REVIEW ARTICLE

Am. J. PharmTech Res. 2012; 2(3)

ISSN: 2249-3387

Journal home page: http://www.ajptr.com/

Drug Regulatory Bodies: Key Role Players in Different Regions

Kamaljit Singh Sandhe1, 2, Vikas Kumar Bhambhu2, Saahil Arora2, RSR Murthy2
1. Global Institute of Regulatory Affairs, Pune.
2. ISF college of Pharmacy, Moga (PUNJAB), India

ABSTRACT
Drug regulation is totality of all measures- Legal, administrative and technical- which the
governments take to assure the quality, efficacy and safety of drugs. With reports of number of
tragic adverse events caused by use of drugs, more stringent controls have been imposed upon
the procedures for marketing authorization of drugs. The research and development,
manufacture, import and export of pharmaceuticals is regulated by different regulatory bodies in
different countries with varying levels of regulation stickiness. This review article provides
useful information regarding the regulatory framework and Pharmaceutical key role players in
many countries which are actively engaged in licensing and approval activities.
Key Words: Drug regulation, Drug registration, Drug Approval, EMEA, Pharmaceuticals,
USFDA.

*Corresponding Author Email: [email protected]

Received 14 March 2012, Accepted 26 April 2012
Please cite this article in press as: Sandhe KS et al., Drug Regulatory Bodies: Key Role Players in
Different Regions. American Journal of PharmTech Research 2012.

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INTRODUCTION
The field of Drug regulatory science, both pharmaceutical and biopharmaceutical is emerging
rapidly. The drug regulatory authorities as well as evaluation agencies either governmental or
private are widening their vision emphasizing more and more on delivering the public with drug
products of high quality, efficacy and safety. A range of regulatory agency and industry
initiatives, including better quality dossiers, has contributed to improving the licensing dossier
review process both for biopharmaceuticals and for pharmaceuticals1. Regulations and derived
procedures have increased globally and this can be partly explained by the great progress of
science in the last 10 years2. Before a drug product is marketed, drug reviewers in regulatory
agencies need to apply review science to thoroughly evaluate whether the research results
support the safety, effectiveness and quality control of the new drug product. Apart from this, as
science is progressing, the existing regulations are also being constantly adapted as well as
updated. They aim to contribute an environment where decisions about the benefits and risks of
medicines are made in a scientically robust and transparent way to serve patients. Evaluating
the safety of prescription drugs prior to approval and monitoring their safety once they have been
marketed is a major priority in any drug regulatory system.
The level of regulations varies significantly in different countries. The developed countries have
set up stringent laws and regulations governing the flow of pharmaceuticals within their
territories while developing countries offer a level of relaxation to back their domestic market
and encourage pharmaceutical growth. In poorer countries regulatory capture is prevalent as
government has little capacity3 No doubt such countries also keep their vision open for moving
parallel to the way by updating their existing system of evaluation and approvals. Same thing is
true with reference to type of medicinal products too. The nonprescription products do not need
to be subject to the same extent of regulation as new prescription medicines at the point of
registration (marketing authorization) or in ongoing usage. The regulatory philosophy for
biopharmaceuticals has differed from that for synthetic organic drugs, because of special
concerns over biological contaminants, process variability, biological assays and preclinical
testing limitations. But with the advancement in analytical and purification technology have now
started to challenge this difference4. In case of cancer vaccine (CaVs) no guidance document or
regulation exists that specifically covers CaVs5. CHMP and WHO guidelines on vaccines
emphasis that cancer vaccines that are not intended for the treatment of infectious diseases and
monoclonal antibodies (mAbs) used as immunogens are not considered within the vaccine
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guidance. The recommendations laid down in these documents may nevertheless be considered
as relevant for the development of CaVs6.
Reporting of ADRs and responding to the same for the safety of patients is one of the most
concerned duties of regulatory bodies. Such drugs usually need to be thoroughly reinvestigation
or withdrawn from market. New Zealand has the highest rate of reporting of ADRs in the world,
due to a variety of methods, including the feedback that it provides to individuals filing reports
and outreach strategies to emphasize the importance of reporting ADRs7. Internet is one of the
best players in drug safety issues. Web sites are the most active media for drug label changes and
warnings, and are used as well for conducting nationwide questionnaire surveys on drug safety
surveillance. The Ryan Haight Online Pharmacy Consumer Protection Act passed by Congress
in 2008, amends the Controlled Substances Act to prohibit the delivery, distribution, or
dispensing of a controlled substance that is a prescription drug over the Internet without a valid
prescription.
The regulations to control the purchases by internet are also an area of consideration. The
harmonization of regulation is emerging area providing more encouragement for industries.
International harmonization such as ICH as well as regional harmonization such as ASEAN
regulations demonstrates the cooperation and willingness of new world for providing the public
best medical care. Many countries regulate the price that consumers pay for pharmaceuticals.
The regulated price is normally well below the market price8. Even it has been observed that
countries with strict price regulation (France, Italy, and Japan) have lower prices than the less
regulated markets of the United States and the United Kingdom9.
International Conference on Harmonization of Technical Requirements for the Registration of
Pharmaceuticals for Human Use (ICH) is a collaborative initiative between the EU, Japan and
the United States with observers from WHO, EFTA (European free trade area) and Canada. ICH
harmonization focuses primarily on technical requirements for new, innovative medicines.
However, countries with limited resources are mostly generic markets and may have difficulties
of

implementing

numerous

sophisticated

ICH

standards.

Pharmaceutical

regulatory

harmonization facilitates the availability of safe, effective and good quality pharmaceuticals.
World Health Organization (WHO) supports harmonization on national, regional, inter-regional
and international levels10. WHOs role in drug regulation is fourfold. First, issuing the necessary
norms and standards through its Expert Committees. Second, supporting regulatory capacity
building leading to implementation of drug regulation on national level and its harmonization on
regional and Global level. Third, in selected areas of essential products, ensuring the quality,
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safety and efficacy of limited high public health value essential medicines and vaccines through
prequalification. Fourth, WHO plays a very important role in facilitating exchange of regulatory
information 11.
1. US-FDA:
The year 2006 marked the 100th anniversary of FDA which is regarded as worlds most
influential regulatory agency in the world. In the US, drugs are regulated by the Food and Drug
Administration (FDA). Every new drug must receive marketing approval from the FDA prior to
commercialization. The US drug approval process is considered to be one of the most stringent
in the world. From the perspective of all consumers, the U.S. constitutes about 40 percent of the
world pharmaceutical market. As a result, its pricing and regulatory policies materially influence
world demand and hence the incentives of pharmaceutical firms to innovate 12. The development
and evolution of US-FDA was not smooth, rather various public health crisis and tragedies
which took place in past century forced the governments to built strong laws and respective
amendments in FDA regulations and setting stringent criteria as well as requirements for moving
products in market.
In 1862 Abraham Lincoln appointed a chemist Charles M. Wetherill to the Department of
Agriculture for detection of food adulterants. Other agricultural chemists also hired to form
division of chemistry. In 1901 the Division of Chemistry was renamed as Bureau of Chemistry.
The administration of Pure Food and Drug Act was charged to Bureau of Chemistry which was
reorganized in two entities in 1927 and the regulatory function became the responsibility of
Food, Drug and Insecticide Administration (FDIA). In 1930 this name was shortened to Food
and Drug administration (FDA). Walter G. Campbell was the first commissioner of agency under
the name FDIA and FDA13. Food Drug and Cosmetic Act was passed in 1938 after the
occurrence of Elixir sulfonamide crisis14. Until this point FDA had been under Department of
Agriculture. It was in 1940 when the agency was moved to new federal security agency. In 1953
it was transferred to Department of Health Education and Welfare (HEW). It became part of
Public Health Services within the HEW. In 1980 the education functions from HEW and rename
it as Department of Health and Human Resources. FDA was officially established in 1988 as
agency of US Department of Health and Human Services15.
FDA needs to establish rules and guidance to fulfill its mission. Rules implement the statute and
are enforceable. The final rule is published in the federal register and becomes the part of the
Code of Federal Regulations (CFR). Guidance is the less formal document that explains the
FDAs current interpretation of policies as well as various issues.
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FDA is organized into 8 centers each having assigned responsibilities and functions 15:
1: CDER (Center for Drugs Evaluation and Research) is mainly concerned with safety and
effectiveness of prescription and OTC drugs.
2: CBER (Center for Biologics Evaluation and Research) evaluates the biotechnological and
biologics including Blood products, vaccines, Protein based products, Xeno-transplantation,
transgenic plants and animals, genomics, proteomics and bioinformatics. 1986 Childhood
Vaccine Act was result of CBER work.
3: Center for food safety and applied nutrition (CFSAN) have the responsibility to evaluate
safety of food consumed within US. It Enforces the 1994 Dietary and Supplemental Health and
Education Act. The Regulations are not as close as Food, Drug, and Cosmetic Act.
4: Center for Devices and Radiological Health.
5: Center for veterinary medicines is engaged in evaluating the safety of food as well as drugs
used for animals.
6: National center for toxicological research keep check on toxicity and contamination of drugs,
pharmaceuticals and food. It also keeps an account on terrorism biomarkers.
7: Office of Commissioner.
8: Office of Regulatory Affair.
The FDA has jurisdiction over administration of regulation and approval of drug products. For
evaluation and approval of drugs, sponsors are required to submit the FDA substantial evidence
of effectiveness and safety accumulated from adequate and well controlled clinical trials16. The
process starts with preclinical testing. First drug sponsor submits an IND containing data from
animal studies to the agency. Then FDA decides whether it is reasonably safe to move forward
with testing the drug on humans. Unless otherwise notified, the sponsor may begin to investigate
the drug 30 days after the FDA has received the application. If IND proves successful, the
sponsor ordinarily submits an NDA. If an IND is withdrawn because of a safety reason, the
sponsor shall promptly inform the FDA, all investigators, and all reviewing IRBs with the
reasons for the withdrawal. A terminated IND is subject to reinstatement based on additional
submissions that eliminate such risk. The pre-NDA period, just before a new drug application
(NDA) is submitted there is a common time for the FDA and drug sponsors to meet. Phase 3 is
the final step before submitting a new drug application (NDA) to the FDA. If a drug survives the
clinical trials, an NDA is submitted to the FDA. An NDA contains all the preclinical and clinical
information obtained during the testing phase. The application contains information on the
chemical makeup and manufacturing process, pharmacology and toxicity of the compound,
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human pharmacokinetics, results of the clinical trials, and proposed labeling 15, 16, 17. When an
NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. In
accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's Center for Drug
Evaluation and Research (CDER) expects to review and act on at least 90 percent of NDAs for
standard drugs no later than 10 months after the applications were received. From analyses of
the data, CDER reviewers assess the benefit to risk relationship. The review division and office
director may decide to convene an advisory committee meeting to seek the advice of external
experts. The FDA reviews information that goes on a drug's professional labeling, guidance on
how to use the drug. The FDA inspects the facilities where the drug will be manufactured as part
of the approval process. Overall, this entire process, on average, takes between 8 to 12 years 17.
Phase 4 studies, or post-marketing studies, are conducted after a product is approved.
Hatch-Waxman Drug Price Competition and Patent Term Restoration Act of 1984 established
the Abbreviated New Drug Application (ANDA) pathway that required only establishing
bioequivalence with the reference drug (eliminating the need to establish safety and efficacy
anew) and compliance with Good Manufacturing Practices15,18. The FDA has two other
mechanisms to facilitate the development of treatments for serious and life-threatening
conditions: accelerated approval, implemented in 1993 and codified in the FDA Modernization
Act of 1997, and fast track, which is a provision of the Act. A treatment with a significant benefit
over existing therapies may receive accelerated approval based on its effect on a surrogate
endpoint or an endpoint other than survival or morbidity, or it can be approved with restrictions
to promote safe use. Therapies that receive fast track approval are those with the potential to treat
patients with serious or life-threatening disorders whose needs are not presently being met 19,27.
FDA approved rofecoxib which was withdrawn from the market in 2004 after the reports of
Heart attack and strokes. It was estimated that it was linked with about 88,000 such cases 22.
2. EUROPEAN UNION:
In the EU, due to the Single European Market legislation, the European Medicines Evaluation
Agency (EMEA) has the power to centrally approve medicines, with one single license 28.
The European medicines evaluation agency is purely concerned for scientific evaluation of
medicines intended to be used in EU29. The Agency gives scientific advice and other assistance
to companies for the development of new medicines. It publishes guidelines on quality-, safetyand efficacy-testing requirements. The medicines that fall within the scope of the centralised
procedure are evaluated by agency but in case of any kind of disagreement between member
states regarding authorization of medicine, they can refer those medicines to EMEA for
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evaluation. Another fact is very much true that agency is not involved in any kind of research,
medicine development or in establishing ethical codes.
The eligibility and requirements are set in the commission regulation (EC) No 726/2004 and
defined in the Article 8 and 10 are of the Directive 2001/83/EC. The article 8(3) is for full
applications whereas Article 10 is for other kind of applications as listed follow 29:
Article 10(1)
Generic
Article 10(a)
Bibliographic
Article 10(b)
Fixed combo
Article 10(3) Hybrid
Article 10(4)
Biosimilars
The scientific committees are responsible for the scientific evaluation of marketingauthorisation application dossiers submitted by pharmaceutical companies. There are 6 scientific
committees the professionals of which are nominated from member states 30. The committees are
as follow:
Committee for Medicinal Products for Human Use (CHMP)
Committee for Medicinal Products for Veterinary Use (CVMP)
Committee for Orphan Medicinal Products (COMP)
Committee on Herbal Medicinal Products (HMPC)
Paediatric Committee (PDCO)
Committee for Advanced Therapies (CAT)
Procedures for conducting environmental risk assessment (ERA) on pharmaceuticals are in effect
in both Europe and United States. The Committee for Medicinal Products for Human Use
(CHMP) of the European Medicines Evaluation Agency (EMEA) has published guidelines for
ERA, which came into effect on the 1st December 2006. An ERA is required for all new
marketing authorization applications for medicinal products. An evaluation of the environmental
impact should also be made if there is an increase in the environmental exposure31,32.
CHMP was first known as CPMP (Committee for Proprietary Medicinal Products) which after
2004 was given the present form. It deals in the marketing procedures for medicines for human
use in the European Union. Assessments conducted by the CHMP are based on purely scientific
criteria and determine whether or not the medicines concerned meet the necessary quality, safety
and efficacy requirements in accordance to Directive 2001/83/EC. The CHMP can issue an
Urgent Safety Restriction (USR) to inform healthcare professionals about changes as to how or
in what circumstances the medication may be used. The agency aids in the preparation of
scientific and regulatory guidelines for the pharmaceuticals industry. Another important task
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performed by agency is close cooperation with international partners on the harmonisation of

regulatory requirements for medicines.
CVMP (Committee for Medicinal Products for Veterinary Use) was established by Regulation
(EC) No 726/2004. The prime act of CVMP is in the marketing procedures for veterinary
medicines in the European Union. A core activity of the CVMP is the establishment of MRLs:
the 'Maximum Residue Limits' of veterinary medicines permissible in food produced by or from
animals for human consumption, including dairy products, meat, honey etc. These limits must be
established for all pharmacologically active substances contained in a medicine before it can be
granted a marketing authorisation. CVMP also involves itself in the preparation of scientific and
regulatory guidelines for the veterinary pharmaceuticals industry.
COMP (The Committee for Orphan Medicinal Products) advises the European Commission on
the establishment and development of a policy on orphan medicinal products in the EU, and
assists the Commission in drawing up detailed guidelines on matters relating to orphan medicinal
products. The committee reviews the applications for 'Orphan Medicinal Product Designation'
for products. The Orphan drugs are those which are used for the diagnosis, prevention or
treatment of life-threatening or very serious conditions that affect not more than 5 in 10,000
persons in the European Union.
HMPC (The Committee on Herbal Medicinal Products) is engaged in assisting the
harmonisation of procedures and provisions concerning herbal medicinal products laid down in
EU Member States. Another main task performed by HMPC is establishment of Community
herbal monographs. Prior to 2004 this task was responsibility of CPMP Working Party on Herbal
Medicinal Products. But in September 2004 HMPC was established in accordance with
Regulation (EC) No 726/2004 and Directive 2004/24/EC, which introduced a simplified
registration procedure for traditional herbal medicinal products in EU Member States.
PDCO (Paediatric Committee) was established in accordance with the 'Paediatric Regulation'
(Regulation (EC) 1901/2006 as amended). The committee assesses the content of paediatric
investigation plans (PIPs) and adopts opinions on them that the data have been generated in
accordance with an agreed PIP or not

30

. This includes assessing applications for full or partial

waivers and assessing applications for deferrals. It is also notable that PDCO is not responsible
for marketing-authorisation applications for medicines for use in children33. This remains within
the remit of the CHMP.
CAT (Committee for Advanced Therapies) performs the task of preparing the draft opinion on
each ATMP (advanced-therapy medicinal products) application submitted to the European
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Medicines Agency, before the Committee for Medicinal Products for Human Use (CHMP)
adopts a final opinion on the granting, variation, suspension or revocation of a marketing
authorisation for the medicine concerned. The committee also advises the CHMP on any
medicinal product which may require, for the evaluation of its quality, safety or efficacy,
expertise in ATMPs. CAT actively participates in Agency procedures for the certification of
quality and non-clinical data for small and medium-sized enterprises developing advancedtherapy medicinal products.

TYPES OF PROCEDURES:
Centralized Procedure: European Council lays down a centralized procedure for the
authorization of medicinal products, for which there is a single application, a single evaluation
and a single authorization allowing direct access to the single market of the Community of 27
countries.
Decentralized Procedure: If no marketing authorization has been granted in the Community,
the applicant may make use of a decentralized procedure and submit an application to all the
Member States where it intends to obtain a marketing authorization at the same time, and choose
one of them as reference Member State (RMS).
Mutual Recognition Procedure (MRP): If the applicant has marketing authorization in one
Member state and wishes to obtain the same in other Member states; MRP is followed 29.In 2006,
the EMEA published the Template for the EU Risk Management Plan (EU-RMP). The
template directs drug developers and license holders to provide risk management plans in four
sections, Safety Specifications, Pharmacovigilance Plan, Evaluation of the Need for Risk
Minimization Activities and Risk Minimization Plan 34.
Within Europe, even with the implementation of the Single European Market, there remains
significant variation in price formation and the reimbursement of medicinal products across
member states, and thus, the single market remains distorted in pharmaceuticals 28.
The European Directive 2001/83/EC, as amended by Directive 2003/63/EC and Directive
2004/27/EC, defines the regulatory process for biosimilars and lays down specific guidelines. A
Biosimilar drug is a medicine that is similar but not identical to a biological medicine that has
already been authorised35. EU currently has the most advanced regulatory pathways for
biosimilars, there is no harmonised worldwide regulatory system for these products 36,

37

Comparable regulatory oversight is currently under discussion in the United States, Canada and
Japan38.
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To ensure that there were no delays in the development of products that are important for
developing countries and that there is no disincentive for the timely discovery and development
of these products, a consultation and collaboration between EMEA and WHO led to the Article
58 in the new Regulation. This provision establishes a mechanism whereby the EMEA may give
a Scientific Opinion, in the context of cooperation with the WHO, for the evaluation of certain
medicinal products for human use intended exclusively for markets outside the Community. In
doing so, EMEA reviews the application with the same evaluation standards being applied with
other products and hence provide an opinion.
3. JAPAN:
Japan is the worlds second largest pharmaceutical market next to the US occupying about 11%
of global sales and generates 67% of Asia-Pacific market 29. The Ministry of Health, Labour, and
Welfare (MHLW) is in charge of pharmaceutical regulatory affairs in Japan. Pharmaceutical and
Medical Devices Agency (PMDA) undertakes main duties and functions of the Ministry and
performs the task of approvals and licensing. PMDA is Japanese counterpart to the FDA and is
involved in operational aspects of drug development. PMDA consists of 22 offices and 2 groups.
It has primary responsibility for administering the approval of new pharmaceutical products and
medical devices in Japan, although final authority to issue approvals still rests with the Ministry
of Health, Labour and Welfare (MHLW) 45. The Pharmaceuticals and Medical Devices
Evaluation Center in the National Institute of Health Sciences was established to strengthen
approval reviews. The Pharmaceutical Affairs and Food Sanitation Council (PAFSC) serves as
an advisory body to the MHLW, and reviews and discusses important pharmaceutical and food
sanitation-related matters.
A company wishing to import a pharmaceutical product into Japan or manufacture and sell a
pharmaceutical in Japan must conduct clinical trials in Japan and apply for approval from the
PMDA. This applies even if the drug has already been authorized and is being sold in one or
more foreign countries. In some cases, the PMDA permits applicants to submit clinical data from
overseas, but this depends on the specific drug. Due to the activity of the International
Conference on Harmonization (ICH), data from clinical trials conducted in foreign countries can
be used as a part of clinical data packages for new drug applications in Japan

46,49

. Average

duration of a clinical trial in Japan is approximately four years, much longer than U.S, France
and U.K. Application forms from both Japanese New Drug Application (J-NDA) and Japanese
Abbreviated New Drug Application (J-ANDA) for approval to market drugs are usually
submitted to the PMDA. When application forms for new drugs are received by the PMDA, an
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approval review of the application data is done in consultation with experts from the PAFSC.
PMDA also does the compliance review of GCP/GMP on-site inspection, and the team prepares
a review report. This report then refers to MHLW which evaluates the application for medical
needs, social issues in addition to scientific review and issues the final decision for approval. In
reviews of new drugs prepared from vaccine or blood, the specifications and test methods are
examined by the National Institute of Health Sciences or by the Infectious Disease Surveillance
Center (IDSC) prior to approval. Applications using the ICH-CTD became obligatory for new
products in applications filed on or after July 1, 2003. In Japan, submission of eCTD is not
obligatory but it is recommended. If the data is being submitted in the form of eCTD as original
then it is no longer necessary to submit a copy of the paper data for approval applications. For
manufacturing facilities located in Japan, the manufacturing license is generally issued by the
governor of the prefecture in which the manufacturing facility is located. For overseas
manufacturing facilities, applications are made directly to the MHLW. Licensed manufacturing
facilities are required to satisfy criteria established by the MHLW.
Pharmaceutical Affairs Law (PAL) enacted in 1943 and has been revised several times since
then. Pharmaceutical Affairs Law (PAL) as revised in 2002 include the revisions such as a new
risk-based classification system for products, adoption of internationally consistent pre-market
submission documents, and a third-party certification system for low-risk medical devices. The
Pharmaceutical Affairs Law has 11 chapters and 91 articles. The Pharmaceutical Affairs Law
specifies that the data submitted to obtain approvals must be obtained and compiled according to
the standards specified in its Article 14, Paragraph 3. Pharmaceutical Affairs Law (Article 77(4)-2-1), requires the reporting of adverse drug reactions and infections by pharmaceutical
companies to the PMDA for information processing47,48.
Approval times differ among the US, the EU, and Japan, but the interpretations of such
comparison results always entail some difficulty because of the differences in the review
systems. According to the classification of therapeutic categories commonly used in Japan,
peripheral nervous system drugs (e.g., anesthetics ;), cardiovascular drugs, gastric drugs except
for peptic ulcer were associated with relatively shorter approval times. Anti-HIV drugs were
approved in exceptionally short periods, showing that the Japanese government as well as the US
FDA handled them differently from other priority drugs56. The Japanese Pharmacopoeia,
Japanese Pharmaceutical Codex, Japanese Pharmaceutical Excipients, and other similar
standards have been specified as quality standards. Laws and regulations related to pediatric field
does not exist in Japan.
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4. CANADA:
Health Canada is the Federal department of Canada which keeps eye on health issues within the
country by encouraging research and fostering partnerships with researchers across the country
and the world. Under Canada's Food and Drugs Act, the Therapeutic Products Programme (TPP)
of the Federal Department of Health (Health Canada) is responsible, on behalf of the Ministry of
Health, to ensure that "new drugs" meet health and safety requirements 57,

58

.Therapeutic

Products Directorate (TPD) is the Canadian federal authority that regulates pharmaceutical drugs
and medical devices for human use. Prior to being given market authorization, a manufacturer
must present substantive scientific evidence of a product's safety, efficacy and quality as required
by the Food and Drugs Act and Regulations. Pharmaceutical products, which are small
molecules (e.g. Chemical Entities), are regulated in Canada under the Part C, Division 8 of the
Food and Drug Regulations. The Therapeutic Products Directorate (TPD) receives and evaluates
submissions, while inspections of pharmaceutical manufacturers are performed by the Health
Products and Food Branch Inspectorate. Biological products are evaluated by the Biologics and
Genetic

Therapeutic

Products

Directorate,

which

also

evaluates

submissions

for

radiopharmaceuticals. TPD consists of 12 offices and bureaux which are listed as follow.

Director General's Office

Medical Devices Bureau

Submission and Information Policy Division

Office of Business Transformation

Office of Clinical Trials

Office of Patented Medicines and Liaison

Office of Risk Management

Bureau of Policy, Science and International Programs

Bureau of Cardiology, Allergy and Neurological Sciences

Bureau of Gastroenterology, Infection and Viral Diseases

Bureau of Metabolism, Oncology and Reproductive Sciences

Bureau of Pharmaceutical Sciences

The Health Products and Food Branch (HPFB) of Health Canada is responsible for review and
approval of clinical trials in humans. Trials involving drugs and medical devices are the
responsibility of the Therapeutic Product Directorate (TPD) while human trials with biological
and radiopharmaceutical drugs, including blood and blood products, viral and bacterial vaccines,
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genetic therapeutic products, tissues, organs and xenografts are the responsibility of the
Biologics and Genetic Therapies Directorate (BGTD) 59. HPFB also created a new organization,
the HPFB Inspectorate. The Inspectorate has the mandate to manage, inspect, investigate,
monitor activities and enforce strategies related to the fabrication, packaging, labelling, testing,
importation, and distribution and wholesaling of regulated health products. The Natural Health
Products Directorate (NHPD) is responsible for the review and approval of products such as
vitamins, minerals, herbal remedies, homeopathic medicines, traditional Chinese medicines,
probiotics and other products such as amino acids and fatty acids. In 2003, the Canadian
Parliament published new regulations for Natural Health Products and Homeopathic
Preparations. The Marketed Health Products Directorate (MHPD) is the part of Health Canada
that collects adverse drug reaction reports through a network of 5 regional reporting centres,
analyzes them, and issues warnings about safety concerns through a variety of means.
On September 1st, 2001, Canada amended its regulations on Clinical Trial Applications (CTA)
for the protection and safety of participants59. The CTA regulation impacts the application,
authorization, notification, amendment and cancellation processes and also defines the sponsors
obligations such as Good Clinical Practices, drug labelling and clinical record keeping.
Canada has been an observer on the International Conference on Harmonization (ICH)
committee since 1990 and hence ICH guidelines are adopted in Canada once they reach Stage-4.
Canada applies the principles contained within the ICH guidelines to both New and Existing
Drugs. All current guidance is formatted according to the ICH M4 "Common Technical
Document" (CTD) guidelines and data submitted to Health Canada for review is to be provided
in the CTD format. Canada accepts information on the drug substance either as part of a
submission, or in a separate Drug Master File (DMF). A DMF can be provided in one of three
formats such as 1) Canadian format 2) European format 3) ICH CTD-Quality format, out of
these the CTD format is most preferable. The DMF holder ensures that the drug substance
manufacturer is able to manufacture material that meets the approved specifications at release
and is acceptable for use up to the retest date. The DMF holder has to update the DMF every two
years, regardless of whether any changes are made. A letter confirming that no changes have
been made is acceptable. In general Canadian approval times are greater than other countries. It
is also observed that the regulations in Canada are more stringent than European countries but
less than America. When an NDS is submitted to TPD, it first undergoes an administrative
screening procedure which does not include any technical review of the information. If the
screening process identifies deficiencies in the NDS, the sponsor will receive a screening
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deficiency notice, and has 45 calendar days to respond and resolve any identified deficiencies.
Once an NDS for a new active substance passes the screening process and is accepted for
review60.
Table: 1 NDS for a new active substance
Submission type
Screening Review
New drug submission
45 days
300 days
Priority new drug submission
25 days
180 days
NOC/c new drug submission
25 days
200 days
The TPD maintains a Drug Product Database on its Web site that lists both active and
discontinued products (www.hc-sc.gc.ca/hpfb-dgpsa/tpd/dpt/dpd_index_e.html). Health Canada
also has a priority review system, which began in 1996. The Canadian criteria are close to those
of the FDA and the performance standard for priority-status medications (225 calendar days) is
also shorter than the standard review target (355 calendar days). In Canada, priority-status
products have longer approval times than those in the US 19,60.
The role of regulatory bodies in public health is evident from the actions taken against approved
drugs. Aprotinin which was sold under the brand name TRASYLOL after approval in 1995 was
withdrawn in 2005 due to increase in all-cause mortality. Gatifloxacin (TEQUIN) approved in
2001 was removed from market due to serious disorders of glucose metabolism. Lumiracoxib
(PREXIGE) approved in 2006 was withdrawn in 2007 for Risk of serious hepatotoxicity which
cannot be safely and effectively managed. Pergolide (PERMAX) entered market in 1991 but was
withdrawn in 2007 due to Valvulopathy. Rofecoxib (VIOXX) approved in 1999 was found to be
responsible for cardiovascular events, such as heart attack and stroke, so withdrawn in 2004 61.
4. ASEAN COUNTRIES:
ASEAN stands for Association of South East Asian Nations. This association includes 10
member countries such as Singapore, Thailand, Malaysia, Indonesia, Myanmar, Cambodia,
Vietnam, Philippines, Brunei Darussalam and Lao PDR. ASEAN was established in 1967 by 5
member states only. In 1992 The ASEAN Consultative Committee for Standards and Quality
(ACCSQ) formed to facilitate and complement the ASEAN Free Trade Area (AFTA). Efforts to
harmonize regulatory requirements amongst ASEAN were initiated through the (ACCSQ) in
1998 when it initiated the PPWG (Pharmaceutical Product Working Group). For import these
countries Accept WHO Certificate of Pharmaceutical Product (CPP) with statement on GMP
compliance issued by Drug regulatory Agencies. Locally manufactured products require
evidence of GMP conformance through inspections of local manufacturers by GMP auditors in
their respective member states. Singapore attained membership to PIC/S in 2000 followed by
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Malaysia in 2002 and they Implemented PIC/S (Pharmaceutical Inspection Co-operation

Scheme) Guide to GMP for local manufacturers of medicinal products. The ASEAN Economic
Ministers signed the ASEAN Sectoral Mutual Recognition Arrangement (MRA) for Good
Manufacturing Practice (GMP). The efforts of PPWG led to the development of ACTR (ASEAN
Common technical Requirements), ACTD (ASEAN Common Technical Dossier) and ASEAN
guidelines.
Due to limited human resources the agencies traditionally performs mainly administrative work
and simply endorse approvals of new drugs which are previously approved by developed
countries. So these countries relay heavily on the Free Sales Certificate or Certificate of
Pharmaceutical Product (CPP). Because of cultural and religious reasons, Indonesia, Malaysia
and Philippines authorities require information on sources of all ingredients of animal origin.
The Indonesian authority will not approve products containing any ingredient of porcine source
Singapore, Philippine and Thailand are only three countries in this region which employ
universal health insurance approach for managing health system.
For New Drug Registration in these countries ASEAN Harmonized ASEAN Common Technical
Dossiers (ACTD) is used which is submitted in 4 parts as follow:
Part 1: Administrative Data and Product Information
Part 2: Quality Document
Part 3: Nonclinical Document
Part 4: Clinical Document
Table 2: ASEAN Quality guidelines
ASEAN Quality guidelines

Safety guidelines

Efficacy
guidelines
adopted
ICH- Adopted
Safety guideline GLs
(15 GLs)

(1)Analytical Validation guidelines.

11
(2) BA/BE Studies guideline.
(3) Process Validation guideline.
(4) Stability Study guideline.
Because the majority of local Pharmaceutical industries in this region are generic industries,
Greater emphasis is given on registration of generic drugs with respect to ASEAN technical
requirements and dossiers. Blood services are usually run by the government (Malaysia,
Myanmar and the Philippines) or the Red Cross (Thailand, Laos and Indonesia). In Singapore,
the government-run blood service outsources the blood donor recruitment program to the Red
Cross in a unique partnership model63.
Singapore: Manufacturers located within Singapore are subjected to licensing and periodic
inspections by Health Sciences Authority (HSA). Center for Drug administration (CDA) is
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responsible for the formulation of drug regulatory policies and guidelines. Drug registration
Branch (DRB) and Innovative therapeutics Group (ITG) are responsible for registration of
medicines and continual review of approved medicines. Dossier submitted can be either in
ASEAN CTD format (ACTD) or The ICH-CTD format. Once approved product is valid for one
year. Among Traditional medicines mainly Chinese medicines are used which are regulated by
Centres Chinese Proprietary Medicine Unit. Among ASEAN countries Singapore has best and
systematic infrastructures and policies for R&D. The investment in pharmaceutics is also highest
among all ASEAN member states. The Health Products Act introduced in Singapore in 2007, is
an example of a modular and flexible system based on smart regulation [Health Products Act,
<http://statutes.agc.gov.sg>; 2007]. It allows incremental inclusion of different categories of
health products in phases and modular application of different parts of the Act to different
categories based on assessed risk profile of that category64, 65.
Thailand: The regulation of medicinal drugs in Thailand is overseen by the Ministry of Public
Health (MOPH). The Drug Control Division of the Food and Drug Administration (THAI FDA),
a department of the MOPH, has the responsibility for Licensing and Drug registration as well as
Post-marketing monitoring and surveillance. The Medical Sciences Department under the
MOPH is the main authority responsible for ensuring the quality and safety of drugs on the
market in Thailand. The legislative basis of this system is the Drug Act BE 2510 (1967) and
amendments. According to the Drug Act 1987 (B.E. 2530), a Drug Committee has been
appointed every two years to advise the Minister of Public Health on both regulatory and
technical aspects concerning administration of the drug control. The Drug Board meets monthly
and may give recommendations or opinions on licensing and registration decisions such as
approval withdraw or suspend the licenses. For the process of New Drug Registration standard
review takes 210 - 280 working days while Accelerated or priority review is completed in 100130 working days. For the process of new generic drug registration standard review is completed
within110 working days while Accelerated or priority review is completed in 70 working days.
Once the review has been passed, the new drugs must undergo a two-year safety monitoring
period. A foreign applicant must be a resident in Thailand to obtain a licence to manufacture, sell
or import drugs. Prices of medicinal products are regulated when they are listed on the National
List of Essential Drugs (NLED). This list is only available to government hospitals. There is no
centralized regulation for clinical trials. To obtain approval for clinical trials in Thailand The
sponsor must then obtain approval to conduct a study in humans from the Ethical Review
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Committee for Research in Human Subjects of the MOPH (ERC) and/or the ethics committee of
the research institute or university that will conduct the trial.
Malaysia: All Pharmaceutical products whether locally manufactured or imported, must be
registered with Drug Control Authority (DCA) prior to being manufactured, imported or sold.
The legislative basis for the registration and marketing authorization of pharmaceuticals
including biopharmaceuticals in Malaysia is the Control of Drugs and Cosmetics Regulations
(CDCR 1984) promulgated under the Sale of Drugs Act 1952 (act 368). The National Regulatory
Authority (NRA) for medicinal products is the National Pharmaceutical Control Bureau (NPCB),
Ministry of Health Malaysia66,67. Quality control is handled by Drug analysis Division based at
NPCB. Medical Research Ethics Committee (MREC) reviews the ethical aspects of the study to
safeguard the rights, safety and well-being of all trial subjects. Any trial conducted in a
government health facility requires the approval of the Director-General of Health, Malaysia.
Malaysia employs the combination of health insurance and public assistance model. There is no
specific regulatory control in matter of price control.
Vietnam: Ministry of Health is responsible for drug regulation. The charge of regulation is in 3
departments, The Pharmacy Department, The Pharmaceutical Inspection department and The
National institute of Drug Quality Control. These departments report directly to Vice-Minister
for Pharmaceuticals68. The production, trafficking and use of illicit drugs are important social
issues for contemporary Vietnam. Vietnams response to drug use has historically focused on
deterrence through punishment and supply-side measures69
Philippines: The Food, Drug and Cosmetic Act provide the legal environment for drug
regulation. The agency within the Philippine Department of Health which is responsible for
activities is the Bureau of Food and Drugs. For the distribution and sale, the pharmaceutical
product must be registered with Bureau of Food and Drugs70.
Cambodia: Department of Drugs and Food is the regulatory agency under the ministry of
Health. Only products registered by DDF are authorized to be imported, manufactured and sold
in market. It does not yet have social health insurance program and almost no private health
insurance at present 71, 72.
Myanmar: The central body is Myanmar Food and Drug Board Authority (MFDBA) within the
MOH, which oversees the enforcement of law73. Central Food and Drug Supervisory Committee
has the responsibility for licensing drug manufacturers. The evaluation is carried out by Drug
advisory committee. According to Law, for a product to be registered the clinical trials have to
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be performed in Myanmar. The registration is valid for 5 years. State Food and Drug advisory
committees license the drug wholesalers.
Indonesia: The Drug and Food control agency is the regulatory body in Indonesia. The
applications for product registration can be submitted only by local manufacturers. The
Indonesian authority will not approve products containing any ingredient of porcine source 75.
Laos: The Food and Drug Department (FDD) is the authority for pharmaceutical regulations.
Drug manufacturers need to obtain license from FDD for production, import or distribution.
Drug Quality Control Center performs the tests.
Brunei: Department of pharmaceutical services is under the Ministry of Health. Drugs are not
manufactured locally. It is the only country in ASEAN which does not require registration of
medicines sold in the country. Brunei has participated in the effort to harmonize the drug
registration for ASEAN even though it does not yet have drug registration system in country.
The Narcotics Control Bureau (NCB) is the main agency to combat drug abuse activities in
Brunei Darussalam.
5. AUSTRALIA:
In Australia, The sale of medicines is governed by legislation at both Commonwealth and State
levels. The Therapeutic Goods Administration (TGA) is responsible for regulating therapeutic
goods in Australia including medicines, medical devices, blood and blood products. TGA is a
division of the Australian Government Department of Health and Ageing which evaluates the
therapeutic goods before they are marketed and then monitors products once they are on the
market. The manufacturers of therapeutic goods are also regulated by TGA to ensure they meet
acceptable standards of manufacturing quality. Medicines must be entered as either 'Registered'
or 'Listed' medicines and medical devices must be 'included' on the Australian Register of
Therapeutic Goods (ARTG) before they may be supplied in or exported from Australia, unless
exempted. The TGA has six statutory expert committees members of which are appointed by the
Ministry. These committees include Advisory Committee on Complementary Medicines
(ACCM), Advisory Committee on Medical Devices (ACMD), Advisory Committee on Nonprescription Medicines (ACNM), Advisory Committee on Prescription Medicines, (ACPM),
Advisory Committee on the Safety of Medicines (ACSOM), and Therapeutic Goods Committee
(TGC). The Therapeutic Goods Act 1989 sets out the legal requirements for the import, export,
manufacture and supply of therapeutic goods in Australia. The Standard is maintained by the
TGA but takes force in legislation at the State level76. Australian Pharmaceutical Advisory
Council which is comprised of representatives of key health professions, the pharmaceutical
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industry, and members of government meets twice yearly to discuss important issues and needs
in relation to the NMP and to advise the minister on priority issues77.
The extent to which companies can supply medicines to Australian pharmaceutical markets is
governed by the operations of two government agencies. One is Therapeutic Goods
Administration (TGA) which is compared to the equivalent organisations in the USA and
Europe. The other government agency is the PBS (Pharmaceutical Benefits Scheme). Most
prescription medicines in Australia are made available to patients under the Pharmaceutical
Benefits Scheme78, 79, 80. Public hospitals are funded by State Governments in the main and they
provide medicines to patients free. State Governments are reimbursed for the cost of those
medicines listed on the PBS. On average patients pay only 19per cent of the cost of their
prescriptions8. Responsibility for reviewing data regarding the clinical- and cost-effectiveness of
medicines that manufacturers seek to have listed on the Schedule falls with the Pharmaceutical
Benets Advisory Committee (PBAC). Following a review, the PBAC advises the Minister on
whether a medicine should be listed on the Schedule and under what conditions. The Minister
cannot list a medicine without a positive PBAC recommendation; evidence suggests it is rare for
the Minister to reject positive recommendations81,8. The TGA requirements for data from
companies making applications are based on the European Union (EU) requirements and the
TGA accepts data dossiers in the European Union format. The guidelines for submissions are
also very similar to those of the EU. In general the TGA follows the EMEA approvals process
quite closely. Australian Drug Evaluation Committee (ADEC) assesses all applications for new
chemical entities, as well as for products which have already been approved but are seeking to
have their indications varied. The average evaluation time for a new chemical entity is about 300
working days or about 420 elapsed days.
6. CHINA:
The drug registration process in China is centrally managed by the State Food and Drug
Administration (SFDA). Sub-organizations which assist SFDA are Center for Drug Evaluation
(CDE) and National Institute for the Control of Pharmaceutical and Biological Products
(NICPBP)

83, 84

. Initially SFDA was an independent authority, but was incorporated into the

Ministry of Health (MoH) in early 2008. There are seven major centers in SFDA which are listed
below85. The fundamental legal document governing the administration of the pharmaceutical
industry in China is the Drug Administration Law of the Peoples Republic of China (The
Law) issued in February 200186, 88.

National institute of the control of pharmaceutical and biological products (NICPBP)

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Chinese pharmacopoeia commission (CPC)

Center for drug evaluation (CDE)

Center for certification of drugs (CCD)

Center for drug reevaluation (CDR)

National committee on the assessment of the protected traditional Chinese medicinal

products (NCAPTCMP)

Center for medical device evaluation (CMDE)

It typically takes four to five years to register a drug in China 87. Currently, there are five types of
drug registration application in China: New drug application, generic drug application, imported
drug application, supplemental application and renewal application. Application for drug license
are submitted to Office for Drug Registration (ODR), which checks the dossier content / format
of the application documents then forward submissions to the NICPBP. No strict CTD format
required currently. Different from the Good Review Practice (GRP) implemented in CDER (The
Centre for Drug Evaluation and Research) at US FDA, the review practice in CDE only
requires key points, instead of all submitted information, be reviewed in details 85. After the
testing results are verified by the NICPBP they are then returned to the ODR which forwards the
application documents and testing results to the CDE for technical evaluation. SFDA reviews the
document and decides whether to issue the license for clinical trial. Applicants conduct the
clinical trial (CT) and send the clinical data to ODR which organizes a CT on-site inspection and
forwards them to CDE. Technical evaluation by CDE and positive / negative recommendations
are given to SFDA. After comprehensive review by SFDA it decides whether to issue the drug
license88. For new molecular entities that are developed for serious or life-threatening diseases or
diseases for which there is no available treatment, there exists fast track evaluation to accelerate
the evaluation process89. Drugs cannot be imported into China without a Registration Certificate
for Imported Drugs (RCID). For a RCID to be issued, prospective importers generally must
satisfy the SFDA criteria for safety and efficacy, but they may be exempt if the drug is for
emergency hospital use or individual use90.
There are two types of drug reimbursement lists in China known as the A List and the B List.
Both lists are compiled by Central Government authorities. The A List receives 100%
reimbursement while 50% for list B91. The process for approving drugs for the reimbursement
lists is dominated by the Ministry of Human Resources and Social Security (MoHRSS). For
public safety and to keep eye on adverse effects of approved drug, a law Regulation for the
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Administration of ADR Reporting and Monitoring was issued in March 2004. National Center
for ADR Monitoring houses the Center for Drug Reevaluation (CDR) joined the SFDA and
reports to both the SFDA and the MOH. Hospitals, drug distributors, pharmacies, and
pharmaceutical companies submit ADR/ADE reports to regional centers

91,92,93

. The regional

center reports all new ADRs/ADEs and all serious ADRs/ADEs within three days to the National
Center. Both western medicines and TCMs (Traditional Chinese Medicines) are covered by the
ADR/ADE reporting system and are regulated by the SFDA

94

. For renewal application, each

approved drug should be re-evaluated after 5 years and the renewal approval will depend on
whether the post-marketing data suggest serious drug safety issues or not during the last 5
years85. Center for Drug Re-evaluation (CDR) is responsible for the post-marketing evaluation
while CDE is in charge of pre-marketing evaluation. The SFDA issued a total of 11 regulations,
guidelines and notices in 2010 covering areas including drug quality, controlled substances, drug
registration, R&D, electronic regulation and pharmaceutical export. In particular, the agency
issued three documents on electronic regulation of drug products in 2010. In 2011, SFDA
introduced a new GMP regulation for pharmaceutical products with effect from March 1,
201191,95.
7. AFRICAN COUNTRIES:
In most parts of Africa, the regulatory frameworks for medicines and clinical trials are not well
established. Currently, many regulatory authorities in Africa have not attained a comprehensive
legal framework suitable to meet the state of art operations expected for RAs. Most RAs are
commonly characterized by inadequate legislation/regulations, severe lack of skilled human
resources, poor logistical capabilities and a general apathy to their functions (WHO surveys
2006/2007). Most countries have marketing authorization offices that make a brief review of
applications and grant authorizations to import and sell specific products on their markets.
African medicine regulatory agencies have traditionally focused on generics relied on western
regulatory agencies for review of innovator products. The WHO standards are taken as minimum
requirement on quality of pharmaceuticals.
Pharmaco-vigilance or post marketing safety surveillance and reporting by the manufactures or
sponsors is still evolving in Africa and hence no sufficient systems are in place to inform the
RAs. Many products which are already approved and marketed in Africa, continued monitoring
for safety and efficacy are greatly compromised. A number of countries in the continent largely
rely on India and China for imports of affordable generics and raw materials74.
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RAs in different countries operate in different forms as per the mandates given by the laws of
that particular country. For instance, in Tanzania the Tanzania Food and Drug Authority (TFDA)
operates as per the mandate given under Tanzania Food, Drugs and Cosmetics Act No. 1 of
2003. Subsequent WHO surveys (2006/2007) on the status of RAs providing oversight to
vaccine research in Africa revealed that: In Africa, only the South African RA was found to have
capacity to adequately regulate vaccines. Six countries, namely, Nigeria, Senegal, Morocco,
Tunisia, Algeria and Zimbabwe where found to have functional national RAs, but these needed
to be strengthened; other countries including Ghana, Uganda, Ethiopia, Egypt, had potential to
quickly become functional, meanwhile the rest of the surveyed countries had limited or weak
RAs or no information at all97.
Progress is being made at national levels across the continent, The WHO have done and continue
to do a commendable job in supporting African RAs to be able to handle the prevailing
regulatory challenges. A number of initiatives have been formulated to serve as expert resources
supporting countries with minimal or none regulatory capacity. A good example of is African
Vaccine Regulatory Forum (AVAREF) which is platform for African countries to discuss with
peers and maximizing the use of resources available in the continent

98

. In January of 1996, the

Health Ministry published a National Drug Policy (NDP). The various studies carried out on the
existence and the capacities of ethics committees reveal a disparity between countries 99, 100. A
study led by the WHO Regional Office for Africa (WHO/AFRO) highlighted the absence of
national ECs for medical research in 36% of its member states101.
SADC (Southern African Development Community): The SADC was formally launched on 17th
August 2002 under a Treaty was originated from the Southern African Development
Coordination Conference (SADCC), which was formed in 1980. It consists of 14 Member States
such as Angola; Botswana; Democratic Republic of Congo; Lesotho; Madagascar; Malawi;
Mauritius; Mozambique; Namibia; Swaziland; United Republic of Tanzania; South Africa;
Zambia; and Zimbabwe. The SADC Pharmaceutical Program was approved by the Integrated
Committee of Ministers (ICM) at its meeting in June, 2004. All SADC Member States have a
national medicines policy, Regulations, Regulatory Shared Network, and are members of the
World Trade Organization (WTO), which automatically makes them signatory to the Agreement
on Trade Related Aspects of Intellectual Property Rights (TRIPS). But fact is also true that weak
regulatory systems lead to concerns on quality, safety and efficacy of medicines with many
unregistered products on the market. Inadequate national and regional medicine quality control
laboratories are another barrier. There is one WHO Pharmaceutical Reference Quality Control
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Laboratory in Zimbabwe and one WHO Collaboration Quality Control Laboratory in South
Africa. About 85% of the generic ARV (Antiretroviral) medicines used in the region are
imported from India and 15% are manufactured within the SADC region. COMESA: (Common
Market for Eastern and Southern Africa): It Comprises 19 member states, 7 of which are in
SADC and 4 in EAC. In March 2003, the Council of Ministers that met in Khartoum, Soudan
noted the variations in legislation and regulations in DRAs and emphasized the need of
harmonization of the regulatory environment. Member States improved the standard of facilities
within national regulatory Authorities, to WHO recommended standards. COMESA GMP
guidelines for industries have been established and efforts have been made on MRA. EAC:
Kenya has the largest economy among the EAC countries. Kenya Medical Supplies Agency
(KEMSA) is the public agency for the procurement and distribution of EMMS.

DISCUSSIONS:
Health is one of the basic rights for human being. In the past decade more than a dozen highprole drugs,including rofecoxib (Vioxx), cisapride (Propulsid), troglization (Rezulin),
terfenadine (Seldane), and cerivastatin (Baycol), were withdrawn from the market. In response to
so many withdrawals, pressure has been building to reform drug safety regulations 94. It should
be noted that most regulatory authorities in different countries have similar but slightly
different requirements for approval of drug products. The necessity to standardize regulatory
requirements has been recognized by both regulatory authorities and the pharmaceutical industry.
As a result, the International Conference on Harmonization (ICH) which consists of the
European Community, the United States, and Japan was formed to evaluate and develop
technical requirements for the registration of pharmaceuticals for human use. A number of
guidance and draft guidelines for good pharmaceutical practices have been developed to assist
pharmaceutical companies in drug research and development.
It is also clear that the developing world lagged behind and was not involved in the articulation
of the international guidelines and standards for RAs. it is also a fact that in the developed
countries the regulatory environment has become bureaucratic, expensive and complex, placing a
greater burden on investigators in terms of compliance, documentation, and training 103.
Unnecessary bureaucratic rules and standard operating procedures produce inefficiencies that
delays product evaluation process. Recent statistics show that pharmaceutical companies are
changing their strategies by moving their sites of clinical trials to developing countries. For
example, out of all clinical trials sponsored by American companies, the proportion of the
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clinical trials sites within the United States regressed from90% in 1999 to 47% in 2007 104.
Throughout the world, medical regulation is a key healthcare issue. However, in many
developing countries it is not satisfactorily addressed. While there has been some research on
health sector regulation in industrialized countries, little has been written about developing
countries105.

REFERENCES:
1. Lumley C, Walker S: improving the Regulatory Review Process -Industry and Regulatory
Initiatives. Dordrecht: Kluwer Academic Publishers; 1996.
2. Baeyens AJ, Lacombe D. Regulatory issues for clinical trials at EORTC: The way forward.
European Journal of Cancer 2002; 38:S142S146.
3. Soderlund N, and Tangcharoensathien V. Health Sector Regulation Understanding the
Range of Responses from Government. Health Policy and Planning 2000; 154: 347-348.
4. Lambert K. Regulatory affairs Biopharmaceuticals regulation-progress and challenges.
Current Opinion in Biotechnology 1997; 8:347-349.
5. Chabicovskya M, Ryle P. Non-clinical development of cancer vaccines: Regulatory
considerations. Regulatory Toxicology and Pharmacology 2006;44:226237.
6. E4: World Health Organization. Guidelines on Nonclinical Evaluation of Vaccines 2003.
<http://www.who.int/biologicals/publications/nonclinical_evaluation_vaccines_nov_2003.
pdf>.
7. Lexchin, J. Drug makers and drug regulators: Too close for comfort. A study of The
Canadian situation. Social Science & Medicine 1990;31(11):12571263.
8. Donald J. Wright DJ. The Drug Bargaining Game: Pharmaceutical Regulation In Australia.
Journal of Health Economics 23 (2004) 785813.
9. Danzon, P, Chao L. Does regulation drive out competition in pharmaceutical markets?
Journal of Law and Economics 2000; 43:311357.
10. WHO. Effective medicines regulation: ensuring safety, efficacy and quality. Geneva:
World

Health

Organization;

2003.

Available

from:URL:

http://whqlibdoc.who.int/hq/2003/WHO_EDM_2003.2.pdf
11. Santoso B. Drug Benets and Risks: International Textbook of Clinical Pharmacology
revised 2nd edition, Chapter-6 Drug Regulation: History, Present and Future. 2008;
edition-2:66-76.

199

www.ajptr.com

Sandhe et. al., Am. J. PharmTech Res. 2012; 2(3)

ISSN: 2249-3387

12. Danzon et al. Cross-National Price Differences for Pharmaceuticals: How Large and
Why? Journal of Health Economics 2000;19(2):159-95.
13. Andrea T et al. The History and Contemporary Challenges of US-FDA. Clinical
Therapeutics 2007; 29(1):1-16.
14. Routledge P. 150 years of pharmacovigilance. Lancet 1998; 351:12001201.
15. Pisano DJ, Mantus DS. FDA Regulatory Affairs: A Guide for Prescription drugs, medical
devices and biologics. Edition 2nd Published 2008.
16. Rawat S, Gupta A. Regulatory Requirements for Drug Development and Approval in
United States: A Review. Asian J. Pharm. Res. 2011;1(1):01-06.
17. Heilman RD. Drug development history, overview, and what are GCPs? Quality Assur
1995; 4:7579.
18. Mossingh off, Gerald J. Overview of the Hatch-Waxman Act and Its Impact on the Drug
Development Process. Food and Drug Law Journal 1999; 54(2):187-194.
19. Nigel S.B. Assessing Prescription Medications for Priority Regulatory Review.
Regulatory Toxicology and Pharmacology 2005; 42:7076.
20. Kertz R. FDA: Evidentiary Standards for Drug Development and Approval. NeuroRx.
2004; 1:307-316.
21. Seiguer E, Smith J. Perception and Process at Food and Drug Administration: Obligations
and Trade-Offs In Rules and Guidance. Food drug law j 2005; 60:17-32.
22. Burstein PD. A Sad Day for Science at FDA. N Eng J Med. 2005; 353:2619-2621.
23. Kennedy D. chess game at the FDA. Science 2005; 310:589.
24. Berndt et al. Authorized Generic Drugs, Price Competition and Consumers Welfare.
Health Affairs 2007; 26(3):790-799.
25. Frank, Richard G. New Estimates of Drug Development Costs. Journal of Health
Economics 2003; 22(2):325-330.
26. Kyle, Margaret K. Pharmaceutical Price Controls and Entry Strategies. Review of
Economics and Statistics 2007; 89(1):88-99.
27. Steven F. et al. Chapter 37- Product registration and drug approval process In United
States. Developing Solid Oral Dosage Forms. 2009;861-863.
28. Casper S, Matraves C. Institutional Frameworks and Innovation in the German and UK
Pharmaceutical Industry. Research Policy 2003; 32:18651879.
29. Ramesh T et al. Regulatory Perspective for Entering Global Pharma Markets. Pharma
Times 2011;43(09):15-19.
www.ajptr.com

200

Sandhe et. al., Am. J. PharmTech Res. 2012; 2(3)

ISSN: 2249-3387

30. Ceci A, FelisiM, CatapanoM, Baiardi P, Cipollina L, Ravera S et al. Medicines for
Children Licensed by the European Agency for the Evaluation of Medicinal Products. Eur
J Clin Pharmaco 2002; 58:495-500.
31. Committee for Medicinal Products for Human Use (CHMP), 2006. European Medicines
Agency Pre-Authorization Evaluation of Medicines for Human Use (Doc. Ref.
EMEA/CHMP/SWP/4447/00) Guideline on the environmental risk assessment of
medicinal products for human use. 12pp.
32. Grung M et al. Environmental assessment of Norwegian priority pharmaceuticals based
on the EMEA guidelines. Ecotoxicology and Environmental Safety 2008; 71:328340.
33. European Medicines Agency. Better medicines for children. EMEA 2008. Available at
http://www.emea.europa.eu/htms/human/paediatrics/regulation.htm
34. European Medicines Agency. Post-authorization evaluation of medicines for human use.
Annex C: Template for EU risk management plan (EU-RMP). Available at
http://www.emea.eurpa.eu/pdfs/human/euleg/19263206en.
35. Mellstedt, H. et al. The challenge of biosimilars. Ann. Oncol. 2008; 19:411419.
36. Gottlieb, S. Biosimilars: Policy, Clinical, and Regulatory Considerations. Am J Health
Syst. Pharm. 2008; 65: S2S8.
37. Moran, N. Fractured European market Undermines Biosimilar Launches. Nat.
Biotechnol. 2008; 26:56.
38. Joung, J et al. WHO informal consultation on regulatory evaluation of therapeutic
biological medicinal products held at WHO Headquarters, Geneva, 2007. Biologicals
2008; 36:269276.
39. Grifn JP, Shah RR. History of drug regulation in the UK. The regulation of medical
products. London: Blackwell BMJ Books; 2003:3-12.
40. Permanand G, Mossialos E, McKee M. Regulating medicines in Europe: The European
Medicines Agency, Marketing Authorisation, Transparency and Pharmacovigilance. Clin
Med 2006;6(1):87-90.
41. Marty M. Drug Evaluation and Approval in the European Community. Eur J Cancer
1996; 32A:574-575.
42. European Medicines Agency Committee for Medicinal Products for Human Use.
Guideline on risk management systems for medicinal products for human use. Available at
http://www.emea/chmp/96268/2005.
201

www.ajptr.com

Sandhe et. al., Am. J. PharmTech Res. 2012; 2(3)

ISSN: 2249-3387

43. European Medicines Agency road map to 2010: preparing the ground for the future.
March 2006. Available at http://www.emea.europa.eu/htms/general/direct/roadmap
44. Hartford CE, Petchel KS, et al. Pharmacovigilance during the pre-approval phases. Drug
Safety 2006; 29(8):657-673.
45. Hayakawa T. New drug approval process in Japan. Current opinion in biotechnology
1999; 10:307-311.
46. Uyama, Y et al. Successful bridging strategy based on ICH E5 guideline for drugs
approval in Japan. Clin. Pharmacol. Ther. 2005; 78:102113.
47. Bareilles M et al. Chapter 5- Japanese regulations. Global Clinical trials 2011;63-85.
48. Ono S et al. New drug approval times and clinical evidence in Japan. Contemporary
Clinical Trials 2005;26:660 672.
49. Ono S, Kato O, Tsutani K, et al. Utilization of Foreign Clinical Data in Japanese New
Drug Approval Review. Int J Pharm Med 2004; 18:159 165.
50. Tsuji K, Tsutani K. Approval of new biopharmaceuticals 19992006: Comparison of the
US,

EU

and

Japan

situations.

European

Journal

of

Pharmaceutics

and

Biopharmaceutics.2008; 68:96-502.
51. Milsted R. Cancer drug approval in the United States, Europe, and Japan. Advances in
Cancer Research. 2006; 96:371-391.
52. Wen-Hua Kuo. Techno-politics of genomic nationalism: Tracing genomics and its use in
drug regulation in Japan and Taiwan. Social Science & Medicine 2011;73(8):1200-1207.
53. Horikawa, H et al. Industry Views of Biosimilar Development in Japan. Health Policy
2009;91(2):189-194.
54. Hirai Y et al. Analysis of the Success Rates of New Drug Development in Japan and the
Lag behind the US. Health Policy 2012;104(3):241-246.
55. Yamaguch T, Arato T. Quality, safety and efficacy of follow-on biologics in Japan.
Biologics 2011; 39(5):328-332.
56. DiMasi JA, Manocchia M. Initiatives to Speed New Drug Development and Regulatory
Review: The Impact of FDA-Sponsor Conferences. Drug Inf J 1997; 31:771 88.
57. Health Canada. Health protective legislative renewal: detailed legislative proposal.
Ottawa; 2003.
58. Health Canada. Improving Canadas regulatory process for therapeutic products: building
the action plan: multi stakeholder consultation: Public Policy Forum; 2003 November 23.
www.ajptr.com

202

Sandhe et. al., Am. J. PharmTech Res. 2012; 2(3)

ISSN: 2249-3387

59. Boisvert J. The Canadian Clinical Trial Regulation Overview and Update. GOR
2003;5(2):35-39.
60. Rawson NSB. The Timeliness of New Drug Approvals in Canada. Int J Health Serv.
1995; 25:153165.
61. Lexchin J. Drug Withdrawals from the Canadian Market for Safety Reasons, 19632004.
CMAJ 2005; 172:76567.
62. Lexchin J, Mintzes B. Transparency in Drug Regulation: Mirage or Oasis? CMAJ 2004;
171:136365.
63. Epstein J et al. Role of Regulatory Agencies. Biologicals 2009; 37:94-102.
64. Lim HH. The Pharmaceutical industry and ASEAN Free Trade Area- Initiatives on Tariff
Reduction and Intellectual Property Protection. Australian Prescriber 1997; 20:217-21.
65. Lim MK. Shifting the Burden of Health Care Finance: A Case Study of Public-Private
Partnership in Singapore. Health Policy 2004; 69:83-92.
66. Abas A. Regulatory Guidelines for Bio-similar In Malaysia. Biologicals 2011; 39:339-42.
67. Ministry of Health Malaysia. National Pharmaceutical Control Bureau, guidance
document

and

guidelines

for

registration

of

bio-similar

in

Malaysia,

portal.bpfk.gov.my/view_le.cfm?leid302; 2008 [accessed on 25.10.11].

68. Vuong T et al. Drug Policy in Vietnam: A Decade of Change? International Journal of
Drug Policy 2011,doi:10.1016/j.drugpo.2011.11.005.(article in press)
69. Reid G. Higgs P. Vietnam moves forward with harm reduction:

An assessment of

progress. Global Public Health: An International Journal for Research, Policy and Practice,
2011; 6(2):16880.
70. Madulid DA. Guidelines and Policies on Collection of Biological Specimens in the
Philippines. J Ethnopharmacology 1996; 51:205-208.
71. Noirhomme M, Meessen B et al. Improving Access to Hospital Care for the Poor:
Comparative Analysis of Four Health Equity Funds in Cambodia. Health Policy and
Planning 2007; 22:24662.
72. Grundy J et al. Health System Strengthening In CambodiaA Case Study Of Health
Policy Response To Social Transition. Health Policy 2009; 92:107115.
73. Tin N. An Approach to Health System Strengthening In the Union of Myanmar. Health
Policy 2010; 95:95102.
74. Guise JW, Carson BM. Biogeneric Regulatory Policies in China and India: A
Comparison Study. Drug Information Journal 2010; 44:55-67.
203

www.ajptr.com

Sandhe et. al., Am. J. PharmTech Res. 2012; 2(3)

ISSN: 2249-3387

75. Kristiansen S, Santoso P. Surviving De-centralization. Impacts of Regional Autonomy on

Health Service Provision in Indonesia. Health Policy 2006; 77:247259.
76. Lofgren H, Boer R. Pharmaceuticals in Australia: Developments in Regulation and
Governance. Social Science & Medicine 2004; 58:23972407.
77. Morgan S et al. Balancing Health and Industrial Policy Objectives in the Pharmaceutical
Sector: Lessons from Australia. Health Policy 2008; 87:133145.
78. Doran E, Henry D. Pharmaceutical Benets Scheme Policy: Confused and Tough On
Patients. Internal Medicine Journal 2006; 36:211213.
79. Duckett SJ. Drug Policy Down Under: Australias Pharmaceutical Benefits Scheme.
Health Care Financing Review.2004; 25:5567.
80. Donovan, J. The benefits of the Pharmaceutical Benets Scheme to the Australian
community and the impact of increased copayments. Health Issues. 2002; 71:1720.
81. Wonder MJ, Neville AM, Parsons R. Are Australians able to access new medicines on
the Pharmaceutical Benets Scheme in a more or less timely manner? An analysis of
Pharmaceutical Benets Advisory Committee recommendations, 19992003.Value in
Health 2006; 9:205212.
82. Roughead EE, Lopert R, Sansom LN. Prices for Innovative Pharmaceutical Products That
Provide Health Gain: A Comparison between Australia and the US. Value in Health 2007;
10(6):514520.
83. Li HZ. The Drug Registration Application. J. Pharm. Pharma Sci. 2003; 6:211-214.
84. Li HZ. Drug Control Authorities in China. Ann. Pharmacother. 2004; 38:346-350.
85. Lu D, Huang W. Overview of Drug Evaluation System in China. Scientific Research and
Essays 2010; 5(6): 514-518.
86. State Food and Drug Administration of China (SFDA). Drug administration law of the
Peoples Republic of China. Available from: http://www.sfda.gov.cn/cmsweb/webportal
[Accessed December 3, 2011].
87. Sun Q et al. Pharmaceutical Policy in China. Health Affairs 2008; 27(4):1042-1050.
88. Deng R and Kaitin K. The Regulation and Approval of New Drugs in China. Drug
Information Journal 2004; 37:2939.
89. Yin H. Regulations and Procedures for New Drug Evaluation and Approval in China.
Hum. Gene. Ther. 2006; 17:970-974.

www.ajptr.com

204

Sandhe et. al., Am. J. PharmTech Res. 2012; 2(3)

ISSN: 2249-3387

90. Zhang Q. The Chinese Regulatory Licensing Regime for Pharmaceutical Products: A
Law and Economics Analysis. Michigan Telecommunications and Technology Law
Review 2009; 15:417-452.
91. James J. Shen. Drug Regulatory Framework in China in China Pharmaceutical Guide.
Published by WiCON International Group. 2011 (6th Edition), 346-449.
92. Cheng RL. Needs for Post-Marketing Evaluations in China. Chin J Pharmacovigilance
2005; 2:2205.
93. Wang Y, Tang Z. The Analysis of ADRs Related To Houttuynia Herb Injections. Chin J
New Drugs 2006; 15:739741.
94. Du et al. Drug Safety Surveillance in China and Other Countries: A Review and
Comparison. Value in Health 2008; 11(1):130-136.
95. LIANG H, Ding J, & Xue, Y. Chinas Drug Innovation and Policy Environment. Drug
Discovery Today. 2011; 16:1-3.
96. Ding J et al. From Imitation to Innovation: A Study of Chinas Drug R&D and Relevant
National Policies. J. Technol. Manag Innov. 2011 ;( 6):1-13.
97. Belgharbi, L.Vaccine regulatory issues in African countriesbuilding and sustaining
national capacity. World Health Organization HTP/IVB/ATT, EDCTP Consultative
Meeting, 11th June 2007.
98. Noor RA. Health Research Oversight in Africa. Acta Tropica 2009; 112:S63S70.
99. Wassenaar DR, Slack CM. Perceived Capacity Of Selected African Research Ethics
Committees to Review HIV Vaccine Trial Protocols. IRB 2006; 28(2):19.
100. Van Rensburg HCJ, Fourie A. Inequalities in South African health care: part I. The
problem manifestations and origins. S Afr Med J 1993; 84:9599.
101. Kirigia JM, Wambebe C, Baba-Moussa A. Status of National Research Bioethics
Committees in the WHO African Region. BMC Medical Ethics 2005; 6:10.
102. Chima, S. Regulation of Biomedical Research in Africa. BMJ 2006; 332:848851.
103. Glickman et al. Ethical and Scientific Implications of The Globalization Of Clinical
Research. NEJM 2009; 360:816823.
104. Karlberg JP .Sponsored Clinical Trial Globalization Trends. Clinical Trial Magnier
2008;1.
105. Kumaranayake, L. The Role of Regulation: Influencing Private Sector Activity within
Health Sector Reform. J Int Dev 1997; 94:641-649.
205

www.ajptr.com