correlated in
136
the field with clinical outcomes. Larger longitudinal and community based
studies are needed;
• Head to head comparisons of blister packs compared to FDCs and/or free
combinations are needed with regard to health outcomes, including
development of AMR;
• For HIV and malaria, it is critical to increase the pace of our understanding of
genetic resistance pathways and mutations, since this understanding has not
kept up with the increasing number of therapeutic options.
Introduction
The emergence of previously unreported infectious diseases and the re‐
emergence of infectious disease thought to have been on the way to elimination
has recently occupied the energies of scientists and policymakers1. Moreover,
this increasing burden of disease must be viewed against the backdrop of the
rapid evolution of infectious pathogens exhibiting antimicrobial resistance
(“AMR”) and in particular, multiple‐drug resistance (“MDR”)2. These two issues
have created a major clinical and public health threat of global dimensions3 4 5.

The idea that AMR can be delayed or even prevented by combining drugs with
different targets as so‐called “free” combinationsi or “fixed‐dose” combinationsii
has been the subject of continuing interest (see Section 3). The underlying
pharmacological theories as to why combination therapies should delay or
prevent clinical resistance are intellectually satisfying6 but not rigorously proven
in the field. Outside of some work in tuberculosis (“TB”)7 and malaria8 9, little
attention has been given to identifying obstacles to the promotion, availability,
and rational use of FDCs in the context of AMR.

In this paper, we briefly summarize the biological basis for clinical antimicrobial
resistance in TB, malaria and HIV/AIDS (Section 2) and review the
pharmacotherapeutic reasons for using combination drugs to eliminate or slow
development of AMR (Section 3). In particular, in Section 4 we summarize the
available information regarding two hypotheses:

1) use of FDCs will ameliorate or inhibit clinical resistance to TB, HIV/AIDs
and malaria, and 2) use of separate dispensing and/or co/blistering is equally
as effective as FDCs in ameliorating or inhibiting this clinical resistance.

We then attempt to identify future research needs.

i Simultaneous dosing of more than one drug contained in several different tablets or pills.
ii Simultaneous dosing of more than one drug contained in a single formulation, in which each
drug has an independent mode of action, or the combination of which are synergistic or
additive or complementary in their effect.
137

Biological basis for drug resistance to anti‐TB, HIV/AIDS and malaria
drugs
Micro‐organisms have several strategies (some used simultaneously) to resist

being killed by chemotherapeutic agents. These include lack of, or a decrease in,
transport of drugs into the cell, the operation of pumps to remove the agent from
the cell, the production of drug‐inactivating enzymes, and the mutations in the
genes encoding drug targets.

Microbes may be inherently resistant to an anti‐infective agent e.g., by lacking a
transport system for an antibiotic). The enterococci are opportunist pathogens
and this may at least partly be due to their inherent resistance to
fluoroquinolones and cephalosporins10. Microbes can also acquire resistance to
anti‐infective agents and this type of resistance results from changes in the
microbial genome. Most antimicrobials cause the selection of preexisting
mutations, not the emergence of new mutants. This acquired resistance is driven
by mutation and selection (sometimes referred to as vertical evolution:
particularly important for Mycobacterium sp., protozoans (Plasmodium sp.,
possibly Leishmania sp.) and viruses (HIV); and exchange of genetic material
between the same, or different, microbes (sometimes called horizontal evolution),
particularly important in pneumococci, Neisseria, Shigella sp., Vibrio cholerae, and
Campylobacter sp11.

With regard to TB, HIV/AIDS and malaria, spontaneous mutations in these
respective microbial/viral/protozoan genomes impart drug resistance to a
member of the population. In the local environment of the drug, non mutants are
killed and the resistant mutant(s) grow. Thus, if non‐killing levels of anti‐
mycobaterial, anti‐retroviral and anti‐malarial drugs are present, organisms that
are resistant naturally or through mutations have a biological advantage since
they can outcompete non‐resistant forms. Resistant populations will produce
more resistant progeny, promoting spread of the resistant forms. In particular,
human immunodeficiency virus (HIV) replicates at an extremely rapid rate
throughout the course of disease, with estimates of between 1 to 10 billion copies
of HIV being produced daily12.
TB
In Mycobacterium tuberculosis complex members, single nucleic acid changes can

potentially produce antibiotic resistance. Mycobacteria are known to acquire
resistance to pyrazinamide (PZA) through mutations in the gene encoding
pyrazinamidase (PZase), an enzyme that converts PZA into pyrazinoic acid, the
presumed active form of PZA against bacteria 13 Rifampin interferes with
conversion of RNA into DNA. The molecular basis of rifampin resistance is
based on substitutional mutations of a limited number of amino acids encoded
by the rpoB gene14. Isoniazid is converted by catalase (encoded by the gene katG)
into an activated form within the bacterium so that katG gene mutations are
often responsible for INH resistance. Other mutations in different genes also
contribute to rifampin resistance. Mutations associated with streptomycin
138
resistance in tuberculosis have been identified in several genes although other
molecular mechanisms of streptomycin resistance exist15. Ethambutol has been
proposed to be an arabinose analog; the specific target is likely to be an
arabinosyl transferase, presumably a functionally important site. In one study,
nearly 70% of ethambutol resistance isolates had an amino acid substitution in
the gene encoding the transferase. For reviews, see16.
Malaria
Analysis by molecular, genetic and biochemical approaches have shown that:

a) impaired chloroquine uptake is a common characteristic of resistant
strains, and this impairment is correlated with mutations of specific
genes;
b) one to four point mutations of dihydrofolate reductase (DHFR), the
enzyme target of antifolates (pyrimethamine and proguanil) produce a
moderate to high level of resistance to these drugs17;
c) the mechanism of resistance to sulfonamides and sulfones involves
mutations of dihydropteroate synthase (DHPS), their enzyme target;
d) treatment with sulphadoxine‐pyrimethamine selects for specific DHFR
and DHPS mutations;
e) parasites that were resistant to some traditional antimalarial agents
acquire resistance to new ones at a high frequency.

The mechanisms of resistance for amino‐alcohols (quinine, mefloquine and
halofantrine) are still unclear18. Malarone® is a combination of atovaquone and
proguanil and is used for treatment and prophylaxis. Atovaquone acts by
inhibiting Plasmodium “respiration” (e.g., mitochondrial electron transport).
Mutations at specific nucleotides of the parasite cytochrome bc 1 gene are
associated with atovaquone/proguanil treatment failure in vivo19. Chloroquine
acts by accumulating in the Plasmodium food vacuole where it inhibits heme
polymerase. Resistant strains are able to actively pump out and release the drug
at least 40 times faster than sensitive strains, thereby rendering the drug
ineffective. Proguanil and pyrimethamine act by sequential inhibition of
enzymes of folate metabolism. Resistance to these two drugs has developed over
the past 30 years and is now widespread. Resistance develops very rapidly and
remains stable due to a single point mutation.
HIV/AIDS
The genetic basis of resistance to antivirals is complex but is primarily due to
mutations in the genome of RNA viruses that occur with high frequency because
RNA polymerase, unlike DNA polymerase, does not have a proof reading
mechanism to correct errors in transcription during replication. On average, the
reverse transcriptase of HIV makes 1 error per 10 000 bases copied. Thus, with 10
billion HIV‐1 virus particles produced every day and each genome containing 1
mutation, it is not difficult to imagine that genetically distinct viral variants
occurring in the same individual are generated containing every possible drug
mutation. Additional genetic variation is produced by the recombining of the
139

genomes of viruses from different quasi‐species. This may occur when 2 viruses
simultaneously infect the same cell and segments of their transcribed genes are
recombined into the progeny virusʹ genome. With some antiretroviral drugs,
high level resistance is conferred by a single mutation, for example lamivudine
and the non‐nucleoside reverse transcriptase inhibitors (NNRTI) e.g. nevirapine.
Monotherapy with these agents results in high level resistance within a month of
treatment. With other antiretrovirals, e.g. zidovudine and the protease
inhibitors, resistance is also inevitable but is more complex, requiring the
accumulation of three or more resistance mutants, and monotherapy with these
agents produces resistance after 6 or more months. In some cases, a mutant
conferring resistance to one drug may resensitize the virus to another anti‐
retroviral. For example, a mutation at one position of the reverse transcriptase
genome confers high grade resistance to lamivudine, but at the same time
resensitizes the virus to zidovudine (This is partially the basis for the efficacy of
the combination of zidovudine and lamivudine.).
Combination drugs in the context of AMR
Table 1 lists the presumed advantages and disadvantages of FDCs. Some of these
advantages and disadvantages are important in the context of AMR.
140
TABLE 1: ADVANTAGES AND DISADVANTAGES OF FIXED‐DOSE COMBINATIONS
ADVANTAGES
Simpler dosage schedule improves compliance and therefore improves treatment outcomes
Reduces inadvertent medication errors
Prevents and/or slows attainment of antimicrobial resistance by eliminating monotherapy (i.e,
one drug is never by itself in circulation)
Allows for syngergistic combinations (i.e., trimethoprim/sulfamethoxazole combination allows
each drug to selectively interfere with successive steps in bacterial folate metabolisms
Eliminates drug shortages by simplifying drug storage and handling, and thus lowers risk of
being "out of stock"
Only 1 expiry date simplifies dosing (single products may have different expiry dates)
Procurement, management and handling of drugs is simplified
Lower packing and shipping costs
Less expensive than single ingredient drugs
Side effects are reduced by using one drug of the combination for this purpose
Potential for drug abuse can be minimized by using one drug of the combination for this purpose
(i.e., excessive use of the antidiarrheal narcotic diphenoxylate is discouraged by side effects of
atropine in the FDC atropine + diphenoxylate)
DISADVANTAGES
FDCs are (possibly) more expensive than separate tablets
Potential quality problems, especially with rifampicin in FDCs for TB, requiring bio-availability
testing
If a patient is allergic or has a side-effect to 1 component, the FDC must be stopped and replaced
by separate tablets
Dosing is inflexible and cannot be regulated to patient’s needs (each patient has unique
characteristics such as weight, age, pharmacogenetics, co-morbidity, that may alter drug
metabolism and effect).
Incompatible pharmacokinetics is irrational because of different elimination ½ lives of individual
components
Reaction of one of the components (e.g., a rash to sulfamethaoxazole in cotrimoximzole) may
result in patient avoiding the “innocent” trimethoprim in the future
Drug interactions may lead to alteration of the therapeutic effect.

We might infer from the circumstantial evidence presented in this Table that
FDCs may be better than free combinations in slowing or even eliminating AMR.
It is well documented in TB treatment7 that multiple interruptions when using
free dose combinations of pills creates the risk of monotherapy on some drugs
and not in others. This fact, coupled with the in vivo mutation rates of the
mycobacterial genome, rapidly leads to drug resistance to one or more of the free
combination drugs. Fixed‐dose combinations make the possibility of
monotherapy even more remote. Effectiveness of FDCs, however, really
depends on detailed knowledge of the epidemiology and microbial ecology of
the particular pathogen. Since in HIV, malaria, or TB, development of AMR
commonly occurs by rapid genetic mutations, deletions and insertions 20 , if
evolution of AMR is occurring within a host during course of therapy (which in
the case of HIV or TB is quite long), then FDCs would theoretically be effective if
141

more than one drug is present in therapeutic concentration at any one time.
Jordan et al21 did a systematic review and meta‐analysis to assess the evidence for
the effectiveness of increasing numbers of drugs in antiretroviral combination
therapy. Evidence from randomised controlled trials supports the use of triple
therapy but more research is needed on the relative effectiveness of specific
combinations of drugs. Unfortunately, to reduce the potential for confounding by
established drug resistance, Jordan et al. looked only at those patients who had
not previously received antiretroviral therapy.

There are several ways that the different components of free or fixed‐dose
combinations produce their antimicrobial effect. The different drugs may attack
the same biochemical target by different mechanisms (e.g., cotrimoxazole).
Strictly speaking, use of different drugs with potentially incompatible
pharmacokinetics is irrational because of the different elimination ½ lives of the
individual components. Yet in combination therapy for dapsone‐resistant
leprosy22 and malaria6, it is often the case that individual drugs have different ½.
lives in the blood. Alternately, combination therapy may use drugs with
completely different modes of action (e.g., artemether‐mefloquine for malaria)
and which in theory do not share the same resistance mechanism. Both these
strategies lie at the heart of the value of combination drugs in the context of
treating infectious diseases and, in theory, combating antimicrobial drug
resistance. The “leprosy” rationale for using combination drugs is based on the
concept that a strong drug (e.g., rifampicin) with a short ½ life will reduce the
number of pathogens to a level at which a second, more slowly acting drug (e.g.,
dapsone) will kill the rest22 23. The second rationale follows from the discussion
in Section 2. Drug resistance in many microbes arises from mutations and the
probability that resistance to two different drugs will emerge is the product of
the mutation rates per microbe (e.g., bacteria, virus, protozoan) for the individual
drugs, multiplied by the number of microbes in an infection that are exposed to
the drugs6. For instance, if one in 109 microbes are resistant to drug. A and one
in 1013 are resistant to drug B, and the genetic mutations that confer resistance are
not linked, only 1 in 1022 will be simultaneously resistant to both A and B. If
correctly given, combination drug treatments should in theory retard emergence
of resistance compared with sequential use of single drugs24. We note, of course,
that if the dosages of the components of either FDCs or free combinations are
incorrect there may be long periods where the concentration of drug is below
levels needed to inhibit the pathogen‐ thus providing selection pressure for
mutations.
142
Overcoming clinical resistance using combinations: what is the evidencei?
The rationale for using FDCs to stem the tide of clinical resistance to TB, malaria
and HIV is intuitively appealing but there is little unequivocal evidence to
support it. Some key references are found in the Annex with regard to the
evidence, if any, supporting or refuting the following hypotheses: 1. FDCs will
limit clinical resistance to a greater extent than free combinations or
monotherapy; and 2. FDCs are superior to blister packs in limiting clinical
resistance. The Annex is not intended to be a critical analysis of the literature‐
although such a review would be very useful. We present our overall conclusions
below:

• The vast majority of head to head comparisons/trials of monotherapy
versus fixed combination versus free combinations are safety and efficacy
studies. They are of two types:

1. individual components are compared to FDCs having these same
components (primarily HIV and TB drugs);
2. Various free combinations are compared to FDCs of a completely
different drug (primarily in malaria studies).

With regard to the question of whether or not antiretroviral FDCs that
are, and have been on the market, will eliminate or slow clinical
resistance, our data suggest that there have been NO direct comparisons
of these FDC with their individual components for this purpose (See
Annex).

• Only relatively recently has individual resistance to anti‐TB and anti‐
malarials been measured at the molecular level. We note that the WHO
has developed a scheme for malaria that grades the degree of resistanceii.
This classification however has limitations (i.e., it may not be easy to
differentiate recrudescence from re‐infection; therapeutic failure could be
due to other causes, failure to detect may be due to pharmacokinetic
variations, multiple infections, noncompliance or interference with the

i We searched MEDLINE and the Cochrance Systematic Review and Register of Controlled
Trials Dataabases. The following table summarizes the number of “hits” with each search
term for the Controlled Trials Databases for malaria, TB and HIV, respectively.
Search terms “Hits” “Hits” “Hits”
a. “Clinical trials” 39451 a. “Clinical trials” 39451 a. “Clinical trials” 39451
b. a+”malaria” 86 a +” tuberculosis” 285 a +”HIV “ 332
c. b + “resistance” 22 b + “resistamce” 63 b + “resistance” 35
d. c + “combination” 8 c + “combination” 29 c + “combination” 20
We also searched the same databases using “blister pack” and “blister package”.
ii In a case of normal response parasite count to fall to 25% of pre‐treatment value by 48 hours
and smear should be negative by 7 days. RI, Delayed Recrudescence: The asexual
parasitemia reduces to < 25% of pre‐treatment level in 48 hours, but reappears between 2‐4
weeks. RI, Early Recrudescence: The asexual parasitemia reduces to < 25% of pre‐treatment
level in 48 hours, but reappears earlier. RII Resistance: Marked reduction in asexual
parasitemia (decrease >25% but <75%) in 48 hours, without complete clearance in 7 days.
143

acquired immune response). Indeed, some have suggested25 that these

tests cannot be applied in practice at all.

• Responses of TB, malaria and HIV pathogens to combination drugs are
very complex, particularly for malaria and HIV and the more and
different combinations that will be used, the more complex will be the
interactions. For malaria, there is some in vitro data on the direct
interactions of different combinations against P. falciparum growth which
have shown interactions from antagonistic to additive and synergistic (see
for example, ref. 26 and references cited therein). Synergism was found
between artemisinin and mefloquine and artemisinin and amodioaquine.
The in vitro combination of artemisinin and sulfadoxine/pyrimethamine
provided evidence of antagonism at drug concentrations of relevance for
in vivo situations26 (ref. citing an article by Mariga S. et al., in preparation).
In clinical trials comparing monotherapy with combination therapy,
parasite clearance and cure rates have consistently shown better efficacy
with combinations27 28 (and references cited therein). One could not infer
from these studies, however, that combinations in the field are better at
preventing emergence/selection of resistance than monotherapies.

• In HIV, multiple drug combinations can synergistically inhibit drug
sensitive‐viral replication but mutations to individual components will
arise anyway. Inclusion in combinations of those drugs to which there is
resistance can actually yield an antagonistic effect (e.g, AZT resistant
virus showed an altered response to AZT combinations‐ synergy was
replaced by antagonism) 29 . HIV‐1 isolates with reduced sensitivity to
abacavir, lamivudine, or zidovudine have been selected in vitro and also
obtained from patients treated with that combination or lamivudine plus
zidovudine. Combination therapy can delay the emergence of mutations
conferring resistance to zidovudine30.

• Free combination drugs are generally more prone than FDCs to
dispensing and patient error. What can be said about “blister packs”,
which we might consider as an “intermediate” between free and fixed‐
dose combinations? Counting returned pills from blister packs may
overestimate compliance because patients could hoard or discard untaken
doses, and so returning nearly empty or empty containers at each visit
falsely suggests compliance31. Many patients empty their blister cards
rather than bring back evidence for noncompliance31.

• No studies of which we are aware have systematically looked at the
effect of blister packs compared to FDCs and/or free combinations with
regard to development of resistant pathogens. In this regard there seem
few studies on health outcomes generally (see, however,32 and references
cited therein). Two very small trials in elderly patients have shown a
benefit of blister packs on adherence by pill counts, in comparison with
pill bottles without an organizer33 34. A study conducted in 1994 showed
that the use of blister packs containing antimalarial drugs significantly
144
increased patientsʹ compliance, compared with traditional means of

dispensing drugs in a paper envelope 35 . Shwe et al 36 [ looked at the
influence of blister packaging on the efficacy of artesunate + mefloquine
over artesunate alone in community‐based treatment of non‐severe
falciparum malaria in Myanmar. They concluded that provision of blister
packs of daily doses is a very effective way to improve compliance with
short courses and drug combinations. However, the efficacy of the
combination in Myanmar in this particular study was only marginally
higher than that of artensunate alone.
Future research needs
Some studies suggest that decreasing overall antibiotic use may reverse bacterial
resistance in human populations 37 38 . One cannot assume from this that
combination therapy will have the same effect. It is thus critical to know if using
FDCs will prevent the appearance of drug resistance and/or reverse existing rates
of drug resistance at both individual and population levels. The primary
difficulty in assessing the evidence will be to actually measure
developing/ongoing antimicrobial resistance in populations in field situations.

• Recent uses of molecular biology techniques might allow for easier
tracking of clinical resistance markers See, for instance,39 40 41 42 although
this genotyping must be correlated in the field with clinical outcomes.
• Larger longitudinal and community based studies are needed. An
important and potentially significant study was performed by Roper et
al. (2003)43 who characterised genetic change in dhfr and dhps genes in the
Plasmodium falciparum population of KwaZulu‐Natal, South Africa, during
1995‐99, a period of rapid deterioration of the effectiveness of
sulfadoxine‐pyrimethamine. They did the same analysis in P falciparum
sampled from communities in northern Tanzania in 2001. The authors
found a large genetic change during 1995‐99 in KwaZulu‐Natal and the
determinants of resistance in this province share a common evolutionary
origin with those found in Tanzania, even though the two sites are 4000
km apart. Their interpretation is that gene flow rather than new
mutations has been the most common originator of resistance in African
countries. Nosten et al. 44 studied in vitro susceptibility patterns to
mefloquine over a 13 year period in Thailand and found a sustained shift
away from P. falciparum resistance, brought about by use of artesunate
plus mefloquine.
• Head to head comparisons of blister packs compared to FDCs and/or free
combinations are needed with regard to health outcomes, including
development of AMR.
• For HIV and malaria, increasing the pace of our understanding of genetic
resistance pathways and mutations, since this understanding has not kept
up with the increasing number of therapeutic options.
145

Conclusion
Fixed‐dose combination therapy may be a critical component of any efforts to
solve the AMR crisis. Combinations make therapeutic sense for HIV, TB and
malaria although the evidence for the utility of combinations in this regard is still
largely circumstantial. Evidence for suppression of resistance by antimalarial
combinations first arose during animal model studies beginning over 20 years
ago45 (and references cited therein). Formal proof in humans will be difficult to
obtain. More field evidence is required outside of the TB and malaria contexts.
The spread of antimicrobial resistance is unrelenting. It is a global crisis and
already is adversely affecting public health. Comprehensive action is urgently
needed.
146
Annex
Selected studies comparing combinations, FDCs, blister packs and
monotherapy with regard to development of antimicrobial resistance
Comparison Tuberculosis HIV Malaria

Monotherapy No relevant AZT + didanosine vs. AZT + Oral artemether alone vs
v. free studies zalcitabine vs. AZT alone artemether + mefloquine
combination Brun‐Vézinet et al., 1997, Lancet, Looareesuwan S, et al., 1997, Am J
350: 983‐990. Trop Med Hyg. 56:613‐7.
Prevalence of zidovudine N=151; randomized, open‐label
resistance lower in monotherapy study Oral artemether alone or
group. At any time point, absolute in sequence with mefloquine.
concentration of zidovudine‐ Group I: artemether (total 500
resistant mutations higher in mg/ 5 days)
monotherapy group than in Group II: artemether (750 mg/7
combination groups days)
Group III: artemether( 600 mg) +
AZT alone vs. AZT + zalcitabine, mefloquine.
vs. AZT + ddI Cure rates for Group I 74% (28
Schooley RT et al.,1996, J. Infect of 38) Group II 98% (48 of 49)
Dis. 173:1354‐66. Group III 98% (43 of 44)
Combination therapy did not In vitro drug susceptibility
delay the emergence of testing for 10 patients.‐ no
zidovudine‐resistant virus decreased response to
isolates. artemether in recrudescent
isolates when compared with
AZT alone vs. AZT + 29,39‐ admission isolates.
Dideoxyinosine or AZT +
29,39‐Dideoxycytidine (I) Brendan Chloroquine alone vs quinine
A et al., 1996. J. Virol. 70: 5922–5929 sulphate + single‐dose SP vs.
No difference in AZT resistance in quinine alone vs. mefloquine
isolates between groups. Low alone
frequency of ddI or ddC Rahman MR, et al.2001, Trans R
resistance in isolates from Soc Trop Med Hyg. 95:661‐7.
combination Open, randomized trial
arms, enhanced efficacy with Chloroquine for 3 days (CQ,
combinations compared with Group I), quinine sulphate for 3
monotherapy. days followed by single‐dose SP
( Group II), quinine for 7 days
AZT vs. AZT + ddI or AZT + ddC (Q7, Group III), and mefloquine
(II). double‐blind, placebo‐ 20 mg/kg single dose (MEF,
controlled study, n= 180 ; delay in Group IV).
AZT resistance in two‐drug
combinations compared with AZT RII and RIII parasitological
alone failures occurred in 56%, 12%,
8% and 14% in Group I‐IV,
Indinavir (IDV) alone v. IDV+AZT respectively.
vs. IDV + AZT + ddI vs. IDV
+AZT +3TC
Drusano Clin. Infect. Dis. 36 (S1):S1
3 drug‐combination therapy
significantly better than 2‐drug or
monotherapy at preventing
emergence of resistance
147


Mono‐ No relevant No relevant studies Atovaquone/proguanil
theraphy v. studies compared with mefloquine
FDC alone
Looareesuwan S, et al., 1999, Am J
Trop Med Hyg. 60:526‐32.
open‐label, randomized,
controlled clinical trial.
Atovaquone and
proguanil/hydrochloride (1,000
mg and 400 mg, respectively,
administered orally at 24‐hr
intervals for three doses) or
mefloquine (750 mg
administered orally, followed 6
hr later by an additional 500‐mg
dose). Atovaquone/proguanil
was significantly more effective
than mefloquine (cure rate 100%
[79 of 79] vs. 86% [68 of 79]; P <
0.002).

CHLOROQUINE ALONE, V.
SULFADOXINE‐PYRIMETHAMINE, V.
MEFLOQUINE ALONE
Marquino W, et al, 2003, Am J
Trop Med Hyg. 68:120‐3.
14‐day in vivo efficacy trials of
chloroquine (CQ; 25 mg/kg) and
sulfadoxine‐pyrimethamine (SP;
25 mg/kg of the sulfadoxine
component) The results from all
three sites were similar. Of the
53 patients treated with CQ,
58.5% had RII/RIII responses.
No RIII failures were observed
among the 112 patients who
received SP, but 4.5% and 1.8%,
respectively, had RII and RI
responses. All 33 patients
treated with MQ showed a
sensitive response.

Chloroquine alone v.
pyrimethamine‐dapsone
Mshinda H, et al, 1996, Trop Med
Int Health. 1:797‐801.
Randomized study in Tanzania.
No cases in the combination
group showed RII resistance,
In chloroquine group, 2 cases
showed RII resistance and a
further 2 cases RIII resistance
(6%).
148

Free Four component TRIZIVIR (GSK) Proguanil‐dapsone v.
combination drugs (INH, RMP, There have been no clinical trials sulfadoxine‐pyrimethamine
v. FDC EMB and PZA) as conducted to compare Trizivir as Mutabingwa TK, et al., 2001,
FDC vs, separate an FDC to its components with Trans R Soc Trop Med Hyg.
formulations regard to resistance. 95:433‐8
Su et al., 2002, Int J 220 children 112 had received a
Tuberc Lung TRIOMUNE‐40 (Cipla Ltd) single dose of SP 108 had taken
Dis.6:1029‐32 d4T 40mg + 3TC 150mg + NVP PG 10 mg/kg with DS 2.5 mg/kg
N= 51 200mg each day for 3 days
Safety/efficacy 64 weeks; n = 171 high failure rate with SP was
only “Among the Safety and efficacy. No not associated with occurrence
patients with a comparisons with regard to of leucine substitution at
drug susceptibility clinical resistance position 164 of the dhfr gene.
test result
available, four in DUOVIR‐N (Cipla Ltd) Artecom (FDC) vs artesunate‐
the FDC group had AZT 300mg + 3TC 150mg + NVP mefloquine
bacilli resistant to 200mg Wilairatana P, et al.2002,
pyrazinamide. In “ patients may be better able to Southeast Asian J Trop Med Public
the separate adhere to triple drug regimens, Health, 33:519‐24
regimen group, thereby enhancing compliance
two patients had and ensuring the success of Open randomized trial in Thai
bacilli resistant to antiretroviral therapy” adults N= 352
ethambutol and six Artecom (group A) and the
had bacilli standard combination of
resistant to artesunate and mefloquine
pyrazinamide” (group B). The 28‐day cure rates
were high as 97% in both
RIFATER (FDC OF groups.
ISONIAZID,
RIFAMPICIN AND Artecom = FDC of dihydro‐
PYRAZINAMIDE) VS. artemisinin, piperaquine,
ITS FREE trimetoprim administered over
COMBINATION three days. FDC produced in
Teo, SK, 1999, Int J China
Tuberc Lung Dis.
3:126‐32
N= 155
At the end of 5
years, there were
15 relapses: three
(2.2%) in the
separate drugs
group and 12
(9.3%) in the
Rifater group.

149


Comparison TUBERCULOSIS HIV MALARIA
“mixed” THREE COMPONENT ZT+nevirapine vs. AZT+ddI vs. ARTESUNATE‐SULFADOXINE‐

combinations DRUGS (INH, RMP, AZT+nevirapine+ddI PYRIMETHAMINE AND
AND PZA) AS FDC CHLOROQUINE‐SULFADOXINE‐
Conway et al., 2001, AIDS, 15:1269‐
VS, SEPARATE PYRIMETHAMINE
1274
FORMULATIONS Tjitra E, et a., 2002, Antimicrob
Random, double blind trial.
Zhang, L‐X et al., Agents Chemother. 46:3947‐53l
Resistance to AZT lower in triple
Current Therapeutic P. vivax malaria, New Guinea
therapy group. 100% isolates
Research., 57:l. Double and quadruple
resistant to nevirapine but
n=102 each mutations in P. vivax DHFR
resistance in triple therapy group
treatment gene were common Treatment
was delayed.
No significant failure with SP‐containing

differences in regimens was significantly
initial bacteriologic higher with isolates with DHFR
resistance between quadruple mutation.
groups. FDC:
five/88 isolates
resistant to INH,
1/88 resistant to
RMP.
Combination: 3/81
resistant to INH,
2/81 resistant to
RMP
Blister pack None None None
v. FDC
v. free
combination
v.
monotherapy

150
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154
Fixed‐dose combination (FDC) drugs availability and use as a global public
health necessity : intellectual property and other legal issues
Fixed-dose combination (FDC) drugs

availability and use as a global public
health necessity : intellectual property
and other legal issues
Warren Kaplan, PhD., JD, MPH
Executive summary
Patented medicines are priced far above marginal cost and patent holders are
rewarded for research and development (R&D) with grants of exclusive
commercial rights (primarily patents, copyrights and trademarks) so that
intellectual property laws allow the “investor” to regain some of the benefits of
their research and innovation. Fixed‐dose combination drugs have the potential
to involve multiple patents held by different parties. The transaction costs
associated with bargaining over property rights for components of the FDC can
arguably lead to both blocking of commercial development and, if already
manufactured, to lack of access “on the ground” .

There are various ways to overcome or ameliorate the negative effects of IPRs on
access to FDCs. Some unilateral mechanisms include:

• Put the ‘invention’ (e.g., fixed‐dosage combinations) into the public domain
and avoid IP/patent rights entirely or try to “design around” existing IP for
FDCs.
• Make patents harder to get so that only real advances in medicines will be
patented.
• Create exceptions to patent infringement so that various entities are spared
the transaction costs of licensing or, more particularly, patent litigation.
• Use voluntary and, if needed, compulsory licensing between patent owners.

Other mechanisms include the creation of multilateral, collective business models
for R&D and transacting IPRs. These might include the creation of voluntary or
government‐mandated patent pools. Another possibility, not yet well thought‐
out, would be to develop various IP information and transactional
155

“clearinghouses” specifically for IP related to fixed‐dose combination drugs.

Such a clearinghouse should be able to identify all relevant IPRs over a given
(i.e., FDC) technology and, indicate which are and which are not available to be
negotiated, and if they are, how they can be accessed. It should create a pricing
scheme and terms of contract and a royalty disbursement accounting system.

Multiple components of FDCs can lead to complex issues of IPR access and
implicates other factors such as R&D funding mechanisms and global IP rules.
Creative approaches to the problem are required. For developing countries, IP‐
resource poor inventors, NGOs, and patients, ways are needed to reduce IPR
transaction costs with regard to fixed‐dose combination drugs.
Introduction
Intellectual property rights (IPRs) are legal and institutional devices to protect
creations of the mind such as inventions, works of art and literature, and designs.
A patent for an invention is the grant of a property right to the inventor, issued
by a national, patent‐issuing authority of a particular country. The term of a new
patent is 20 years from the date on which the application for the patent was filed
in the particular patent office or, in special cases, 20 years from the date an earlier
related application was filed. Patent grants are creature of national, NOT
international law and are effective only within the granting country and its
territory and possessions. Recent global frameworks for intellectual property
under the auspices of the World Trade Organization (WTO) (see Section 5) offer
guidance as to minimal levels of IP protection that countries must have. There is
a forum for resolving IP disputes between countries within the WTO but, unless
individual countries’ provide subsequent legislation or influence subsequent
policy, such resolutions have no direct force of law in terms of dictating
domestic IP policies.

A patent grant is NOT a positive right to make, use, offer for sale, sell or import,
but it is a negative right to exclude others from making, using, offering for sale,
selling or importing the patented invention. This is an important distinction and
is often difficult to grasp. Obtaining an issued patent does not provide the
patentee with the right to practice her own patented invention. Thus, “freedom
to operate” (the ability to practice your own invention without having to obtain
needed patented technology from third parties) and having an exclusive position
in the market in which your invention is the only one practiced, are independent
concepts. A patented drug can enjoy market exclusivity, but still have no
complete “freedom to operate” because making the drug requires one or more
third party manufacturing patents or patents to active pharmaceutical
ingredients.

By pricing medicines far above marginal cost, patent holders are rewarded for ex
ante research efforts with ex post grants of exclusive commercial rights1 so that
intellectual property laws allow the “investor” to regain some of the benefits of
their research and innovation. However, the net effect of IPRs on innovation,
156
creativity and economic development are uncertain and it is probably not
possible, on the basis of present knowledge, to be sure that a given patent system
confers a net benefit or a net loss upon society. For developing countries the
situation continues to be extremely unclear. IPRs create their own problems1.

For the present discussion of FDCs, there are two related IPR issues:

a) IPRs can be a barrier to research and development into new FDCs,
b) IPRs can bar access to existing FDCs by the healthcare system.

That is, strong property rights arguably stifle research by creating a climate
where researchers face legal action for using patented materials, processes or
research tools (See Section 2). Fixed‐dose combination drugs have the potential
to involve multiple patents held by different parties. The transaction costs
associated with bargaining over rights can arguably lead to both blocking of
commercial development and, if already manufactured, to lack of access “on the
ground” (See Section 3). High prices of patented medicines are but one
important barrier to access. There are various ways to overcome or ameliorate
the negative effects of IPRs on access to FDCs, some of which implicate other
legal issues, notably antitrust and competition law (Section 4). Recently, the
global community has, more or less (See Section 5), agreed that IPRs should be
subservient to public health needs.
IPRs and Fixed‐dose Combinations: Introduction to the “Anticommons
Problem”
Garrett Hardin’s “tragedy of the commons” 2 conceptualized resource

overutilization topics such as overgrazing on renewable crops, species extinction,
and market behavior. In each case, an under assignment or inability to enforce
property rights leads to a set of incentives that cause overuse of a commonly‐held
property resource. In Hardin’s view, too many owners of a common resource,
each having the right to use, leads to overuse. Heller and Eisenberg 3 have
developed the mirror image “tragedy of the anticommons” in which an over
assignment of property rights for a privately‐held resource leads to under
utilization of the resource. In the “anticommons”, multiple owners each have the
right to exclude others from a resource and this leads to underuse since no one
person can use the whole. One example occurs when patents for gene fragments
in biomedical research lead to lack of freedom to operate since users of whole
genes in downstream applications are required to license numerous already‐
patented gene fragments. The “cost of doing business” in this environment can
be disruptive. Many IP stakeholders drive up the cost of establishing value for
the IP and incompatible ownerships require individual negotiations. Within the
communities of scientists, university technology transfer professionals, and
private firms in the pharmaceutical and biotechnology industries, “there seems to
be a widely shared perception that negotiations over the transfer of proprietary
research tools present a considerable and growing obstacle to progress in
biomedical research3.”
157

IPRs and Fixed‐dose Combinations: The “Anticommons Problem” (II)
Multiple/conflicting IP ownership will lead to multiple access requirements and
this, in turn, can create significal technology access problems. An extreme
example is that of agricultural biotechnology and vitamin A golden rice which is
made using recombinant DNA technology. Each plant contains several
exogenous DNA fragments that allow the plant to synthesize large amounts of
Vitamin A 4 . Depending upon the country, between zero and 40 (!) separate
patents need to be accessed in order to create a “golden rice” planti.

The “anticommons” barrier to improved availability of FDCs revolves around
IPRs of the individual FDC components, exemplified by the antiretroviral FDCs.
Trizivir ®, approved by the FDA in November 2000 for the treatment of HIV in
adults and adolescents, is an FDC of Ziagen® (abacavir sulfate 300mg/ABC),
Retrovir® (zidovudine 300mg/AZT), and Epivir® (lamivudine 150mg/3TC).
Ziagen® was discovered and is being developed by GlaxoSmithKline and all
rights to technology, including intermediates used in its were licensed to Glaxo
Wellcome by the University of Minnesota in 1992. Lamivudine was discovered
by BioChem Pharma of Laval, Quebec, Canada and licensed to Glaxo Wellcome
in 1990. GlaxoSmithKline therefore has outright intellectual property ownership
or exclusive rights to all components of Trizivir®. CIPLA, Ltd, the Indian drug
company, makes an FDC (“Triomune”) which contains nevirapine, stavudine
(d4T) and lamivudine (3TC). Each component is owned by a different party; Yale
(stavudine), BioPharma/Glaxo (lamivudine) and Boehringer Ingelheim
(nevirapine)5,ii. Thus, even if components of FDCs may be patented separately
and owned by different parties or all components may be owned by the same
party, requiring a license to even one component of an FDC is enough to block
access to the whole.

Table 1 lists the components of these FDCs (column 3: Triomune; column 4:
Trizivir®). Data from Attaran and Gillespie White 6 allows us to list those
countries that have patent protection for all three components of the particular
FDC (“+++”) or just individual components. We note that Combivir® is an FDC
of lamivudine and zidovudine. Thus, the presence of patent protection for a
Combivir® product might also effectively block production, sale, or use of
Trizivir®®, since Trizivir® contains within it the components of Combivir®.
Even if the healthcare systems in the countries of Table 1 were entirely efficient in
delivering medicines (which they are clearly not), the blockage of these FDCs by
IPRs affects tens of millions of people. Table 1 lists the prevalence of HIV+ adults
affected by this lack of FDC access 7 . In this regard, Aspen has received a
voluntary license for the components of Trizivir® and recently received a

i Kryder, RD. Kowalski, SP. & Krattinger, AF. (2000), The intellectual and property components of
pro‐vitamin A rice (Golden Rice): A preliminary freedom to operate review, ISAAA Briefs No. 20.
ISAAA, USA. (http://www.agbiotechnet.com).
ii India can manufacture these antiretrovirals domestically because its patent system, albeit
only until 2005, only allows pharmaceutical method of manufacture patents. India can
“design around” method patents by making them using a different method than that
described in the patent.
158
voluntary license (terms unknown) apparently allowing it access to nevirapine
and and stavudine. The terms of the license are such that FDCs can be made
from these two components (Richard Laing, personal communication, 10
November 2003).

Table 1: Components of various FDCs that are patented in selected African
countries

Triomune components under Trizivir® components
HIV prevalence
patent protection under patent protection
Stavudine/Lamivudine/ Lamivudine/Zidovudine/
Country Adult (%)
Nevirapine Abacavir
Botswana 38.80 Nevirapine, lamivudine +++

Zimbabwe 33.73 Nevirapine, lamivudine +++
Swaziland 33.44 Nevirapine, lamivudine +++
Lesotho 31.00 Nevirapine, lamivudine +++
Namibia 22.50 Nil Nil
Zambia 21.52 Nevirapine, lamivudine +++
South Africa 20.10 ? +++
Kenya 15.01 Nevirapine, lamivudine +++
Malawi 15.00 Nevirapine, lamivudine Combivir®, lamivudine
Mozambique 13.00 Nil Nil
Central African 12.90 Nevirapine, lamivudine Combivir®, lamivudine
Republic
Cameroon 11.83 Nevirapine, lamivudine Combivir®, lamivudine
Djibouti 11.75 Nil Nil
Cote dʹIvoire 9.65 Nevirapine, lamivudine Combivir®, lamivudine
Rwanda 8.88 Nil Combivir®
Burundi 8.30 Nil Combivir®, zidovudine
United Republic of 7.83 Nevirapine, lamivudine +++
Tanzania
Congo 7.15 Nevirapine, lamivudine Combivir®, lamivudine
Sierra Leone 7.00 Combivir®, abacavir
Burkina Faso 6.50 Nevirapine, lamivudine Combivir®, lamivudine
Ethiopia 6.41 Nil Nil
Togo 6.00 Nevirapine Combivir®, lamivudine
Nigeria 5.80 Nevirapine Combivir®, lamivudine
Angola 5.50 Nil Nil
Uganda 5.00 Nevirapine, lamivudine +++
Democratic 4.90 Nil Combivir®
Republic of Congo
Gabon 4.16 Nevirapine, lamivudine Combivir®, lamivudine
Ghana 3.00 Lamivudine +++
Sudan 2.60 Nevirapine, lamivudine +++
Gambia 1.60 Nevirapine, lamivudine +++
Seychelles Lamivudine +++

+++ signifies that all three components are under patent (as of 2001)
Data in column 2 are as of the end of 1999 (Sourcevii)

159

Fortunately, the major components of FDCs for tuberculosis are off patent but the
problem will resurface as new TB drugs become available and anti‐mycobacterial
resistance to existing drugs increasesi. With regard to patented malaria FDCs,
one example is Coartem , marketed by Novartis. This patented FDC
(artemether/lumefantrine) is being provided at cost by Novartis and distributed
through the WHO as part of the worldwide ʹRoll Back Malariaʹ initiative.
Coartem contains the same ingredients as far more expensive Riamet, a
Novartis medication approved in Europe for travellers visiting malaria‐endemic
regions. The incentives for a third party (i.e., a generics manufacturer in India) to
make Coartem at a profit are necessarily undercut since Novartis is selling the
drug at zero margin.
Overcoming IP/Legal barriers
Mechanisms exist for overcoming these IP “access” barriers to using FDCs. Some
relate to collective ways of innovation and management of IPR issues Some are
not specific to FDCs inasmuch as they deal with novel methods of funding R&D
and many are radical enough not to be considered part of the mainstream ideas
about IPRs. Some are unilateral, others are multilateral. All, however, are worth
thinking about.

Put the ‘invention’ (e.g., fixed‐dosage combinations) into the public domain and avoid
IP/patent rights entirely
The genomes of major parasites are being sequenced and the data released into
the public domain (see8,9, 10,11). There are numerous discussions at the present
time regarding open source research systems, inspired by open source software
development. Advocates of open‐source innovation want research results to be a
freely available commodity, with drug companies competing to market generic
versions of drugs 12. The common availability of information would help to
overcome two serious barriers to fair trade in patented technologies: ‘imperfect
information’ and ‘information asymmetry’, situations where one or both parties
in a transaction lack some of the information on which their decisions to buy or
to sell rest. Moreover, according to principles of patent rights “exhaustion”, once
a patented product is sold for the first time, then the patent rights attached to it

i In the US at least, there exist multiple incentives to stimulate the development of
antimicrobial agents. They include orphan drug exclusivity (James Love Comments on the
Orphan Drug Act and Government Sponsored Monopolies for Marketing Pharmaceutical Drugs.
United States Senate, Committee on the Judiciary, Subcommittee on Antitrust, Monopolies
and Business Rights, Anticompetitive Abuse of the Orphan Drug Act: Invitation to High
Prices, January 21, 1992, Serial Number J‐102‐48, pages 259‐283), the Waxman‐Hatch
initiative (Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98‐
417, 98 Stat. 1585, codified at 15 U.S.C. §§ 68b‐68c, 70b, 1994), pediatric exclusivity (see, for
example, the FDA’s report (htpp://www.fda.gov/cder/pediatric/reportcong01.pdf), a certain
prioritization for expedited review of agents effective for certain resistant organisms, higher
consideration for expedited review of drugs in new classes with novel mechanisms of action,
and federally funded clinical study groups. Most pharmaceutical companies are aware of
these incentives and utilize them although for some of these intiatives, the public health
consequences are far from clear. However, the real problem is that there is significantly
diminishing FDA submissions and diminishing approvals of newer antimicrobials.
160
disappear. Unless the sales contract stipulates something different, patented

medicines sold to a third party can be made with impunity into FDCs or blister
packs.

“Design around” existing IP for FDCs
This is being done in India (see above, section 3) and at least is theoretically
possible provided there are sufficient resources for IP review and product
development. It is not clear that relevant FDC users (i.e., NGOs, developing
countries) have the means to do this.

Make patents harder to get so that only real advances in medicines will be patented
This involves legislative/legal changes to the patent system. Stimulated by the
proliferation of patents to DNA sequences of dubious usefullness, the United
States has raised the standards for the requirement that inventions have practical
“utility”13. It is too early to tell what the effect of this will be on innovation and
development/access of new FDCs.

Create exceptions to patent infringement so that various entities are spared the
transaction costs of licensing FDCs and components or, more particularly, spared the
costs of patent litigation
Such exceptions do exist such as the so‐called “Bolar safe harbor” in the U.S.
which generally allows entities, such as generic drug makers, to legally infringe
a patent if the allegedly infringing activities are performed pursuant to filing for
FDA approval of a drug. Other countries have similar exceptions. Many people
believe that universities are allowed a “research” exemption from patent
infringement but, if this ever was true, this exemption is rapidly being eroded14.

Manage the risk of poor FDC access by voluntary licensing
In the case of FDCs, this would involve negotiating a series of voluntary licenses
so that an FDC manufacturer could have freedom to produce the combination.
Cross licensing (i.e., where two or more entities license IP to each other) is very
common in the biotechnology industry, although probably less common between
pharmaceutical companies. “Set off” clauses in license contracts are often the
subject of much voluntary negotiation, but provide language to deal with this
“anticommons” problem. These clauses are primarily for the licensees’ benefit.
In their simplest form, they essentially state that “ … if I need any patent from a
third party that is not part of this negotiated IP package from company X, I will
still pay ‘rent’ to access patents of company X but decrease them by the amount
owed for the company Y patent”. Notwithstanding cross licensing, the
pharmaceutical industry has not consolidated its potentially conflicting IPRs to
assist companies like CIPLA (although the voluntary license(s) to Aspen offer
some hope that this will happen). The spectre of dealing with multiple IP owners
in those countries that do recognize pharmaceutical product patents ( see Table 1)
is a difficult task for any governmental agency wishing to procure FDCs. With
regard to Trizivir®, GlaxoSmithKline has the “dominating” patent position.
Voluntary license IP transaction costs to access this FDC in the countries listed in
Table 1 may be daunting, although this in part depends on the terms of the
license(s).
161

Create new business/R&D models
There is certainly ample precedent for the ownership of intellectual property
generated by collective business/R&D models such as research consortia to
develop new FDCs that include universities as well as operating companies.
These collective organizations are best suited to dealing with ambitious scientific
plans that are too large in scope to be carried out by any individual organization.
IPRs can become the common property of all the members involved in the
project. Alternatively, ownership of the intellectual property can be retained by
the consortium which then licensed it back to the members on a variety of
schedules. The SNP Consortium was an important undertaking that testifies to
the success of this R&D strategy15. The mission of the SNP Consortium was to
create a high‐quality, dense, genome‐wide single nucleotide polymorphism
(SNP) map that would be available to the public. The SEMATECH consortium,
for example, was instrumental in recapturing the semiconductor market from the
Japanese16.

Manage the risk of poor FDC access by compulsory licensing
One way to have use of the potential for FDCs is to make full use of compulsory
licensing provisions in the world trading system (i.e., TRIPS) frameworks.
Compulsory licenses can be used to force availability of an FDC whose
components are owned by different entities. Compulsory licenses can be issued
for a variety of reasons, including use by the government. i Under compulsory
licensing, a national authority gives a local producer the right to produce a
patented product without explicit permission from the patent holder. The
United States and Canada have much experience with compulsory licensing17. In
Canada, between 1969 and 1992, there were 1,030 applications to import or
manufacture medicines under such licenses, of which 613 licenses were granted18.
European countries have fairly broad authority to issue compulsory licenses on
public interest grounds. Threats of compulsory licensing influence the issuance
of voluntary licenses 19 . Many developing countries have laws allowing for
compulsory licensing but, aside from the aggressive threats and use of this
remedy by Brazil (see http://www.cptech.org/ip/health/c/brazil), most
developing countries still have little experience with compulsory licensing but
this may change quickly. In October 2003, the South African Competition
Commission ruled that the government should override patents to allow lower
priced medicines and in particular fixed‐dose combinationsii. In November 2003,
Canada proposed to amend its Patent Act in order to add a new section
authorizing third party use of patented inventions to address public health

i Globalization and Access to Drugs, Health, Economics and Drugs, DAP No. 7, World Health
Organization, DAP 98.9, Geneva , Switzerland.
ii Moreover, in the same month, the Clinton Foundation announced that they would be able to
broker deals for generic AIDS drugs in some developing countries at dramatically reduced
prices – the new price of $0.36 per day nearly halves the lowest price to date. The generic
companies involved in this agreement (Ranbaxy Laboratories Ltd., Cipla Ltd. and Matrix
Laboratories Ltd., all of India, and the South African company Aspen Pharmacare Holdings
Ltd.) could easily produce fixed‐dose combinations. As noted above in Table 1,
unauthorized production, or use or sale of certain FDCs in many countries in Africa would
in principle be blocked by existing IP rights.

162
problems afflicting developing and least‐developed. The new section in question
will allow for the issuance of royalty‐bearing compulsory licences to Canadian
firms, typically generic drug companies, authorizing them to manufacture in
Canada specific patented pharmaceutical products for the sole purpose of
exporting them to least‐developed and developing countries that are unable to
produce domestically the needed pharmaceuticals.

Create patent pools
Another way to disentangle multiple ownership issues of FDC would be to
encourage patent pooling20. A “patent pool” is an agreement between one or
more patent owners who agree to license one or more of the patents to one or
more third parties. Patent pools have played an important role in shaping the
industry and the law in the United Statesxx. The U.S. government considers that a
patent pool is procompetitive (and therefore legally acceptable on first principles)
when the pool integrates complementary technologies, reduces transaction costs,
clears patent “blocking” positions, avoids costly litigation and promotes the
dissemination of technologyxx. These would seem to be just those goals that
would allow wider use of FDCsi. Patent pools currently in existence primarily
involve industry standards in telecommunications and computer technology (i.e.,
MPEG‐2 compression technology standards; DVD‐Video and DVD‐ROM
standard specifications). As long as the blocking patent/technology could be
reasonably defined, and the terms of the patent pool were fair, a patent pool
including biotechnology/FDC patents is possible in principle. It is worth further
study into these arrangements to see if they can improve access to FDCs (indeed
to drugs in poorer countries generally).
Back to the Future: TRIPS, Public Health, Access to Medicines
The World Trade Organization meetings in Doha, Quatar21 confirmed what was
clear to many, that TRIPs allows compulsory licensing to provide patented
medicines, including FDCs, to low income countries22. Therefore, one short‐term
way out of the multiple ownership problem exemplified by “Triomune” would
be, under TRIPS imprimateur, forcing availability of FDCs when IPR issues
become too complex. Compulsory licensing is only obviously useful for that

i Features common to most US patent pools include: 1. A technology standard that is definite
and well defined; 2. An evaluator/independent expert to determine which patents are
essential to the implementation of the standard, thereby defining a group of essential patent
holders; 3. A license drafted and approved by the essential patent holders that allows the
technology to be licensed on a reasonable and nondiscriminatory basis; 4. A patent pool
administrator appointed by the essential patent holders to handle administrative tasks such
as signing up licensees, collecting royalties from the licensees, and distributing the royalties
to the essential patent holders; and, 5. The essential patent holders retaining the right to
license the patents outside of the patent pool. Patent pools that conform to the above criteria
should be approved and promoted by the government, industry, and the public, as they
provide a win‐win situation for all involved. If one of the above factors is not included in
the patent pool, it does not necessarily mean that the patent pool is anticompetitive or in
violation of the antitrust laws. It merely means that the patent pool will need to be more
carefully scrutinized.
163

group of “rich” poor countries that have both domestic expertise and domestic
pharmaceutical manufacturing capacity (Brazil, India, South Africa). However,
there is nothing in the TRIPs agreement to prevent a country without significant
local manufacturing capacity from importing the or its ingredients from a
country where no patent protection exists on that drug . Until recently, it was
not settled if TRIPs will be interpreted to cover the same situation if the drug or
ingredient was under a valid patent in the exporting countryi. It has, however,
become clear since the August 2003 WTO meeting in Cancun, Mexico that TRIPS
compulsory license provisions will be interpreted broadly enough to cover the
situation where a country lacking domestic production capacity can import a
drug from a producer in a third country. The Cancun agreement does not limit
the scope of diseases for compulsory licensing, and it also does not require high
standards such as epidemics or emergencies. Routine public health problems can
be addressed. New proposed amendments to domestic Canadian law (Section 4)
make export of patented medicines a possibility for Canadian generic drug
manufacturers.

Those middle and lower income countries capable of producing FDCs (Brazil,
India, Eastern Europe, probably Thailand, South Africa, Egypt, Jordan and a few
others) are required by TRIPS to ensure full product patent protection by 2005.
Thus, countries like India must provide patent protection for FDC components
and can no longer “design around” method patents. Thus is likely to
fundamentally change the nature of the pharmaceutical industries in those
countries that have previously relied on weak domestic patent protection to
make cheap copies of important drugs that are patented elsewhere. Now, these
medicines will have to be patented in‐country. There are, at least, three
consequences of the post‐2005 IP world for FDC manufacture, use and sale:

a) Voluntary licensing and the threat of, if not actual use of, compulsory
licensing will become more important;

b) Prices of patented FDCs in these “post‐2005” countries are likely to remain
high or increase, as pharmaceutical companies continue to try and recover their
sunk costs of R&D;

c) Combinations of off‐patent drugs or combinations containing at least one off‐
patent drug will become of interest;

d) More creative ways to incentivize development of new FDCs and provide
R&D funding (open sourcing, R&D consortia and so on) without exacerbating IP
and market failures will be needed.

i This was true notwithstanding the 14 November 2001 Doha Declaration on TRIPS and
Public Health, which said: ʺWe agree that the TRIPS Agreement does not and should not
prevent members from taking measures to protect public health. Accordingly, while
reiterating our commitment to the TRIPS Agreement, we affirm that the Agreement can and
should be interpreted and implemented in a manner supportive of WTO membersʹ right to
protect public health and, in particular, to promote access to medicines for all.ʺ The Doha
Declaration also said: ʺ Each member has the right to grant compulsory licences and the
freedom to determine the grounds upon which such licences are granted.ʺ
164
Recommendations
Make IP information more freely available

Make available, at minimal or no cost to all users, a readily searchable
database of US, European, and international (PCT) patents augmented by
advisory and educational services so that end users can decide upon
appropriate IP management tactics, such as whether to invent around or to
negotiate with a patent owner.

Integrate IP/legal issues regarding FDCs of both HIV and TB

The epidemics of HIV/AIDS and tuberculosis have converged in much of the
world. To combat the seemingly inexorable march of antimicrobial resistance,
new anti‐TB FDCs as well as new ARVs are needed, with an integrated
approach to treating both diseases. An integrated approach, involving
collective R&D and IP ownership (See Section 5), that can manage R&D and
the resulting IP for both TB and HIV would complement this;
To assist in this, there already exist dedicated groups of IP specialists who
provide advice on IPR “access” issues to NGOs, developing countries.
Specialists in agricultural biotechnology have developed interesting views on
this topic23;
Contractually or legislatively require non‐exclusive licenses for critically
needed IP such as FDC components;
Create voluntary or compulsory patent pools;
Create an FDC IP clearinghouse to reduce costs of transacting for IP rights,
stimulate private sector incentives, education in practical policy/legal IP
issues, conduct objective “due diligence”, coordinate IP policies. Again, we
can look to agricultural biotechnology for models24.

Incentivize private sector FDC development
Previously suggested private sector incentives might be modified for FDCs to
include:

1) The development of federal consortia to expedite and partially fund the
development of a new selected FDCs, thereby reducing costs of development to a
given pharmaceutical company;

2) ʺWild Card Exclusivityʺ where the patent life of an agent, such as a lipid
lowering agent, would be extended for a short time, if a valuable FDC were
developed;

3) A ʺModified Wild Card Exclusivityʺ where a short‐term patent extension
would be given to another drug in the same class (such as an anti‐malarial) as a
newer FDC;

4) Possible tax credits for the development of antimicrobials;
165


5) The adjustment of business loan rates for companies pursuing FDCs.

More controversial suggestions might include requiring regulatory agencies (i.e.,
the FDA) to make sure that FDCs are created as a vehicle for certain anti‐infective
agents or to treat certain diseases. Since it is always in the best long‐term
business interests of the private sector to extend their market share, this can be
accomplished by combining a new drug with an off‐patent generic into an FDC,
as has been done with Malarone®25. For less developed countries, mechanisms
of price differentiation26 should be developed so that the private sector will get to
extend market share and recoup R&D expenses (which are likely to be small for
old drug combinations) in the developed countries, and the less developed
nations will receive a low‐cost FDC drug.

Even more radical proposals would include new forms of public support for FDC
R&D and new types of collaborative partnerships, fueled by public funds. With
regard to FDCs, one can imagine a consortium of private and public actors
creating a clearinghouse for creating FDC drugs whose components are from
different owners. The organization will sponsor clinical trials and/or provide
quality assurance/quality control expertise and/or contract out manufacturing
capacity. Initial support might come from pharmaceutical companies and
international donors or NGOs. The respective governments would create tax
incentives for the pharmaceutical companies. Some portion of the profits
realized from IP licensing fees and drug sales would be placed into a global fund
to be used to provide grants to developing countries to improve efforts to combat
Conclusions
The “anticommons” problem for FDCs is one of ACCESS and this implicates
other factors such as R&D funding mechanisms and global IP rules.
Multidisciplinary approaches to the problem are required. The perceptions of
the different IPR stakeholders have lead to the evolution of different kinds of
transactions. For developing countries, IP‐ resource poor inventors, NGOs, and
patients, creative ways are needed to reduce IPR transaction costs with regard to
fixed‐dose combination drugs.
166
References

1 Love,J. Paying for Healthcare R&D: Carrots and Sticks ,
http://www.cptech.org/ip/health/rnd/index.html) accessed 10 October 2003.
2 Hardin, G. 1968 The Tragedy of the Commons Science, 162:1243‐1248.
3 Heller, MA. & Eisenberg, RS. 1998 Can Patents Deter Innovation? The Anticommons in
Biomedical Research Science, 280: 698‐701
4 Ye, X. Al‐Babili, S. Klöti, A. Zhang, J. Lucca, P. Beyer, P. Potrykus, 2000, I,
Engineering the provitamin A (ß‐carotene) biosynthetic pathway into (carotenoid‐free) rice
endosperm Science, 287:303‐305.
5 Love, J. A 3‐drug fixed‐dose ARV combination for USD 250? e‐drug, May 9, 2001,
available at pharm‐[email protected]
6 Attaran, A. and Gillespie‐White, L. 2001 Do patents for antiretroviral drugs
constrain access to AIDS treatment in Africa? J. Am. Med. Assn., 286:1886‐92.
7 UNAIDS 2000 Report on the global HIV/AIDS epidemic
(http://www.unaids.org/epidemic_update/report/index.html#table) accessed 11
November 2002.
8 Blackwell, JM and Melville, SE. 1999 Status of protozoan genome analysis:
trypanosomatids Parasitology, 118 (Suppl): S11‐4.
9 Degrave, WM. Melville, S. Ivens, A. Aslett, M. 2001 Parasite genome initiatives Int J
Parasitol. 31:532‐6.
10 Gardner, MJ. et al. 2002 Genome sequence of the human malaria parasite
Plasmodium falciparum,Nature, 419:498‐511.
11 Holt, RA. et al. 2002 The genome sequence of the malaria mosquito Anopheles
gambiae Science, 298:129‐49.
12 Butler, D. Drive for patent‐free innovation gathers pace 10 July 2003, 118 Nature vol.
424 (http://www.nature.com/nature).
13 Kaplan, WA. and Krimsky, S. 2001 Patentability of Biotechnology Inventions
Under The PTO Utility Guidelines: Still Uncertain After All These Years? J. Biolaw
& Business Supplement, 2001: 34‐48.
14 Madey v. Duke University, Fed. Cir. 2001 (Research exception to patent
infringement liability does not apply to research performed in universities)
(http//www.ll.georgetown.edu/federal/judicial/fed/opinions/01opinions/01‐
1567.html) accessed 5 October 2001. This case is being appealed to the US Supreme
Court.
15 SNP consortium website, Single Nucleotide Polymorphisms for Biomedical Research
(http://snp.cshl.org) accessed 4 October 2003.
16 SEMATECH website (http://www.sematech.org) accessed 4 September 2003.
17 Consumer Project on Technology: Compulsory Licensing
(http://www.cptech.org/ip/health/cl/cptech) accessed 6 October 2003.
18 Reichman, JH. and Hasenzahl, C. 2002 Non‐voluntary Licensing of Patented
Inventions: The Canadian Experience UNCTAD/ICTSD Capacity Building Project on
Intellectual Property Rights and Sustainable Development.
19 Blood Screening HIV Probe License Agreement Between Chiron Corporation F.
Hoffmann‐La Roche Ltd. and Roche Molecular Systems, Inc. Article 5
(http://lists.essential.org/pipermail/ip‐health/2002‐February/002709.html).

167


20 Clark, J. Piccolo, J. Stanton, B. Tyson, K. 2000 Patent Pools: A Solution to the Problem
of access in Biotechnology Patents?
(http://www.uspto.gov/web/offices/pac/dapp/opla/patentpool.pdf) U.S. Patent and
Trademark Office, Accessed October 10, 2003.
21 The Fourth Ministerial Conference, Doha, Qatar Meeting, World Trade
Organization, November 2001
(http://www.wto.org/english/thewto_e/minist_e/min01_e/min01_e.htm) accessed 3
September 2002.
22 The dispute over setting aside patents that limit cheap drug supplies became the
key issue. Particularly in light of Canada’s overriding the Bayer patent on
ciprofloxacin with regard to the anthrax bioterrorism scare in late 2001 and the U.S.
refusing to override the patent, certain developing countries were asking if there
was a double standard at work. In the United States, federal statutes under the
U.S Clean Air Act and the Atomic Energy Act, mandate compulsory licensing
under certain circumstances.
23 CAMBIA (http://www.cambia.org.au/main/ipwhy_inv.htm) access 12 November
2003.
24 February 2001 IP Clearinghouse Mechanisms for Agriculture
(http://www.farmfoundation.org/pubs2/berkeleyagbioworkshop.pdf) accessed 12
November 2003.
25 Looasreesuwon, S. Chuylay, JD. Canfield, CH. Hutchinson, DB. 1999 Malarone®
(atovaquone and proguanil (HCL): a review of its clinical development for treatment of
malaria Am. J. Trop. Med. Hyg. 60: 533‐54.
26 Report of the Workshop on Differential Pricing & Financing of Essential Drugs April
2001, Hosbjor, Norway, WHO/WTO Secretariat Workshop, Høbsjør, Norway,
(http://www.who.int/medicines/docs/par/equitable_pricing.doc) Background
papers to this conference
(http://www.wto.org/english/tratop_e/trips_e/wto_background_e.doc) Accesssed
15 November 2001.
168

Pharmaceutical development and quality assurance of FDCs
Pharmaceutical development and quality

assurance of FDCs
Susan Walters B Pharm PhD
Consultant and adjunct Associate
Professor Faculty of Medicine,
University of New South Wales
Abstract
Therapeutic outcomes depend in part on product quality. This paper
provides clinicians with a background to minimum quality standards.

Good results in clinical trials can be repeated only if subsequent batches
behave in the same way as those used in the trials. Consistent quality is
essential between and within batches. It is not desirable to find out via a
therapeutic failure that new batches of a product are of poor quality.

Key factors influencing quality include:
‐ Suitability of the formulation, including appropriate specifications
for the finished product, ingredients and the container
‐ A validated and controlled manufacturing procedure
‐ Stability under the conditions of storage and for the duration of
the claimed shelf life
‐ Good and consistent bioavailability

Preformulation studies based on scientific principles carry some cost but are
rewarded by
‐ Long term benefits for consistent quality and good patient
outcomes, and
‐ A much increased probability that the product will pass
regulatory hurdles.
Ongoing monitoring of product quality is essential, for example when new
field storage conditions are envisaged or when changes to the product are
inevitable following non‐availability of ingredients, containers, sites of
manufacture etc. Changes can alter product characteristics and must be
validated according to the nature of the change. Validation of major changes
may include new stability and/or bioavailability studies.

In general, the more complex a product, the more that can go wrong and
consequently the more effort must be put into specifying and controlling
169

ingredients, method of manufacture etc. Fixed‐dose combinations are more

complex than single entity products.

There is already considerable experience with formulation and manufacture
of FDCs and the problems that can arise for quality. New combinations are
under development, with the potential for new problems in product quality.
Without ongoing literature reviews, known problems may be repeated.

Recommendations at the end of this paper are intended to facilitate the
development and quality control of the FDCs that are the subject of this
meeting.
Introduction
The consequence for the patient of poor product quality can be therapeutic
failure or toxicity. Some examples follow.

Low potency:
‐ A WHO press release in November 2003 stated inter alia:
‐ ʺA recent WHO survey of the quality of antimalarials in seven African
countries revealed that between 20% and 90% of the products failed
quality testing. The antimalarials in question were chloroquine‐based
syrup and tablets, whose failure rate ranged from 23% to 38%; and
sulphadoxine/pyrimethamine tablets, up to 90% of which were found to
be below standard. The medicines were a mixture of locally produced and
imported productsʺ 1

‐ Therapeutic failures in the Amazonian region have been attributed at
least in part to poor and variable potency of antimalarial drugs 2 as
assessed by chemical assay.

‐ It has been suggested that suboptimal potencies observed in chloroquine
and amoxicillin products purchased in Nigeria are likely to be a factor in
the selection pressure for drug‐resistant organisms3.

‐ Samples of chloroquine, amoxicillin, tetracycline, co‐trimoxazole and
ampicillin‐cloxacillin taken in Nigeria and Thailand had lower than
expected potencies, and six samples of chloroquine had no detectable
potency4.

Method of manufacture:
‐ Variations in particle size, excipients or manufacturing process of the
experimental preparations or capsules produced a marked change in
bioavailability of rifampicin5.
‐ The order in which drugs were mixed during production had an
ʺalarmingʺ effect on bioavailability of rifampicin6.
170

‐ A change in the method of manufacture of carbamazepine tablets led to
intoxication in some patients7.

Excipients:
‐ Formation of non‐absorbable insoluble complexes between drugs and
excipients is known for tetracyclines and dicalcium phosphate,
amphetamine and sodium carboxymethylcellulose, and phenobarbitone
and polyethylene glycol 40008.
‐ Change of excipients in a formulation led to an outbreak of phenytoin
intoxication in an Australian city9.
‐ Use of an excipient without prior information on its toxicology led to an
outbreak of toxicity in Haiti10.

Impurities:
‐ Fever, tachycardia, hypotension and rigors occurring with once daily
dosing of gentamicin were attributed to impurities from a particular
supplier of the drug11.

Stability:
‐ Decomposition was the cause of a number (but not all) of the observed
low potencies of antimalarial and antibiotics in Nigeria and Thailand4.
‐ Fanconi syndrome has been known to result from consumption of
degraded tetracycline12,13
‐ Allergic reactions to penicillin are enhanced by formulations that
encourage polymerization and reactions with certain carbohydrates14.

Bioavailability
‐ Therapeutic failures due to poor bioavailability are well known, for
example to rifampicin15.
‐ Higher bioavailabilities of artemether and benflumetol were associated
with improved parasitic clearance time and 28 day cure rate respectively16
‐ Different brands of rifampicin have been shown to have different
bioavailabilities at the same dose17.
‐ The bioavailability of rifampicin is sometimes reduced when formulated
in an FDC, but the effect is inconsistent18,19,20,21,22
Preformulation studies
Once a formulation and method of manufacture have been developed, the
temptation is to proceed with this design even if stability and/or bioavailability
testing show that it is suboptimal. Probably at least a year will have passed by
the time bioavailability studies are completed and stability studies produce
meaningful long term results, during which time rival manufacturers will have
been developing their own products. So how can a manufacturer increase the
probability that a particular formulation will be successful in terms of consistent
quality and regulatory compliance? Answer ‐ by conducting a thorough review
of relevant scientific literature and by undertaking preformulation studies.
171


Systematic preformulation studies on the active pharmaceutical ingredient (API)
and on pilot formulations attempt to predict the viability of various formulations
and methods of manufacture.
So what exactly are preformulation studies?
Preformulation studies include studies of:
‐ The physicochemical properties of manufactured batches of the API, and
an assessment of their relevance to the final formulation
‐ The chemical and physical stability of the API
‐ The impurity profiles of the API, including the typical content of synthetic
by‐products and degradation products
‐ Chemical compatibility of the active with potential excipients
These studies give clues as to how to achieve the desired performance of the
finished product.
Even after developing a formulation and method of manufacture on these
principles, it is still necessary to confirm stability and bioavailability, but there is
a smaller probability that the formulation will fail. If two or three formulations
are developed in parallel, there is an even greater probability that one will be
successful. Whilst there are costs associated with preformulation studies, they
significantly minimize the risks of failure and increase the likelihood of
producing a high quality product.
Outcomes to be expected from preformulation studies
The expected outcomes are that the product:
Will deliver the drug to the site of action at the intended concentration.
Will meet product specifications, including limits for content of drug and
impurities, and suitable physicochemical tests such as dissolution rate,
particle size of suspensions etc.
Will be consistent from one dosage unit to another (eg tablet to tablet), from
batch to batch, and from one manufacturing site to another. That includes
consistent bioavailability.
Will be chemically and physically stable for a suitable time period under
convenient storage conditions. That is it continues to meet specifications.
Can be manufactured at a cost that is consistent with the price that will be
paid.
As far as is possible, will be acceptable to the patient in terms of convenience
and palatability.
Some specific benefits of conducting preformulation studies
Setting specifications for the API
With relevant in vitro information to hand, a manufacturer is in a better position
to establish appropriate specifications for batches of the API so as to ensure an
optimum and consistent performance for successive batches of the finished
product.

172

Minimising development costs
By optimising the formulation before commencing costly bioavailability and
bioequivalence studies, fewer such studies need be conducted.

Avoiding failures during long‐term stability
Failure after say 2 or 3 years of long‐term stability testing can set back a
registration program significantly. Sound predictions as to the chemical and
physicochemical stability of the active, and compatibility with excipients, other
actives and the container, can minimize such failures.

Minimizing the need for in vivo bioavailability/ bioequivalence studies
FDAʹs ground‐breaking development of the Biopharmaceutical Classification
System 23 has narrowed the range of products for which bioavailability/
bioequivalence studies must be conducted. In particular, BCS class 1 drugs can
now avoid (or obtain a waiver of) in vivo (bioequivalence) studies. In Australia
(and probably in other countries too), a drugʹs BCS classification is taken into
account when deciding whether or not a bioequivalence study is needed for a
new product or a change to an existing product24.

Biopharmaceutical classification involves determining:
1 The solubility of the active itself in aqueous media of various pH, and
2 The ability of the active to cross the gut wall (ʹgastrointestinal
permeabilityʹ).

The more recent advent of ʹbiorelevant dissolution mediaʹ in an attempt to better
predict in vivo dissolution rate has the potential to extend this waiver to BCS class
2 drugs. Dressman et al25,26developed a series of these media, with some success
in predicting the in vivo behaviour of different formulations of BCS Class II
drugs, and alteration of their bioavailability in the presence of food. With more
development, these studies may provide a means of optimizing formulations of
BCS Class 2 drugs without the need for bioavailability or bioequivalence studies.
As defined by Dressman et al, ʹbiorelevantʹ dissolution media are of biological
tonicity, pH and content of lecithin (mimicking bile salts). They attempt to
reproduce conditions in the human stomach or proximal intestine.

In addition, development of suitable assay procedures is critical at this stage,
both to ensure that the results of assay, stability and bioavailability and
bioequivalence testing are sound, and so as to ensure that results are credible at
the later (and critically important) regulatory stage. For the purposes of quality
control and stability testing, assays must be established for each active in the
presence of the others, thus requiring additional validation for specificity.
Validated and specific methodology is needed for assays of drugs in a biological
fluid, usually plasma. The presence of more than one drug complicates assays,
especially for bioavailability studies when multiple metabolites and sometimes
degradation products are also present.

173

Preliminary stability studies involve chemical, physicochemical and, when

necessary, microbiological tests.
Stability studies are sometimes thought of as concerning only chemical stability
but the stability of physicochemical and microbiological characteristics are also
important. These are some examples of non‐chemical characteristics that can
change on aging:
‐ Particle size of suspensions (often ʹdisproportionationʹ, that is big particles
get bigger and small particles get smaller)
‐ Polymorphic form of the active when the active is present in solid form,
eg in tablets, capsules, and suspensions
‐ Dissolution rate of solid dosage forms
‐ Preservative efficacy of multidose suspensions, both sterile and non‐
sterile

Failure to control the first three of these may compromise the rate and extent of
absorption of the active.

It probably goes without saying that in general stability is reduced at higher
temperature. For some drugs, stability is also reduced at high humidity.

An issue that occasionally rears it head is the acceptability of various excipients
in different regulatory jurisdictions. WHOʹs Manual for a Drug Regulatory
Authority discusses internationally available lists of acceptable excipients for
different routes of administration27. Many authorities are vague on this point,
and it is probably less of an issue in countries that do not have a strong DRA.
Some examples of the relevance of the properties of the API to product
formulation!
Solubility
‐ If water solubility is low, then the formulator will also examine:
‐ The effect of solubilising agents on solubility. Selection of the
optimum dissolution enhancer for a formulation can improve
dissolution rate
‐ The properties of solid dispersions of the drug. For example
Abbott Labs have published information on the properties of
ritonavir in solid dispersions28.
Formulation as soft gelatin capsules containing a fatty matrix is an
alternative for low dose actives.
pKa
pKa indicates how solubility will change with pH.

Polymorphic form
If polymorphs of the active exist, it is important to ensure that batches of the API
are always of the optimum polymorphic form. See below for more information
and a relevant example.

174

Bulk density
Hygroscopicity }
Flow properties } These properties are important in designing
Wettability / contact angles } a reliable manufacturing method
Compressibility )
Ability to maintain a static charge }

Taste/palatability ‐ Caution toxicity!

Stability
‐ The effect on the API of heat, light, moisture, oxidative conditions, and
altered pH
‐ Compatibility of the API with potential excipients

Polymorphic form
Polymorphism is the ability of a substance to exist as more than one type of
crystal, each crystal having a different internal arrangement of molecules. The
different types of crystal can have different physicochemical properties such as
melting point and, significantly for pharmaceuticals, the rate at which the
substance dissolves in a solvent. Because biological environments are aqueous in
nature, polymorphism is generally most relevant for drugs that have low water
solubility and for which bioavailability may dissolution‐limited.

During chemical synthesis, the conditions of final purification (usually
recrystallisation or slurrying) largely dictate the final polymorphic form. The
nature of the solvent and the rate and temperature of crystallisation are
particularly important. Once the most suitable polymorph has been identified,
purification conditions can be adjusted so as to produce it more reliably.

Some polymorphs are physically unstable and can metamorphose into another
polymorph, thus providing a mechanism by which the dissolution rate of a
finished product can change over time.

It is important to know the polymorphic forms in which a substance can exist, the
stability of each, and how they can be distinguished during quality control, in
order to ensure that the API (the raw material form of the drug) is always
presented for use in manufacture in the most suitable polymorphic form.

In 1998, soft gelatin capsules containing ritonavir were found to have a poor
dissolution rate and different to earlier batches 29 . Ritonavir has low water
solubility and manufacture of capsules involves initial dissolution in ethanol
followed by mixing with other excipients. Investigation showed that a hitherto
unknown polymorph of even lower solubility than the only one previously
known had formed in some batches of the capsule. Insidiously, once detected,
polymorph #2 spread to batches of the oral solution, which could no longer be
stored in a refrigerator without crystallising. The product was consequently
reformulated.
175

Good Manufacturing Practice (GMP)
Codes of GMP are now established internationally30,31,32 and are recognised as an
important means of controlling and improving pharmaceutical quality.
Regulatory authorities conduct audits (or inspections) of pharmaceutical
manufacturing premises within their jurisdiction and an ʹacceptableʹ rating is a
prerequisite to issue of a manufacturing licence. Authorities exchange
information in the form of certificates of acceptability for various types of
manufacturing, such as sterile products, solid oral dosage forms or APIs. Both
the Pharmaceutical Inspection Cooperation Scheme31 and the WHO Certification
Scheme33 exist to facilitate and promote such exchanges.

The underlying principles for GMP are these:
‐ Buildings used for manufacture must be suitable for the purpose.
‐ Staff must be qualified and experienced.
‐ There should be an effective system of quality assurance in place and
fully functioning.
‐ Documentation trails should exist and should be readily accessible.
Quality assurance systems include comprehensive standard operating
procedures and batch manufacturing instructions, which should be sufficiently
detailed to ensure that all batches are manufactured in exactly the same way and
result in a consistent product.
Issues that may arise in the formulation of FDCs that do not arise for
single entity products include:
‐ Possible chemical incompatibility between the drugs
‐At first manufacture
‐On aging
‐ Assay of multiple but similar components in a manner that is accurate,
precise and specific

In the case of blister products that contain multiple products, control of
manufacturing procedures must ensure that packs contain exactly what is
intended and that there are no mix‐ups. There is precedent for this type of
product in ʹsequentialʹ oral contraceptives for which a single blister can contain
up to four different types of tablet. Multiple containers in a single carton exist for
triple combination therapy of gastric ulcers.
Chemical compatibility of drugs with excipients and with each

other
Some interactions are predictable given a good knowledge of organic chemistry,
whilst others are not as obvious. If the nature of any interaction is known,
conditions of manufacture can be adjusted to as to minimise its occurrence.

176

Some known interactions in the group of drugs of interest at this meeting
include:
‐ Acid/base interactions. Sulphonamides are mildly acidic and can form
salts with bases. An interaction between sulfamethoxazole and
trimethoprim is known and has caused manufacturing problems for
combinations of these drugs. Stability problems could also result in the
form of altered dissolution rate on aging if a reaction occurs slowly. Other
such interactions could occur under certain conditions, for example
between sulfadoxine and pyrimethamine.
‐ Schiffʹs base formation occurs between primary amines and carbonyl‐
containing molecules. Flavouring agents commonly contain aldehydes
and ketones that can potentially react with primary amines such as
lamivudine, primoquine, trimethoprim and pyrimethamine.
‐ When the primary amine component of a hydrazine reacts with a
carbonyl group, the resulting compound is called a hydrazone. This
reaction is the basis of the reduced bioavailability of isoniazid in the
presence of food.

Consequently carbonyl‐containing excipients (such as reducing sugars and many
flavouring agents) are best avoided in the formulation of drugs that contain
primary amine and hydrazine moieties, including isoniazid, lamivudine,
primoquine, trimethoprim and pyrimethamine.
‐ The Maillard reaction and Amadori rearrangement have been proposed
in relation to pharmaceuticals, including fluoxetine34 but, at least in that
case, was not in practice a problem.
Changes to registered products (variations)
Ongoing monitoring of product quality is essential. A product does not stand
still; it changes over time. Not just in its stability, but in the materials and
processes that contribute to manufacture. Perhaps the manufacturing equipment
is replaced with something more modern? Or one of the ingredients is no longer
available from the same supplier. Or the old pack size is no longer economically
viable and marketing wants a pack that holds twice the quantity. Or storage
conditions in the field are more extreme than was envisaged. Or the
manufacturer wishes to extend the shelf life that was approved at first
registration. The sponsor must ensure that there is no change to quality, safety or
efficacy, including bioavailability. The key word here is validation. It must be
demonstrated that changes/variations do not lead to a reduction in quality, either
at batch release or on storage. Guidelines exist as to how to validate such
changes35,36,37.

In addition, random postmarket testing by regulatory authorities is intended to
(as we say in Australia) ʹkeep the bastards honestʹ. Targetted sampling is more
efficient when a history is available for the type of product or for the
manufacturer.
177

Quality control of FDCs
Whilst, in most jurisdictions, manufacturers are not obliged to use the test
methodology of the locally applicable pharmacopoeia, they do have to ensure
that their products will meet that standard. Consequently when a
pharmacopoeial monograph already exists for an FDC and its APIs, the task of
the regulator in assessing a dossier and testing samples is simplified. The absence
of monographs on a number of FDCs therefore means that regulatory agencies
must commit more resources to assessment and testing, including often scarce
technical skills.

Complexity of analyses increases with the number of active ingredients.
However todayʹs analytical procedures can cope provided they have been
suitably validated. High pressure liquid chromatography (HPLC) is commonly
the method of choice today, being relatively inexpensive and usually not
complex. Suitable equipment and columns are now widely available, although
this may be less true in developing countries. In relation to the International
Pharmacopoeia, the Essential Drugs and Medicines Policy team at WHO has
stated:
ʺWhenever possible, classical procedures are used in the analytical methods so
that the pharmacopoeia can be applied without the need for expensive equipment.
In addition, alternative methods have been introduced for use whenever a more
complex method is suggested.ʺ 38

Validation of HPLC methods is called system suitability testing. Contrary to
popular opinion, an HPLC method is not always specific for the target analyte.
Methods should be tested in the presence of known and likely contaminants, and
refined as necessary. Note also that a long retention time does not in itself
guarantee that an assay will separate the target analyte from related substances.

In an unpublished and confidential report to WHO, Wieniawski has reviewed
analytical specifications for the antiretroviral and antimalarial combination
products that were assessed during the WHO pilot project on drug procurement
and sourcing39. Some of the following comments address issued raised in that
report.
Availability of reference standards for quality control
To allow for variation in the conditions under which an analysis is conducted,
assay of a test sample is always conducted in parallel with an identical assay of a
standard reference substance that has a nominal 100% response. This is true for
assays of the active and of impurities in APIs and finished products, and during
dissolution studies. Assays of unknown impurities, or of impurities present in
very small proportions, are sometimes conducted without a reference standard
and these are termed semiquantitative assays.

Availability of reference standards is then an important factor in conducting
meaningful quality control. Reference standards are not available for all of the
178

actives under consideration at this meeting. Even when they are available, there
is often a substantial cost. For example, reference standards provided by the
United States Pharmacopeia can be at a significant cost because companies based
in the USA can afford those prices.
Specifications at batch release and throughout the shelf life

(ʹexpiryʹ limits)
Although many companies resist, DRAs should seek tighter limits at release than
at expiry, especially for drugs that show chemical or physicochemical instability.
This provides a margin of patient safety in the event of instability and
interlaboratory variation.
Monographs on individual APIs
It is preferable, but not an absolute requirement, that monographs on individual
APIs be available before a monograph is published on an FDC containing those
APIs. I do not believe that monographs on single component dosage forms need
be available prior to monographs on FDCs.

Impurities
A degree of contamination with impurities is an inevitable result of chemical
synthesis and, in some cases, instability of the active ingredient or interaction
with excipients. The responsibility of the regulator is to ensure that active
ingredients are as pure as is consistent with patient safety and the economic
viability of the product.

Wieniawski suggests39 that separate tests for impurities are not necessary because
limits can be incorporated into an HPLC assay procedure for the active. This may
often be true but only if the assay procedure has been validated for the impurities
in question. HPLC assays are often conducted with short retention times to allow
fast laboratory throughput and may not be capable in that form of separating and
quantifying (or semiquantifying) impurities.

It is not necessary to identify impurities or degradation products in active
ingredients and finished products if they are present below threshold
concentrations that depend on the daily dose of the active40,41.
Registration ʹpackagesʹ
Networks exist internationally amongst generic manufacturers for the sale of
complete registration ʹpackagesʹ. These comprise a complete registration dossier
including formulation, method of manufacture (with in‐process controls and
limits), quality control methodology and specifications, and the results of
stability and bioavailability studies. Whilst some adaptation may be necessary for
certain jurisdictions, the package is often acceptable to even relatively advanced
regulatory authorities.
179

WHO may wish to consider purchasing, or even commissioning, regulatory
packages for FDCs that could be made available free of charge in less well‐
resourced nations. The economics of such a strategy would have to be carefully
considered.
Recommendations
The following recommendations are intended to facilitate the development and
quality control of the FDCs that are the subject of this meeting. They are not
necessarily listed in order of priority.

Pharmaceutical development
1 Publish formulations and methods of manufacture for the FDCs in
question.
2 Consider the possibility of WHO purchasing a registration package for a
generic and making it publicly available. Such a package would include
inter alia formulation, method of manufacture (with in‐process controls
and limits), methods of QC testing and limits, stability data,
bioavailability data.
3 Publish preformulation information on the drugs in question, including
information on stability. The format of the series Analytical profiles of drugs
substances and excipients42 could serve as a model.
4 Determine whether the Biopharmaceutical Classification System3 can
reliably be applied to FDCs. If yes, then ascertain the GI permeability of of
the drugs in question.

Quality control
5 Develop and publish monographs on the individual APIs and finished
products in question where these do not already exist.
6 Ensure that reference standards are available for the drugs in question,
and at a price that is acceptable to the manufacturers and the regulatory
authorities involved.
References

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2 Petralanda I: Quality of antimalarial drugs and resistance to Plasmodium vivax in
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3 Taylor RB, Shakoor O, Behrens RH: Drug quality, a contributor to drug resistance?
Lancet 346(8967):p122, 1995
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Hospedales CJ, Lewis MJ, Schwartz B, Philen RM, St Victor S, Espindola J,
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14 Bungaard H: Pharmaceutical aspects of penicillin allergy: polymerization of
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Meer JWM, Burger D, Nelwan RHH: Low plasma concentrations of rifampicin in
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Disease 6(6):497‐502, 2002
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response of CGP 56697 (artemether + benflumetol) in malaria patients. British
Journal of Clinical Pharmacology 46(6): 553‐561, 1998
17 Garg SK, Chakrabarti A, Panigrahi D, Sharma M, Talwar P, Kumar N, Sharma PL:
Comparative bioavailability & in vitro antimicrobial activity of 2 different brands
of rifampicin. European Journal of Drug Metabolism & Pharmacokinetics 16(3):223‐229,
1991
18 Pillai G, Fourie PB, Padayatchi N, Onyebujoh PC, McIlleron H, Smith PJ, Gabriels
G: Recent bioequivalence studies on fixed‐dose combination anti‐tuberculosis drug
formulations available on the global market. International Journal of Tuberculosis &
Lung Disease 3(11):S309‐316,1999
19 Doshi BS, Bhate AD, Chauhan BL, Parkar TA, Kulkarni RD: Pharmacokinetic
interaction of oral rifampicin & isoniazid in normal subjects. Indian
Drugs 23(12):672‐676, 1986
20 Ellard GA, Ellard DR, Allen BW, Girling DJ, Nunn AJ, Seng‐Kee T, Tiong‐Har T,
Hin‐Kwong N, Siu‐Lun C: The bioavailability of isoniazid, rifampicin, and
pyrazinamide in two commercially available combined formulations designed for
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Disease 133: 1076‐1080, 1986
21 Panchagnula R, Kaur K, Singh I, Kaul CL: The WHO simplified study protocol in
practice: investigation of combined formulations supplied by the WHO.
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22 Gurumurthy P, Ramachandran G, Vijayalakshmi S, Hemanth Kumar AK,
Venkatesan P, Chandrasekaran V, Vjayasekaran V, Kumaraswami V, Prabhaker R:
Bioavailability of rifampicin, isoniazid & pyrazinamide in a triple drug formulation:
comparison of plasma & urine kinetics. International Journal of Tuberculosis & Lung
Disease 3(2):119‐125, 1999
23 FDA: Waiver of in vivo bioavailability & bioequivalence studies for immediate‐
release solid oral dosage forms based on a biopharmaceutics classification system,
in, 2000
24 McLachlan A: Personal communication
25 Dressman J, Reppas C: In vitro‐in vivo correlations for lipophilic, poorly water‐
soluble drugs. European Journal of Pharmaceutical Sciences 11:S73‐S80, 2000
26 Kostewicz E, Brauns U, Becker R, Dressman JB: Forecasting the oral absorption
behavior of poorly soluble weak bases using solubility & dissolution studies in
biorelevant media. Pharmaceutical Research 19:345‐349, 2002
27 WHO: Marketing authorization of pharmaceutical products with special reference
to multisource (generic) products: A manual for a drug regulatory authority, 1999
28 Law D (Abbott Laboratories): Physicochemical considerations in the preparation of
amorphous ritonavir‐poly(ethylene glycol) 8000 solid dispersions. Journal of
Pharmaceutical Sciences 90:1015‐1025, 2001
29 Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J: Ritonavir: An
extraordinary example of conformational polymorphism. Pharmaceutical Research
18:859‐866, 2001
30 WHO: Good Manufacturing Practices for pharmaceutical products: Main principles.
Annex 4 in WHO Technical Report Series No. 908, 2003
31 Pharmaceutical Inspection Cooperation Scheme: Guide to good manufacturing
practice for medicinal products. September 2003 (http://www.picscheme.org/docs)
32 The Commission of the European Communities: Medicinal products for human
and veterinary use; Good manufacturing practices. October 2003.
33 WHO: Guidelines for implementation of the WHO certification scheme on the
quality of pharmaceutical products moving in international commerce. Annex 10 in
WHO Expert committee on specifcation for pharmaceutical preparations, 34th report,
Geneva 1998
34 Wirth DD, Baertschi SW, Johnson RA, Maple SR, Miller MS, Hallenbeck DK, Gregg
SM: Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine.
Journal of Pharmaceutical Sciences 87:31‐39, 1998
35 Food & Drug Administration: Guidance for Industry, Changes to an Approved
Application for Specified Biotechnology and Specified Synthetic Biological
Products. FDA July 1997
36 Therapeutic Goods Administration: Changes which may be made to
Pharmaceutical Aspects of Drug Products without Prior Approval ( Self‐
Assessable Changes). Appendix 8 in Australian Guidelines for the Registration Of
Drugs: Volume 1, Prescription and other specified drug products. TGA 1994
37 European Commission: Chapter 5 ʹVariationsʹ. In Volume 2, Pharmaceutical
legislation : Notice to Applicants, Volume 2A ‐ Procedures for marketing authorisation.
Date unclear.
38 WHO (EDM): The International Pharmacopoeia, 2003
39 Wieniawski W: Review of analytical specifications used in quality evaluations of
antiretroviral and antimalarial combination products. WHO unpublished, 2003
40 ICH: Impurities in new drug substances (revised), http://www.ich.org, 2002
41 ICH: Impurities in new drug products (revised), www.ich.org, 2003
42 Various authors: Analytical profiles of drug substances & excipients, Academic Press,
Various dates of publication
182

Annotated agenda

WORLD HEALTH ORGANIZATION

ORGANISATION MONDIALE DE LA SANTE

FIXED-DOSE COMBINATIONS FOR HIV/AIDS, TUBERCULOSIS AND

MALARIA
Current status and future challenges from clinical, regulatory, intellectual
property and production perspectives
Salle A, WHO/HQ, Geneva 15-17 December 2003
Annotated agenda
Monday 15 December
09h00‐09h30 Opening session

09h30‐13h00 Experiences with Fixed‐dose Combinations
Objective This session provides an overview of experiences with the use of FDC
products for the treatment of TB, malaria and AIDS. The different papers
and presentations highlight the issues related to selection, production,
quality assurance, bioavailablity and stability. The issues of field research
on packaging and co‐blistering will provide practical examples of
attempts to address this delivery problem

09h30‐10h00 Fixed‐dose combinations for tuberculosis: lessons learned from a clinical,
production and regulatory perspective (R. Panchagnula)
Comments/Feedback
Bernard Fourie to comment

10h00‐10h30 Fixed‐dose combinations for malaria: translating clinical
recommendations to
product supply (Peter Olumese and Andrea Bosman)
Comments/Feedback
Clive Ondari to comment

10h30‐11h00 Discussions

11h00‐11h30 Coffee break

11h30‐12h00 Fixed‐dose combinations for HIV/AIDS: the pros and cons of experiences
to date (Sanjay Pujari)
Comments/Feedback
Joep Lange to comment
183


12h00‐12h30 Analysis of the impact of introduction on Fixed‐dose combinations on
supply management and security when compared with separate
dispensing and/orʺco‐blisteringʺ (Jane Masiga)
Comments/Feedback
Cécile Macé to comment on field experiences with FDCs and co‐blistered
products

12h30‐13h00 Discussion

13h00‐14h00 Lunch

14h00‐17h15 Public Health Needs for Fixed‐dose Combinations
Objective This session reviews the evidence available related to the value of FDC’s
in improving compliance and outcomes as well as the effect on the
emergence of antimicrobial resistance.

14h00‐14h30 Review of the evidence on better compliance and treatment outcomes
with Fixed‐dose combinations when compared with separate dispensing
and/or ʺco‐blisteringʺ (Jennie Connor)
Feedback/experience

14h30‐15h00 Review of the evidence on effect of fixed‐dose combinations on the
development of clinical resistance when compared with separate
dispensing and/or ʺco‐blisteringʺ (Warren Kaplan)
David Lee to comment on both papers


15h30‐15h45 Tea break

15h45‐16h15 Field research on packaging, co‐blistering; and experiences with other
combinations (Jane Kengeya Kayondo)
David Hoos to comment on the use of co‐blistering for the MTCT+ program

16h15‐16h45 Comparison of the product cost of Fixed‐dose combinations in
comparison with separate dispensing and/or ʺco‐blisteringʺ (Robert
Bwire)
Comments/Feedback
Yolanda Tayler to comment on cost and FDC procurement issues
Harvey Bale to comment on effect of tariffs and taxes on drug costs


18h00 Reception/Cocktail
Tuesday 16 December
09h00‐13h00 Public Health Priorities
Objective These three presentations in the morning are designed to lay out the
issues and experiences relating to the production, procurement, quality
assurance and use of ARV FDCs.
184

Annotated agenda
09h00‐09h30 Preferred fixed‐dose combinations of ARVs for first line use in HIV/AIDS
(Joseph Perriens/Marco Vitoria)
Comments/Feedback

09h30‐09h45 Clinical perspective from the field on dosing flexibility (Joep Lange)

09h45‐10h00 Clients perspective on Fixed‐dose combinations versus dosing flexibility

Bernard Pécoul to comment


Objective This session will highlight the experiences faced in bringing FDC anti
malarials to the stage of them being widely supported and promoted.
The process which was used of undertaking clinical trials to demonstrate
efficacy and additionality will be presented. The lessons learned about
dealing with regulatory hurdles will be highlighted.

11h30‐12h00 Additional fixed‐dose combinations for malaria (Piero Olliaro and Robert
Taylor)
Comments/Feedback
Andrea Bosman and Tom Kanyok to comment


13h00‐14h00 Lunch

14h00‐17h00 Intellectual Property Rights and Legal Options
Objective This session will address the legal and practical issues around patent
barriers. The first paper and discussion will focus on the issues, the
definitions and the options. The discussion will allow different
perspectives to be expressed. The second part of this session will be an
opportunity for members of industry to present the key results of the
meeting held the previous Friday in Washington DC.

14h00‐14h30 Legal options for overcoming patent barriers of fixed‐dose combinations
(Warren Kaplan)

14h30‐15h00 Discussion led by Richard Wilder
Ellen ʹt Hoen and Cecilia Oh to comment
Cynthia Cannady (WIPO) to comment

15h00‐15h45 Summary of Gates Foundation sponsored meeting on FDCs held in
Washington DC December 12th 2003 Panel Presentation and Discussion


Objective These two sessions will focus on country experiences around the
procurement of ARVs particularly FDC ARVs and also issues around TB
FDCs. This will be done from the perspective of the major UN
Pharmaceutical supplier and a major NGO responsible for both TB and
AIDS treatment programmes.
185

16h00‐16h15 Country level experience (Hanne Bak Pedersen)

16h15‐16h30 MSF’s experience in procuring ARVs. Lessons from the field (Bernard
Pécoul)


Wednesday 17 December
09h00‐13h00 Pharmaceutical Development and Quality Assurance and Regulatory

Requirements
Objective The sessions for the morning will all address the issues around
formulation and registration and regulation of FDCs. The first
presentation will outline the range of issues to be addressed in planning
to produce an FDC product. The next session will report on practical
experiences gained in producing FDCs from the perspective of a
manufacturer. Issues around prequalification assessments will be
presented by a regulator closely involved in this process. Thorny issues
around when clinical trials are needed to validate FDCs and which
comparators should be used for assessing bio availability will be
addressed.

09h00‐09h30 Development of Fixed‐dose combinations; pharmaceutical considerations
(Susan Walters)

09h30‐09h50 Product formulation of Fixed‐dose combinations; practical experiences
(Vinod Arora)



11h00‐11h30 Assessment Experiences with fixed‐dose combinations (ARVs and
Tuberculosis) (János Pogány)

11h30‐11h50 When are new clinical trials needed? (Leonard Sachs)

11h50‐12h10 What comparator products should be used for bioequivalence?
(Roger Williams)

Jérôme Barré to comment

13h00‐14h00 Lunch

14h00‐17h00 General Discussions

Objective The afternoon session will be devoted to synthesizing what has been
covered in the meeting, identifying areas of clear agreement, areas of
dispute that could be investigated further and areas where further work
is needed to clarify the issues. After the tea break a session will be held
for WHO staff to agree on conclusions and recommendations for WHO
actions.
186

Annotated agenda

14h00‐15h30 Discussion by all participants
Overview of main observations and recommendations for each of the
main subject areas


16h00‐17h00 Conclusions and recommendations for WHO actions
Note: This final session will be WHO staff members only.
Identification of next steps (action points, research priorities, etc.)
facilitated by Robert Ridley

187

188

List of participants

Mr. Vinod Arora Dr Nubia Boechat
Ranbaxy Pharmaceuticals Inc. Ministry of Health
19, Nehru Place Oswaldo Cruz Foundation
New Delhi Institute of Drug Technology
India Far-Manguinhos
+91 11 26452666-72 Rua Sizenando Nabuco, 100
+91 11 26002076 21041-250 Manguinhos
[email protected] Rio de Janeiro
Brazil
Dr Harvey E. Bale, Jr +55 21 3977-2454/2455
Director-General +55 21 2290-1297
International Federation of [email protected]
Pharmaceutical
Manufacturers Associations Mr Anthony F. Boni
PO Box 758 USAID/GH/HIDN/HSD
1211 Geneva 13 Pharmaceutical Management Advisor
022 338 32 00 Office of Health, Infectious Diseases and
022 338 32 99 Nutrition
[email protected] Room 3.07-073, 3rd floor, RRB
Washington, DC 20523-3700
Dr Jérôme Michel Barré USA
Head of the Pharmacology and +1 202 712 4789
Toxicology Unit +1 202 216 3702
Centre Hospitalier Intercommunal [email protected]
Service de Pharmacologie
40, avenue de Verdun Dr Robert Bwire
94010 Créteil Cedex Berkenboog 24
+33 1 45 17 53 80 5386 GC Geffen
+33 1 45 17 53 72 The Netherlands
+33 1 45 17 53 89 +31 735320418
[email protected] +31 735320418
[email protected]
Dr Jaydip Bhaduri
Lupin Limited Ms Cynthia Cannady
Medical Director Director
159, CST Road World Intellectual Property
Kalina, Santacruz (E) Organization
Mumbai 400 098, India Intellectual Property Policy and New
+91 22 56931001-10, Ext. 331 Technologies
+91 22 26526842 (direct) 34, chemin des Colombettes
+91 22 26526755 Geneva
+91 22 26540484 [email protected]
[email protected]
189

Mr Andrew Clark [email protected]

Director of Medical Affairs
Infectious Diseases and Immunology, Dr Bernard Fourie
Bristol Myers Squibb Company National TB Research Programme of the
Medical Research Council (MRC)
Dr Jennie Connor Programme Director
Senior Lecturer, Epidemiology 1 Soutpansberg Road
Section of Epidemiology and Private Bag X 385
Biostatistics 0001 Pretoria
School of Population Health South Africa
University of Auckland +27 12 325 5970
Private Bag 92019 [email protected]
Auckland
New Zealand Ms Isabelle Girault
+64 9 3737599 Ext. 84400 Director, HIV/AIDS
+64 9 3737494 External Relations
[email protected] Global Government Affairs & Public
Policy
Mr Robert Dintruff GlaxoSmithKline
Abbott International GSK Home CN10
Abbott Laboratories 980 Great West Road
Dept 06MQ Brentford
Building AP34-3 Middlesex TW8 9GS
Abbott Park, IL 60064-6189 United Kingdom
USA +44 20 8047 5488
+1 847 938 7945 +44 20 8047 6957
+1 847 938 8497 [email protected]
[email protected]
Mr Michiel de Goeje
Mr Jean-Pascal Ducret IDA Foundation
Director Pharmaceutical Advisor & GMP
Sanofi-Synthelabo Compliance
Impact Malaria QA Department
82, avenue Raspail PO Box 37098
94255 Gentilly Cedex 1030 AB Amsterdam
France The Netherlands
+33 1 41 24 65 11 +31 20 4033051
+33 6 86 16 11 82 +31 20 4031854
+33 1 41 24 61 24 [email protected]
Jean-Pascal.Ducret@sanofi-
synthelabo.com Dr Jaideep A Gogtay
Cipla Ltd
George Dunstan Mumbai Central
Merck & Co., Inc. Mumbai 400 008
One Merck Drive India
PO Box 100 +91 309 5521
Whitehouse Station, NJ 08889-0100 +91 308 2891
USA +91 414 9778 (res.)
+91 412 4359 (res.)
Dr Christopher J. Elias +91 22 23070013
President +91 22 307 0393
Path (Programme for Appropriate +91 22 307 0385
Technology in Health) [email protected]
1455 NW Leary Way
Seattle, WA 98107
USA
+1 206 285 3500
+1 205 285 6619
190

Mr William F. Haddad Dr Valérie Lameyre

Chairman/CEO Medical Manager
Biogenerics, Inc. Impact Malaria
Representing Cipla, Ltd (India) Sanofi-Synthelabo
120 Manor Road 82, avenue Raspail
Patterson, NY 12563 94255 Gentilly Cedex
USA France
+1 845 278 8800 +33 1 41 24 63 64
+1 845 878 3046 +33 6 74 44 78 08
+1 347 693 3322 +33 1 41 24 61 24
+1 845 878 8015 [email protected]
[email protected]
[email protected] Dr Joep M.A. Lange
Professor of Medicine
Mr Ton Hoek Chief Scientific Adviser
General Secretary International Antiviral Therapy
Fédération internationale Evaluation Center (IATEC BV).
pharmaceutique Meibergdreef 99
Andries Bickerweg 5 1105 AZ Amsterdam
2517 JP The Hague PO Box 22700
PO Box 84200 1100 DE Amsterdam
2508 AE The Hague The Netherlands
The Netherlands +31 20 566 75 37 (direct)
+31 70 3021870 +31 20 566 44 79
+31 70 3021972 (direct) +31 20 691 88 21
+31 620139954 [email protected]
[email protected]
Dr David Lee
Dr David Hoos Deputy Director
Assistant Professor of Clinical Technical Strategy and Quality
Epidemiology Center for Pharmaceutical Management
Mailman School of Public Health Management Sciences for Health, Inc.
Columbia University 4301 North Fairfax Drive, Suite 400
722 West 168th Street - Room 707 Arlington, VA 22203-1627
New York, NY 10032 USA
USA +1 703 524 6575
+1 212 342 0464 +1 703 248 1612 (direct)
+1 212 342 0412 +1 703 524 7898
[email protected] [email protected]
Mr Sandeep Juneja Ms Cécile Macé

HIV Project Head Pharmacist
Ranbaxy Laboratories Limited Médecins sans Frontières
Devika Tower Access to Essential Medicines
6, Nehru Place 8, rue Saint-Sabin
New Delhi - 110019 75544 Paris Cedex 11
India France
+91 11 26002120 (direct) +33 1 4021 2758
+91 11 26452666-72 Extn. 2621 +33 6 1404 5697
+91 11 26002121 +33 1 48066868
[email protected]
191

Mr Kevin Mak Dr Eric Noehrenberg

Holleykin Director
Chongqing Holley Holding Co. Ltd International Trade and Market Issues
12/F, Guangyu Building International Federation of
76 Jianxin North Road Pharmaceutical Manufacturers
Jiangbei District Associations (IFPMA)
Chongqing 30, rue de St-Jean
China 400020 PO Box 758
+86 23 67755788 1211 Geneva 13
[email protected] Switzerland
+41 22 338 32 00
Dr Lynn Marks +41 22 338 32 99
GlaxoSmithKline e.noehrenberg@ifpma@org
Philadelphia, PA
USA Dr Ramesh Panchagnula
+1 610 917 5011 National Institute of Pharmaceutical
[email protected] Education and Research (NIPER)
Head of the Department of
Ms Jane E.N. Masiga Pharmaceutics
Head of Operations Sector 67
Mission for Essential Drugs & Supplies S.A.S. Nagar - 160 062
(MEDS) Punjab
PO Box 78040 India
Viwandani +91 172 2214 682/685
00507 Nairobi +91 9815901875
Kenya +91 172 2214692
+254 20 551642
+254 20 551653 Dr Atul K Patel
+254 734 600310 Chief: Department of Infectious Diseases
+254 722 202106 Sterling Hospital & ID Clinic
+254 20 556632 Adit Medical Centre
+254 20 556635 Navrangpura
[email protected] Ahmedabad-380 009
[email protected] Gujarat
India
Dr John B. Morris +91 79 644 0816 (clinic)
Associate Director, CMC Project +91 79 685 0708 (residence)
Global Pharmaceutical Research and +91 79 644 0816
Development [email protected]
Abbott Laboratories
Dpt. R4R1, Bldg. R13-4 Ms Mariclaire T Payawal
1401 Sheridan Road Senior Director
North Chicago, IL 60064-6290 Global Access Program
USA Bristol-Myers Squibb Company
+1 847 938 4996 Corporate Policy
+1 847 935 8000 PO Box 4000
[email protected] Princeton, NJ 08543
USA
+1 609 252 4469
+1 609 456 8337
+1 609 252 7356
[email protected]
192

Mr Bernard Pécoul Dr Sanjay Pujari

Médecins sans frontières Director HIV Unit
78, rue de Lausanne Ruby Hall Clinic
PO Box 116 2, Jai Bhagirathi Apts.
1211 Geneva 21 881/B, Sadashiv Peth
Switzerland Pune 411030
+41 22 849 84 84 India
022 849 8488 +91 9822058985

Mrs Hanne Bak Pedersen Mr Rudy van Puymbroeck
UNICEF The World Bank
UNICEF Plads Procurement Policy and Service Group,
2100 Copenhagen OE OPCS VP
Denmark Global HIV-AIDS Program, HDN
+45 35 27 30 60 1818 H Street N.W.
+45 35 26 94 21 Room G8-135 MSN G8-802
[email protected] Washington
USA
Mr Greg Perry
International Generic Producers Dr Françoise Renaud-Théry
Alliance (IGPA) Care & Support Network Adviser,
PO Box 193 SIF/SMI, UNAIDS
B-1040 Brussels 4 20, avenue Appia
Belgium 1211 Geneva 27
+32 2 736 8411 Switzerland
+32 2 736 7438 022 791 36 66
[email protected] 022 791.41 87
[email protected]
Mr Laurence Phillips
Head of Customer Group HIV- Dr Renee Ridzon
Specialist/Virologist Senior Program Officer
Boehringer Ingelheim GmbH Bill & Melinda Gates Foundation
55216 Ingelheim am Rhein HIV, TB & Reproductive Health
Germany 1551 Eastlake Avenue
+49 6132 77 2081 Seattle, Washington 98102
+49 6132 77 3829 USA
[email protected] +1 202 709 3383
ingelheim.com +1 202 709 3170
[email protected]
Dr János Pogány
Consivers Consulting & Translation Dr Lise Riopel
Group Scientific Officer
Sasadi út 140 Medicines for Malaria Venture
H-1112 Budapest International Center Cointrin
Hungary Block G, 3rd Floor
+361 246 3341 Route de Pré-Bois 20
+361 246 3341 PO Box 1826
[email protected] 1215 Geneva 15
Switzerland
+41 22 799 4070
+41 22 799 4061
[email protected]
193

Dr Reeta Roy Mr Chang-Sik Shin

Divisional Vice President Director
Global Citizenship and Policy R&D Department
Abbott Laboratories Shin Poong Pharm. Co. Ltd
Dept. 0383 772, Yoksam-Dong, Kangnam-Ku
Bldg. AP6D Seoul
100 Abbott Park Road Korea
Abbott Park +82 2 553 0241-5
IL 60064-6048 +82 2 557 4372
USA [email protected]
+1 847 936 0645
+1 847 937 9555 Dr Anthony So
[email protected] Associate Director, Health Equity
The Rockfeller Foundation
Dr Leonard Sacks 420 Fifth Avenue
Medical Officer New York, NY 10018-2702
U.S. Food and Drug Administration USA
Division of Special Pathogens and +1 212 852 8340
Immunologic Drug Products +1 212 852 8279
5600 Fishers Lane, HFD 590 [email protected]
Rockville MD 20857
USA Mr Robert Staley
+1 301 827-2336 Principal Program Associate
+1 301 827 2475 Management Sciences for Health
[email protected] Center for Pharmaceutical Management
Mangement Sciences for Health, Inc.
Dr Himadri Sen 4301 North Fairfax Drive, Suite 400
President Arlington, Virginia 22203
Pharma Research & Regulatory Affairs USA
Lupin Limited +1 703 524 6575
46A/47A, Nande Village +1 703 248 1602 (direct)
Mulshi Taluka +1 703 524 7898
Pune 411 042 [email protected]
India
+91 20 512 6690 Mr David Stanton
+91 20 512 6451 Global AIDS Coordinator Planning Task
+91 20 512 6161/9 Force (S/GAC)
+91 98230 20111 Room 1004, Harry S Truman Building
+91 98230 38402 U.S. Department of State
[email protected] Washington, D.C. 20520
USA
Mr Dilip Shah + 1 202 647 1145
Secretary General +1 202 647 5792
The Indian Pharmaceutical Alliance [email protected]
Vision Consulting Group
201 Darvesh Chambers Mr Joe Steele
2473 P.D. Hinduja Road Vice President
Khar, Mumbai 400 052 Commercial Development
India Gilead Sciences, Inc.
+91 2226 00 0632 333 Lakeside Drive
+91 2226 00 0633 Foster City, CA 94404
[email protected] USA
+1 650 522 5740
+1 650 504 5375
+1 650 522 5696
[email protected]
194

Mr Jeffrey Sturchio Ms Maria Vigneau

Vice President, External Affairs Director, External Relations HIV/AIDS
Europe, Middle East & Africa F. Hoffmann-La Roche Ltd
Human Health Pharmaceuticals Division
Merck & Co., Inc. Pharma International
One Merck Drive Bldg 071/316
PO Box 100 4070 Basel
Whitehouse Station, NJ 08889-0100 Switzerland
USA +41 61 688 92 91
+1 908 423 3981 +41 79 506 99 41
+1 908 735 1704 +41 61 688 27 78

Ms Yolanda Tayler Dr Susan Walters
The World Bank Consultant
Procurement Policy and Service Group, 10 Maria Place
OPCS VP Lyons - ACT 2606
Global HIV-AIDS Program, HDN Australia
1818 H Street N.W. +61 2 6281 6948
Room G8-135 MSN G8-802 +61 2 6281 6948
Washington [email protected]
USA
+1 202 473 0810 Mr Witold Wieniawski
+1 202 522 3317/3235 Polish Pharmaceutical Society
[email protected] Dluga Street 16
00-283 Warsaw
Ms Ellen F.M. t'Hoen Poland
Médecins sans frontières +48 22 842 09 31
Access to Essential Medicines Campaign [email protected]
8, rue Saint-Sabin
75544 Paris cedex 11 Mr Richard Wilder
France Consultant IPR
+33 1 4021 2836 Sidley, Austin, Brown & Wood
+33 6 22375871 1501 K Street, N.W.
+33 1 40212962 Washington, D.C. 20005
+1 202 736 8017
Mrs Trix Janet Tuin +1 202 736 8711
Pharmacist, Medical Export Group BV [email protected]
Manager Quality Assurance
Papland 16 Dr Roger L. Williams
PO Box 598 Executive Vice President and
4200 AN Gorinchem Chief Executive Officer
The Netherlands The United States Pharmacopeia
+31 183 356 130 12601 Twinbrook Parkway
+31 183 356 131 Rockville, MD 20852-1790
+1 301 816 8300
+1 301 816 8299
[email protected]
195

WHO secretariat
Dr Jim Yong Kim Dr Warren Kaplan (Rapporteur)
Adviser to the Director-General Policy, Access and Rational Use,
x13910 EDM/PAR
[email protected] x12436
[email protected]
Dr Vladimir K. Lepakhin
Assistant Director-General Dr Richard Laing (Secretary)
Health Technology and Pharmaceuticals Policy, Access and Rational Use,
(HTP) EDM/PAR
x14417 x14533
Dr Jack Chow Ms Cecilia Oh

Assistant Director-General Drug Action Programme, EDM/DAP
HIV/AIDS TB and Malaria x11547
x13800 [email protected]
[email protected]
Dr Clive Ondari
Dr Jonathan D. Quick Policy, Access and Rational Use,
Director EDM/PAR
Essential Drugs and Medicines Policy x13676/12902
(EDM) [email protected]
x 14443/13834
[email protected] Mr Adriaan van Zyl
Quality Assurance & Safety, EDM/QSM
Dr H.V. Hogerzeil x13598/13527
Coordinator [email protected]
Policy, Access and Rational Use,
EDM/PAR Dr Sabine Kopp
x13528/14318 Quality Assurance & Safety, EDM/QSM
[email protected] 13636/13642
[email protected]
Dr Lembit Rägo
Coordinator Dr Pascale Vanbel
Quality Assurance & Safety, EDM/QSM Quality Assurance & Safety, EDM/QSM
x14420/12657 x13669/13642
Mr Peter Graaff Mr Olivier Gross

Policy, Access and Rational Use, Quality Assurance & Safety, EDM/QSM
EDM/PAR x14805
[email protected]
Ms Ivana Tasevska
Mr Rajesh Gupta Quality Assurance & Safety, EDM/QSM
Director General Office x13717
[email protected]
196

Other WHO sections

Dr Virginia Arnold Dr Philip C. Onyebujoh
Stop TB UNDP/World Bank/WHO Special
x12399 Programme for Research and Training
[email protected] in Tropical Diseases
x14478
Dr Mohammed Akhtar [email protected]
Stop TB
x11895 Dr Joseph Perriens
[email protected] Director, HIV/CRE
Dr Yevgeny Goryakin x14456/13477
Stop TB [email protected]
x11278
[email protected] Dr Robert G. Ridley
Coordinator
Dr Ernesto Jaramillo Product Research and Development
Stop TB x13767/13778
x13034/14650 [email protected]
[email protected]
Dr Allan Schapira
Dr Fabienne Jouberton Roll Back Malaria
Stop TB x11864/13419
[email protected]
Dr Kenji Tamura
Dr Thomas Kanyok (Rapporteur) HIV/CRE
UNDP/World Bank/WHO Special x11641
Programme for Research and Training [email protected]
in Tropical Diseases
x13684 Dr Walter R.J. Taylor
[email protected] Product Research and Development,
TDR/PRD
Dr Kayondo J.F. Kengeya x13853
UNDP/World Bank/WHO Special [email protected]
Programme for Research and Training
in Tropical Diseases Dr Paulo Teixeira
x13737 Director, HIV/AIDS
[email protected]
Dr Robert H. Matiru
Stop TB Dr Marco Vitoria
x13971 HIV/CRE
[email protected]
Dr Stéphanie Meredith
IMD/BLT Dr Hugo Vrakking
x12070 Stop TB
Dr Peter Olumese x14267
Roll Back Malaria [email protected]
x14424
[email protected]

197

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Please go to the Table of Contents page to access the entire publication.

Annotated agenda ..................................................................................................................... 183

List of participants .................................................................................................................... 189

The overall objectives of treatment for HIV/AIDS, malaria and

1. Safe, effective, quality treatment of three major communicable diseases,

6. In practice, pharmaceutical companies have routinely developed and

6. Monitoring outcomes of the programmes in health‐care systems is

1. WHO treatment guidelines provide indications of desirable FDCs and

1. For HIV/AIDS, WHO‐recommended combinations involve one or more

9. In addition to the WHO Prequalification Project, quality specifications

1. Improved medicines quality requires substantial political commitment

Hanne Bak Pedersen (UNICEF, Copenhagen) presented the experiences of

permeability), some APIs will require more complex formulations (reduced

ranges, as regulatory authorities have sometimes noted. For some

Fixed-dose combinations for

The TB treatment regimens given above have standard codes.

Directly observed treatment short‐course (DOTS) – an effective

novel mechanisms of action such as PA‐824, isocitrate‐lyase inhibitors,

Figure 1. Percentage of FDCs in the USA for different therapeutic classes

Upper dose limit Lower dose limit & Ideal dose

Dose (mg) (mg)

Patient Intensive Phase Continuation Phase

FDCs precludes monotherapy, forms a persuasive argument for using these

Distributio • Diffusion coefficient

bioavailability studies is costly, WHO and IUATLD developed a simplified,

BE [22] Not BE [12] BE [5] Not BE [7] BE [6] Not BE [9]

Rationale for biopharmaceutic and pharmacokinetic studies of

absorption, dissolution and dose, described by Absorption number (An),

Product costs of fixed-dose combination

Drug Strength 2002 unit price No. of tablets

H 300 R 150 R 300 Z 400 E 400

Figure 2: Pricing trend for intensive phase treatment w ith single-drug

Single-drug 4-drug FDC

* Samples were judged to have “failed” if

Given the potential of artemether/lumefantrine (Coartem®) as a fixed‐dose

While the prequalification and sourcing project for artemisinin‐based

Developing combinations of drugs for

Safety and long-term effectiveness of

Highly active antiretroviral therapy (HAART) has changed dramatically the

Figure 1: Box plot of CD4 response over time

CD4-0 CD4-3 CD4-6 CD4-9 CD4-12 CD4-15 CD4-18 CD4-21 CD4-24

Although this was a non‐comparative study, mortality amongst patients taking

Effect of introduction of fixed-dose

Effect of fixed-dose combination (FDC)

Low adherence to prescribed self‐administered medication is well documented

Trial Intervention Clinical outcomes Adherence Comments

Effect of fixed-dose combination (FDC)

Micro‐organisms have several strategies (some used simultaneously) to resist

In Mycobacterium tuberculosis complex members, single nucleic acid changes can

acquired immune response). Indeed, some have suggested25 that these

increased patientsʹ compliance, compared with traditional means of

Comparison Tuberculosis HIV Malaria

Comparison Tuberculosis HIV Malaria

Comparison Tuberculosis HIV Malaria

“mixed” THREE COMPONENT ZT+nevirapine vs. AZT+ddI vs. ARTESUNATE‐SULFADOXINE‐

Fixed-dose combination (FDC) drugs

“clearinghouses” specifically for IP related to fixed‐dose combination drugs.

Garrett Hardin’s “tragedy of the commons” 2 conceptualized resource

Botswana 38.80 Nevirapine, lamivudine +++