Clinical Pharmacology in Healthcare, Teaching and Research

Clinical
Pharmacology
in Health Care,
Teaching and
Research
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Teaching
Clinical Pharmacology
in Health Care, Teaching
and Research
Foreword and Acknowledgments
This position paper regarding the roles of clinical pharmacology in health care, teaching and research was composed
and edited by representatives of the International Union of Basic and Clinical Pharmacology (IUPHAR), the World Health
Organisation (WHO) and the Council for International Organizations of Medical Sciences (CIOMS). It is an updated
and edited version of a recent publication entitled Clinical Pharmacology in Research, Teaching and Health Care-
Considerations by IUPHAR, the International Union of Basic and Clinical Pharmacology which was published in the
journal Basic and Clinical Pharmacology and Toxicology (BCPT) in 2010, Volume 107, pages 531 559. This document
contains new chapters of special relevance to global health.
We thank Professor Kim Brsen, the editor of BCPT, the publishers of the journal, and the original and new authors for
generous collaboration during the editorial process.
We gratefully acknowledge financial support for the printing and publication of this paper from:
The World Health Organisation
The Council for International Organizations of Medical Sciences
The International Union of Basic and Clinical Pharmacology
The British Pharmacological Society
The Swedish Foundation for Clinical Pharmacology and Pharmacotherapy
For WHO Lembit Rgo
For CIOMS Gunilla Sjlin-Forsberg
For IUPHAR Michael Orme (Liverpool, UK), Folke Sjqvist (Stockholm, Sweden), and Donald Birkett, (Sydney, Australia).
IV Clinical Pharmacology in Health Care, Teaching and Research

CONTENTS
Abbreviations .................................................................................................................................................................................................................................... 2
1. Executive Summary....................................................................................................................................................................................................... 3
2. Introduction................................................................................................................................................................................................................................ 5
3. Definition of Clinical Pharmacology................................................................................................................................................. 7
4. History of Clinical Pharmacology.......................................................................................................................................................... 9
5. The Global Medicine Scene: The Place of Clinical Pharmacology..........................................11
6. The Clinical Pharmacologist in Patient Care..................................................................................................................13
7. Drug Therapy in Paediatric Patients.............................................................................................................................................17
8. Drug Therapy in Geriatric Patients..................................................................................................................................................19
9. Teaching Clinical Pharmacology.........................................................................................................................................................21
10. Research Domains of Clinical Pharmacology..............................................................................................................27
11. Emerging Roles of Clinical Pharmacology: Biologics and Biosimilars 31
12. Clinical Pharmacology and the Pharmaceutical Industry 33
13. Governments: Essential Roles for Clinical Pharmacology 37
14. The Clinical Pharmacologist and Traditional Medicines 41
15. Collaboration with Other Drug Experts 43
16. Organisation: Structural Models for Clinical Pharmacology 45
17. The Central Place of Clinical Pharmacology in Global Public Health 47
18. Overview.....................................................................................................................................................................................................................................53
19. References.................................................................................................................................................................................................................................57
20. Editors and Contributors..................................................................................................................................................................................65
21. Addendum I.
Model Core Curriculum for Clinical Pharmacology,
Therapeutics and Prescribing for Medical Students.........................................................................................67
22. Addendum II.
Model Curriculum for Medical Specialisation in Clinical Pharmacology 73
Clinical Pharmacology in Health Care, Teaching and Research 1

Abbreviations
ADR Adverse drug reaction
ADME Absorption, distribution, metabolism and excretion
AIDS Acquired immunodeficiency syndrome
CIOMS Council for International Organizations of Medical Sciences
CME Continuing medical education
CNS Central nervous system
CP Clinical pharmacology
CPT Clinical pharmacology and therapeutics
CRO Clinical research organisation
CVS Cardiovascular system
CYP Cytochrome P450
DNA Deoxyribonucleic acid
EMA European Medicines Agency
EU European Union
FDA Federal Drug Administration (in the USA)
GCP Good clinical practice
GLP Good laboratory practice
GMP Good manufacturing practice
GxP The combination of GCP, GLP, and GMP
HIV Human immunodeficiency virus
HTA Health technology assessment
IP Intellectual property
IUPHAR International Union of Basic and Clinical Pharmacology
NIH National Institute of Health (in USA)
NMRA National Medicines Regulatory Authority
OTC Over the counter
PD Pharmacodynamics
PK Pharmacokinetics
R&D Research and development
RCT Randomised Controlled Trial
RUM Rational use of medicines
TDM Therapeutic drug monitoring
TNF Tumour necrosis factor
WHO World Health Organization
2 Clinical Pharmacology in Health Care, Teaching and Research

Executive Summary 1
I Definition individual patients and for patient populations

Clinical Pharmacology is the scientific discipline that wherever they may reside. Clinical care of paediatric
involves all aspects of the relationship between and geriatric patients needs special attention from
drugs and humans. It is a multidisciplinary science the clinical pharmacologist and these special
that encompasses professionals with a wide variety interests are addressed in chapters 7 and 8. The
of scientific skills including medicine, pharmacology, clinical pharmacologist is expert in the critical
pharmacy, biomedical science and nursing. The evaluation of new and old therapies, and uses drug
term clinical pharmacologist is commonly used in utilisation studies and pharmacoepidemiological
the professional sense to refer to physicians who services to help in this task as well as skills such as
are specialists in clinical pharmacology. They have pharmacogenetics. Clinical pharmacologists have an
undertaken several years of postgraduate training important role on Drug and Therapeutics Committees
in many aspects of the above relationship involving where they help the rational introduction and use
health care, teaching, and research. Such clinical of new and expensive medicines into the delivery
pharmacologists have as their primary goal that of health care. Clinical pharmacologists provide, in
of improving patient care, directly or indirectly, by collaboration with other health care staff such as
developing better medicines and promoting the safer pharmacists, drug information services to a wide
and more effective use of drugs. variety of prescribers. Specialist services may include
therapeutic drug monitoring, involvement in clinical
I Aims drug toxicology and pharmacovigilance. Adverse
This document aims to set the scene for clinical reactions to drugs still cause many problems for
pharmacology in the early part of the 21st century patients, and health care systems could do more
following the concepts of an earlier report by to prevent these since most of them are predictable
the World Health Organisation in 1970 (1). This through a knowledge of pharmacology.
document is aimed primarily at decision makers in a
variety of organisations, particularly in Governments The concept of personalised medicine is one where
and their health care ministries, in addition to chief drug therapy can be based on the pharmacogenetic
executives and board level directors of primary or other characteristics of a particular patient. While
and secondary care systems and directors in in its infancy as a discipline there are now good
pharmaceutical companies. It lays out in detail the examples whereby adverse effects can be minimised
great benefits that expertise in clinical pharmacology and drug efficacy enhanced by a knowledge of
can bring to the delivery of better health care for all the genetic makeup or other characteristics of the
populations. individual patient.
I The Clinical Pharmacologist I Teaching Clinical

in Patient Care Pharmacology
Clinical pharmacology has developed a number The teaching of clinical pharmacology is a vital
of ways in which the clinical care of patients can part of the work of a clinical pharmacologist (see
be improved (see chapter 6). The prime aim is to chapter 9 and addenda I and II). Perhaps the most
improve the Rational Use of Medicines both for important area is the training of new prescribers,

primarily medical students and new physicians. With in such companies are useful for the general training
the increasing trend for nurses and pharmacists to of a clinical pharmacologist (e.g clinical trials) a long
prescribe, usually in particular areas, attention needs term career in such a company requires a new set of
to be paid also to their training in prescribing. The skills for which training and experience is needed.
ability of new young physicians to prescribe safely
and effectively has been criticised in recent years, I Governments: Essential Roles
and new systems are being developed to enhance for Clinical Pharmacology
these skills in the training of medical students. Governments need clinical pharmacologists to help
Since assessment drives learning, the assessment deliver the goal of ensuring safe and effective drug
systems are being improved too. Specialist training therapy for their populations, whether the clinical
of physician clinical pharmacologists is addressed in pharmacologists are working in hospitals, regulatory
Addendum II, since there is a world wide shortage of agencies or in Health Technology Assessment (HTA)
such specialists. However the needs, the resources, (see chapter 13). With a few notable exceptions the
and the regulatory arrangements available in different discipline of HTA has emerged in the absence of
countries mean that the approach suggested is a contributions from clinical pharmacology.
general one.
Clinical pharmacologists have a crucial role to play
I Research Domains of Clinical in helping to deliver the WHO agenda of Guidelines
Pharmacology for the Development of National Drug Policies to
Research is a vital part of the training and everyday which more than 150 countries are now signed up
work of a clinical pharmacologist (see chapter 10). (2). The policies aim to ensure:
The endeavour of a pharmacologist working in the
clinical environment is to develop methods and The quality, safety and efficacy of medicines
strategies that improve the quality of drug use Equitable access to medicines for all the population
in individual patients and in patient populations. The rational/quality use of medicines
Clinical pharmacological research has always A viable and responsible local pharmaceutical
been translational in the sense that the discipline industry.
aims to translate new scientific data on drugs into
rational patient care. An increased engagement Clinical pharmacologists are paying increasing
of clinical pharmacologists in the design, conduct attention to the health needs of those peoples who
and execution of clinical trials, particularly early have in the past been marginalised. They include
phase I studies, would be advantageous. However, children, those with rare diseases, and those with
enhanced training in these areas may be required. conditions that are endemic in the poorest parts of
the world. The training of clinical pharmacologists
I Clinical Pharmacology and to meet these needs is rather different from that
the Pharmaceutical Industry envisaged in 1970 when the first WHO report was
The pharmaceutical industry has been at the published (1).
forefront of helping to train clinical pharmacologists
(see chapter 12). While many of the skills acquired

Introduction 2
Some forty years ago the World Health Organisation is worsened by the increasing use of combination
brought together a group of experts in Clinical therapies and the higher proportion of elderly patients
Pharmacology and Therapeutics to define the in the population. We know that ADRs (the formal
discipline of Clinical Pharmacology, and to outline study of which has now given rise to the discipline
how it could help to improve the use of drugs in the of pharmacovigilance) cause some 7% of admissions
delivery of health care (1). In the last four decades to hospital and they are also a not uncommon
the importance of drug therapy has changed cause of death, particularly in elderly patients (4,5).
markedly in terms of the potency of the drugs we Many of these ADRs are predictable and could be
use, in the number and diversity of drugs that are prevented if the process of educating prescribers was
available, and in the number of diseases that can taken more seriously. Another problem that has not
be treated. In addition the discipline of molecular improved significantly over the years since 1970 is
biology has had an increasing impact on the the errors made during the prescribing process in
development of drugs, but solid knowledge about spite of the widespread availability of computers and
the pharmacological principles that underpin the the internet providing easy access to appropriate
Rational Use of Medicines (RUM) is just as relevant information and knowledge (6). These problems are
now as it was in 1970. more written about in resource rich countries but are
just as relevant in resource-poor countries.
Since the production of the 1970 report the cost of
developing drugs has risen substantially and the cost It is clear then that the time has come to modernise the
of taking a new chemical entity to market can easily original WHO report in the light of lessons that have
be in excess of $US 1000 million (638 million, 764 been learned and problems addressed. This updated
million). As a result newly developed drugs are very report arises from a partnership between the World
expensive, making it more difficult for resource poor Health Organisation (WHO), the International Union
countries to fund drug therapy for their inhabitants of Basic and Clinical Pharmacology (IUPHAR) and the
although there are welcome exceptions in the Council for International Organizations of Medical
provision by Big Pharma of modern drugs at a very Sciences (CIOMS). After a period of expansion in
low or no cost (eg ivermectin for onchocerciasis). Even the last 20 years of the twentieth century, clinical
resource rich countries have limitations in financing pharmacology as a discipline declined somewhat
drug therapy and this has led to new concepts such in many countries. However during the last few
as the cost effectiveness of drug therapy and to the years there have been signs both of new growth
discipline of pharmacoeconomics. in and new enthusiasm for the discipline (7),
although the importance of clinical pharmacology
While clinical pharmacology is learning to face these to pharmaceutical companies has never been in
new problems we are still dealing with problems in doubt. A recent report on the relationship between
drug therapy that were recognised in the 1970s. We the pharmaceutical industry and the National Health
knew then that adverse reactions to drugs (ADRs) Service (NHS in the United Kingdom) has stated that
were among the more common causes of admission re-building clinical pharmacology as a core discipline
to hospital (3) and this problem has not decreased in the NHS is of vital importance for the future of
in importance over the decades largely because little health care in the UK and this is likely to be true in
is done about it. In addition the problem of ADRs many other countries (8).

This document aims to set the scene for clinical have a particular interest in improving drug therapy
pharmacology in the early part of the 21st century and making it safer and more effective as exemplified
by updating the concept of the original WHO report. in the WHOs Rational Use of Medicines policy (9).
We have gathered a group of distinguished clinical However, this document is particularly aimed at
pharmacologists who have written the individual decision makers in a variety of organisations, in
sections which are designed to address the essential Governments and their health care ministries as
role of clinical pharmacology in health care, teaching well as chief executives and board level directors
and research as well as describing the disciplines of primary and secondary care organisations
link with industry and governments. We hope that and directors in the pharmaceutical industry. The
the document will prove useful to many people, document details the great benefits that expertise
perhaps particularly young doctors who are looking in clinical pharmacology can bring to the delivery of
to establish themselves in a clinical specialty and who better health care for all populations.

Definition of Clinical Pharmacology 3
Clinical Pharmacology is the scientific discipline that The descriptor clinical pharmacologist is normally
involves all aspects of the relationship between drugs used in a professional sense to refer to physicians
and humans. Its breadth includes the discovery and involved in the medical care of patients who are
development of new drugs, the application of drugs specialists in clinical pharmacology. They have
as therapeutic agents, the use of drugs, the beneficial usually undertaken several years of postgraduate
and harmful effects of drugs in individuals and training (see Addendum II) focussing on important
society, and the deliberate misuse of drugs. Clinical aspects of clinical pharmacology including clinical
pharmacology is a multidisciplinary team science trials, drug evaluations, pharmacoepidemiology,
that encompasses professionals with a wide variety pharmacoeconomics, pharmacovigilance and clinical
of scientific skills including medicine, pharmacology, drug toxicology. Some countries have accreditation
pharmacy, biomedical science and nursing. Other programmes for clinical pharmacology as a physician
professionals who are important in various aspects of specialty but many do not. The present document
clinical pharmacology include social and behavioural refers essentially to medical clinical pharmacologists.
scientists, dentists, economists, epidemiologists,
geneticists, toxicologists, mathematicians and
computer scientists.

History of Clinical Pharmacology 4
Clinical pharmacology is both old and young. There is no doubt that the most vigorous attempts
The practice of drug therapy goes back to ancient to develop clinical pharmacology as an academic
times and the discovery of drugs such as quinine, discipline were made in the United States (13,14).
reserpine and artemisinin which were first used as Important landmarks are the first edition of
herbal medicines. William Witherings publication on Goodman and Gilmans The Pharmacological Basis
the use of foxglove in the treatment of heart failure of Therapeutics and the successful attempt (1960)
(see10) may very well be considered the first scientific by Walter Modell, also at Cornell, to launch the
account of the discipline but it took 200 years first scientific journal in the subject entitled Clinical
before the pharmacology of digitalis was explored Pharmacology and Therapeutics.
with accurate, clinical pharmacological methods.
As a scientific discipline, clinical pharmacology is In the early 1960s, the United States became
young having originated from the middle of the the world centre for the training of clinical
20th century. It is difficult to find who first coined pharmacologists. The NIH chief James Shannon and
the name as opinions differ between countries. his colleagues Bernard B. Brodie and Julius Axelrod
Several distinguished pharmacologists active in introduced biochemical pharmacology as a science
the middle of the century brought pharmacology and drug measurements in body fluids as tools in
and clinical know-how about drugs together and clinical pharmacology. Several centres of excellence
helped to transform drug evaluation from the trial in clinical pharmacology offered training to potential
and error state to a scientific discipline. In the Anglo- clinical pharmacologists from all parts of the world.
Saxon literature, Harry Gold at Cornell (10,11) is The efforts to improve clinical drug evaluation by
commonly quoted as the person who first introduced Louis Lasagna, a pupil of Harry Beecher at John
the name clinical pharmacology in the early 1940s. Hopkins Hospital, should be especially recognised
However, in 1914, a textbook was written by Hans (13,14). In1966, Lasagna published a brilliant,
Horst Meyer and Rudolf Gottlied in German the title still valid, account in Science of the present status
of which was translated as Pharmacology, Clinical and future development of clinical pharmacology
and Experimental. In addition, also in the German (14). The birth of clinical pharmacogenetics can be
literature, Paul Martini, professor of medicine in ascribed to the pioneering contributions of Werner
Bonn, published his monograph in 1932 entitled Kalow and A.G. Motulsky (15,16).
Methodology of Therapeutic Investigation and
he is considered by some as the first clinical Parallel developments occurred in Europe, particularly
pharmacologist (12). According to Shelley and Baur, in the UK, where the strong infrastructure in basic
his contributions escaped the attention of the English- pharmacology and clinical medicine formed an
speaking world (12). In the English literature, there excellent basis for a rapid growth of the discipline.
is a long tradition of materia medica, particularly Names that are usually mentioned in this context
in Scotland. In 1884, John Mitchell Bruce wrote his are those of Sir John Gaddum, Sir Horace Smirk
textbook entitled Materia Medica and Therapeutics. and Sir Austin Bradford Hill (10). Chairs in clinical
An Introduction to the Rational Treatment of Disease pharmacology were created at the end of the 1960s
and this, in its 20th edition, became Dillings Clinical in Germany, the UK and Sweden, although chairs
Pharmacology. This book was published in 1960, in Materia Medica had long been established in
the same year as Desmond Laurences textbook Scotland. Academic growth of the discipline also took
entitled Clinical Pharmacology. place in France (17). IUPHAR took early initiatives to

develop clinical pharmacology. A section of clinical Europe put together a booklet and a series of papers
pharmacology was formed in the early 1970s and in the European Journal of Clinical Pharmacology
a division in the 1990s. Several IUPHAR executives about the roles of clinical pharmacology in teaching,
strongly supported the discipline, particularly the research and health care (18). For the first time,
first president Brje Uvns in Sweden, but also Sir the potential usefulness of the discipline for the
Arnold Burgen in the UK and Helena Raskova in RUM in primary health care was emphasised.
Czechoslovakia, who all realised that pharmacology Several Nobel Prize laureates in medicine can
had to reach out to the bedside in order to develop. be considered as representatives of clinical
WHO brought together a Study Group in 1970 (1) to pharmacological research at its best such as Sir John
write a report on the scope, organization and training Vane, Sir James Black, George Hitchings, Gertrude
of clinical pharmacology, led by the late Sir Derrick Elion and Arvid Carlsson. They all practiced clinical
Dunlop (UK), and containing, amongst others, the pharmacology during their efforts to introduce
late professors Louis Lasagna (USA), Franz Gross, new pharmacotherapeutic principles into clinical
(Germany) and Leon Goldberg, (USA). In 1991, WHO medicine.

The Global Medicine Scene:
The Place of Clinical Pharmacology 5
Modern drug therapy has unquestionably chemical libraries available to most pharmaceutical
transformed the health of peoples in developed companies, coupled with high throughput screening
countries over the last 50 years. Conditions such as and combinatorial chemistry, offer unimaginable
poliomyelitis, diphtheria and pertussis have largely rewards for us all. In addition, the emergence of an
been eliminated in wealthier nations. Many lethal array of biotechnological techniques offers unique
communicable diseases can be cured by modern approaches to the development of innovative
antimicrobial agents. And complex surgery, beyond medicines.
the imagination of our forefathers, can be performed
safely and effectively using modern anaesthetic Yet, despite the promise from the science, the
agents. Those with chronic diseases have benefited outlook is not favourable. Despite record investment
immeasurably with the emergence of safe and in biomedical research by the public sector and not-
effective treatments for asthma, hypertension and for-profit organizations, as well as by pharmaceutical
hypercholesterolaemia. and biopharmaceutical companies, the number of
new active molecules registered by drug regulatory
Nevertheless, there remains massive unmet clinical authorities has fallen dramatically. The costs of
need in developing, emerging and developed bringing a new product to the market are increasing
countries. There is, for example, a pressing need at a rate of 10% per annum, due in part to the
for effective vaccines against HIVAIDS, malaria failures of products during development, but also
and tuberculosis. We have nothing to prevent the to the extended requirements for evidence-based
inexorable decline in neurological function in people documentation from regulatory authorities (e.g. in
with neurodegenerative disorders such as Alzheimers elderly patients). Added to this, many of the largest
disease, Parkinsons disease or Huntingtons disease. pharmaceutical companies face large reductions in
And, when effective vaccines and treatments have turnover as their blockbusters come off patent.
been developed, they are too often unavailable to
those in the poorer parts of the world. During most There have also been spectacular withdrawals
of the second half of the 20th century, research- of some marketed medicines because of safety
based pharmaceutical companies were, for practical concerns. As a consequence, drug regulatory
purposes, the sole source of new medicines. They authorities have become increasingly risk averse and
discovered, developed and delivered products place ever greater demands on manufacturers to
often with considerable ingenuity for healthcare demonstrate the safety of their products before and
systems that were able to afford the costs required after marketing. While this may have some benefits
to maintain the industrys infrastructure. for drug safety, these measures are likely to increase
the cost of medicines unless they are implemented
People in poorer countries, unable to meet these with considerable care. Moreover, healthcare systems
costs as well as lacking an appropriate healthcare across the world are struggling to meet the apparently
infrastructure only rarely benefited. The prospect high prices that pharmaceutical companies seek to
for satisfying unmet medical need has, in some charge for new products that do reach the market.
senses, never been brighter. Advances in molecular Those responsible for meeting the health needs of the
techniques offer the promise of identifying drug- populations they seek to serve are under increasing
sensitive targets that might attenuate or cure many pressure to provide affordable care. The increasing
miserable and life threatening conditions. The massive numbers of elderly and very elderly people (many

with long-term chronic diseases requiring multiple 4. Some major pharmaceutical and biopharmaceu-
drug therapy), the greater availability of effective tical companies are increasingly recognising that
screening measures (especially in the elderly), and their traditional models of discovery, development
the growing expectations of the public, all mean that and pricing no longer meet the needs of patients,
resources are constrained. One of the reasons for the healthcare systems or their shareholders (21).
rapid emergence of HTA facilities, across Europe and Changes include moving away from seeking
North America, is because of the necessity to look blockbusters; expanding sales to include the
ever more closely at the clinical efficacy and cost- emerging markets in Asia; and discussing, with
effectiveness of therapeutic strategies. healthcare systems themselves, what future
products would bring most value for money.
I The Future Prospects
Despite this gloomy outlook, a number of initiatives I Conclusions
suggest that remedial action is being taken: These changes in the global medicines scene require
the contributions of appropriately trained clinical
1. Drug regulatory authorities themselves recognise pharmacologists if innovative new medicines are to
the need for change if people are to have access reach those in need:
to innovative medicines. Both the Food and Drug
Administration in the United States (19) and the 1. Clinical pharmacologists should be better
European Medicines Agency (EMA) in the EU equipped to undertake translational research,
(20) have published plans for expediting the especially the design and execution of Phase 1
regulatory process of innovative medicines that studies.
are appropriately safe and effective. 2. Too few contemporary clinical pharmacologists
2. The process of drug discovery, confined for are actively engaged in the design and conduct
most of the 20th century to the laboratories of of clinical trials. The founding fathers of the
research-based pharmaceutical companies, has discipline (such as Lou Lasagna (13)) made crucial
become much more pluralistic. In particular, contributions to health care by undertaking clinical
academic scientists working in universities have trials often in relatively small patient populations
become drug hunters and some have been that characterised a compounds properties
spectacularly successful. Whereas 25 years ago, (especially doseresponse relationships).
major pharmaceutical companies were unwilling 3. With a few notable exceptions, the discipline of
to even contemplate developing products HTA has emerged in the absence of contributions
that had not been discovered in their own from clinical pharmacology. This needs to change
laboratories, they are now prepared to do so with if HTA is to meet its full potential.
enthusiasm. Indeed, companies are pursuing truly 4. Clinical pharmacologists could do so much more
collaborative projects with academic scientists to to meet the health needs of those peoples who
the extent that they are allowing access to their have in the past been marginalised. They include
chemical libraries. children, the elderly, those with rare diseases and
3. An increasing number of not-for-profit those with conditions that are endemic in the
organizations such as the Bill and Melinda Gates poorest parts of the world.
Foundation (in Seattle) and the Hereditary Disease
Foundation (in New York) are supporting drug
discovery and development in co-operation with
both academia and pharmaceutical companies. I Introduction

The Clinical
Pharmacologist in Patient Care 6
The ways in which clinical pharmacological services controlled clinical trials and observed effectiveness
could be integrated in healthcare systems were first in clinical care (24,28). Clinical pharmacology with
outlined in 1970 in a WHO Technical Report referred its emphasis on critical drug evaluation, scientific
to earlier (1). methodology, drug development and involvement
in the work of drug and therapeutics committees
The quality and outcome of drug therapy in patient is strategically positioned to bridge the knowledge
care can be greatly improved by using cost-effective gap between stakeholders including patients,
and evidence-based treatment with drugs adapted clinicians, pharmacists, administrators, politicians
to the needs of patient populations and individual and pharmaceutical companies within and outside
patients. Advances in drug development provide healthcare institutions (26,27).
patients with new drugs, novel drug combinations,
expensive biological drugs and targeted drug therapy The quality of drug therapy can be improved in all
adapted to the molecular characteristics of the disease healthcare settings irrespective of the resources of the
(22,23,24). Increasingly cost-effective generic country or of individual health care facilities. Patients
drugs are available and should be used as first- can be provided with effective and safe therapy if well-
hand therapies to balance the economic pressures documented drugs are prescribed, and the drugs are
on all healthcare systems today (25). The rate of used according to medical, social, environmental and
implementation of this strategy varies widely across financial circumstances. The gap between knowledge
health care systems (25). Easy access to evidence- about drugs and their use in clinical practice needs
based drug information will assist physicians and to be reduced in order to promote the principles
healthcare staff in monitoring the effectiveness and governing the Rational Use of Medicines (RUM).
safety of drug therapy and optimal allocation of limited These principles have to be communicated, learnt and
resources (26,27).This is a priority since patients and practiced by students, doctors, healthcare staff and
patient organizations are eager to explore what patients in their daily clinical practice (24,27,29,30).
new therapies can offer in terms of health benefits An optimal strategy for eliminating the knowledge
compared to existing treatments, but new drugs practice gap in drug therapy is to apply a multifaceted
and drug combinations may not be affordable for all approach including practice-governed quality
patients and healthcare institutions. It needs also to assurance programmes combined with interactive
be considered that newly registered drugs are rarely continuous medical education and prompt electronic
innovative (24,27). As a result, great emphasis must access to evidence-based guidelines (24,27,31).
be placed on the overall cost-effectiveness and safety The principles of RUM have to be integrated with
of new drug therapies from a societal perspective in healthcare planning and with resource allocation
order to guide drug selection and reimbursement given the scarcity of resources that healthcare
decisions (22,28). The use and value of new drug institutions are facing. Clinical pharmacologists with
therapies have to be monitored within the healthcare their focus on drug evaluation and on the principles
institutions as part of a systematic introduction and of RUM are needed in patient care (22,27,28,29).
follow-up of new therapies by involving drug experts They should train healthcare staff in the principles of
across medical specialties and systematic use of drug evaluation and promote the use of guidelines
clinical outcome data (24,28). Such a procedure will and drug recommendations based on scientific
diminish the gap between documented efficacy in evidence. At the level of individual hospitals and

healthcare institutions, limited resources cannot be efficacy, safety and cost-effectiveness for a specific
used effectively and safely without a local knowledge drug therapy as compared with alternative therapies.
and the practice of the principles of critical drug The method of critical drug evaluation requires
evaluation among clinicians and pharmacists (26,27). medical, clinical pharmacological and scientific skills
Decisions on drug use and reimbursement for (13, 26, 27). Applying critical evaluation methods
specific indications can rationally be adapted to local in local health care settings is complementary to
circumstances in health care facilities by involving key evaluations by drug registration bodies. Key elements
medical opinion leaders at a local level supported by of critical drug evaluation include assessment of the
clinical pharmacologists and pharmacists trained in quality and completeness of a clinical drug study.
critical drug evaluation (27,29,30,31). In doing so, By using a rating scale (0, 1, 2) this methodology
unbiased decisions free from improper influence by can assist healthcare staff to assess the value of a
special interest groups is particularly important in specific drug therapy in clinical practice (33). In
view of the relentless increase in the promotion and short, an evaluation of a clinical drug study should
cost of new drugs (27). preferably include rating of the following aspects:
I Key clinical pharmacology - aims of the trial

services in patient care - relevance of the trial for health care
The form these services take may vary from country - the quality and precision of criteria for diagnosis
to country and facility to facility depending on the and selection of patients
professional and financial resources available. The - the type of controls used in the study
key bodies providing overall coordination and control - the quality of the design of the study
of these services are the Drug and Therapeutics - adequacy of randomisation to treatment
Committee (DTC) and Clinical Pharmacology - the quality of pharmacokinetics data
Departments at hospitals or in primary care. - drug-drug interactions problems if any
Therefore, all health care facilities should have a well- - how adequately drug effects were recorded
developed DTC with clear instructions, resources and - how well adverse effects were monitored and
a comprehensive approach (27,32). evaluated
- the quality of statistical planning and analysis
(a) Critical evaluation of new and old therapies - the precision of conclusions of study results and
is fundamental for patient care. It should be a core shortcomings
activity in clinical consultations, in the provision of
drug information, in services to DTCs, in consultations By applying this procedure it is feasible to rate the quality
with clinical colleagues clinics, in drug selection and of a drug study with a maximum of 24 points that will
in the design of clinical trials. Critical drug evaluation help to guide the clinician about the strength of a specific
is the cornerstone for RUM and is important in rich as clinical drug study and drug therapy. It will be possible to
well as in resource-poor settings. The role of critical choose between suggested drug therapies by comparing
drug evaluation is particularly important when new outcomes of ratings of several clinical drug studies.
and expensive drug therapies and drug combinations
are introduced (see also Chapter 12).
Critical drug evaluation assists the practicing physician

in rating the strength of documentation about

(b) Drug and Therapeutics Committees (DTC) pharmacologists or clinical pharmacists depending on
All institutions, no matter what size, should have the availability of staff at the particular facility. Drug
some appropriate version of a DTC. It should information services build on systematic literature
preferably recruit both hospital based specialists and searches in databases and reference books combined
primary care physicians in order to provide the same with an evaluation of the literature on patient-related
type of recommendations irrespective of the level diagnostic problems. This service should assist DTCs
of healthcare (26,27). The membership will vary in literature searches as the foundation of evidence-
depending on local circumstances and resources based drug recommendations. A drug information
but may include physician clinical pharmacologists, service is also helpful for provision of unbiased
relevant medical staff, clinical and other pharmacists drug information in academic drug detailing, which
and other staff as appropriate. Where available, is well documented to improve adherence to drug
physician clinical pharmacologists provide a recommendations and guidelines and should be part
leadership role bridging medical, pharmacy and other of the activities of the DTCs (36).
staff (26,27). DTCs should issue recommendations
for drug use within the facility based on scientific (e) Services in pharmacovigilance may
evidence and medical needs at the local level. This include the responsibility to be a coordinating
will usually take the form of a local formulary or centre for reports of adverse drug reactions (ADRs)
Wise List with the WHO Essential Drug concept from clinicians and other prescribers at a regional or
being a useful model (27,34). national level (37). ADR reports should be evaluated
systematically and the conclusions fed back to the
(c) Drug utilisation studies and pharma- reporting clinicians and the DTC. Regional clinical
coepidemilogical services are closely linked to pharmacology centres for pharmacovigilance have
the work of DTCs and to quality assurance of drug been successfully implemented in countries such as
therapy in clinics and in hospitals (30, 35). Ideally, France and Sweden (37). Pharmacovigilance should
a multi-professional approach is preferred involving be given priority in resource poor settings when
experts in clinical specialties, pharmacoepidemiol- implementing population based therapies to control
ogy, pharmacoeconomics and clinical pharmacology. major infectious diseases such as HIV/AIDS, malaria
These services are important for a systematic intro- and tuberculosis (38).
duction and monitoring of new drug therapies in the
facility and can then be linked to forecasting future (f) Continuing medical education. The focus
drug use in healthcare organisations. Knowledge should be on major pharmacotherapeutic areas, on
about the use of drugs is a prerequisite for follow- the principles of RUM and on new drug therapies
up studies of the adherence of prescribers to drug and drug combinations. Interactive models for
recommendations and of the effectiveness of drug learning such as integration of e-learning tools in
information and educational activities (27,30,35). academic drug detailing and open access internet
should be considered and will help to improve the
(d) Drug information services are primarily quality of knowledge in drug therapy in remote
targeted to guide clinicians in evaluating and solving healthcare institutions in resource poor countries.
drug problems in patients. The services provided Continuing medical education should preferably be
are usually both descriptive and problem oriented. interactive as this will foster the best involvement of
The latter, addressing problems at a patient level clinical colleagues.
are appropriately provided by physician clinical

(g) Therapeutic drug monitoring (TDM) and pharmacologists are mainly used for their skills in
pharmacogenetic services ideally involve the the evaluation of clinical drug problems such as
participation of a Division or Department of Clinical therapeutic polypharmacy. Clinical pharmacologists
Pharmacology. TDM services should always involve can assist in the development, implementation and
clinical interpretation of the data taking diagnosis, evaluation of efficacy and safety of combination
drug-drug interactions, kidney function and therapies in the treatment of major infectious diseases
pharmacogenetics into consideration. An important such as HIVAIDS, tuberculosis and malaria. In both
service, particularly for elderly patients, is to ensure rich and poor countries, drug abuse problems cause
that drug dosages are adapted to the reduction considerable harm (41). Preventive programs as well
in kidney function that occurs with age (see also patient care require access to clinical pharmacological
Chapter 8). An example of successful translation of expertise supported by adequate drug analytical
the scientific development of pharmacogenetics into resources.
the clinic is the abacavir hypersensitivity syndrome
which now can be prevented (39). Moreover, (j) Electronic Pharmacological (e-Pharmaco-
the discipline of personalised medicine is rapidly logical) Services. Evidence-based databases for
growing, particularly in the field of cancer. rational drug prescribing are now available through
websites in many countries (42,43). They can be
(h) Measurement of drug concentrations integrated into electronic medical journals and
for the diagnosis and prevention of drug linked to lists of prescribed drugs. E-pharmacological
abuse and other toxicological services. In services include tools, knowledge databases on
many hospital settings, clinical pharmacologists are drug recommendations, drugdrug interactions,
involved in toxicological services such as diagnosis drugs to be used in pregnant or lactating women,
and treatment of drug intoxication. Although the ADRs and tools for the solution of drug related
availability of causal treatment with antidotes is problems. E-pharmacological services provide
limited, a correct diagnosis of the drug involved a link between published evidence and clinical
through drug analysis is important for follow-up and practice. These services are predicted to become of
future prevention. A new function in some countries particular importance with the accelerating spread
is to participate in the prevention of the abuse of of mobile phones and internet access in lesser
doping agents such as anabolic steroids among developed countries and will, in the future, require
athletes and in society at large (40). extension to the public and to patients (24). This
multidisciplinary field will be of great importance
(i) Direct Patient Services. Clinical in resource poor settings where the clinical
pharmacologists provide care for patients in a pharmacological community with a natural global
variety of ways. In some countries, physician clinical professional network can help to provide electronic
pharmacologists take responsibility for the direct drug information from different countries. The
care of patients with particular clinical problems contents of e-pharmacological services are heavily
(e.g. intensive care), in patients with particular organ dependent on expertise in critical drug evaluation.
diseases such as hypertension or areas such as
paediatrics and geriatrics. In some countries, clinical

Drug Therapy in Paediatric Patients 7
The well-known paediatric therapeutic disasters of between drugs and humans during growth,
the late 1950s (eg sulfisoxazole, chloramphenicol) development and maturation. Its breadth includes
revealed the need and gave the impetus for the the continuum between discovery, development,
development of paediatric clinical pharmacology. regulation and utilisation of medicines (as regards
Despite the fact that training of paediatric compounds and formulations) intended to benefit
clinical pharmacologists has been going on for the paediatric population. As well, paediatric clinical
decades, training capacity remains very small. pharmacology is concerned with the response to
Consequently the number of trained paediatric and the adverse effects of medicines, their use
clinical pharmacologists in the world is relatively and misuse, and the economics of drug therapy.
small, with the majority of countries having only a As the great majority of scientific research and
handful if any (44). In this context, paediatric clinical drug development is for many reasons first done in
pharmacologists are physicians with training in both adults, paediatric clinical pharmacology adds the
paediatrics and clinical pharmacology. However, translational element of adapting scientific methods
over the past two decades, professionals outside the and translating scientific information from adults to
discipline of medicine but who possess specialised paediatric patients (45).
expertise that is germane to the field of paediatric
clinical pharmacology have entered the discipline By virtue of the comprehensive scope of paediatric
and participate in a variety of settings (eg academic, clinical pharmacology, it involves numerous
regulatory, clinical and industrial). professional groups whose training and skills
are relevant to one or more of the scientific and/
The need for more and better development, scientific or clinical facets of the discipline of paediatric
study, regulatory assessment and appropriate use clinical pharmacology (eg physicians, biomedical
of paediatric medicines is recognised in the US, scientists, and non-physician health care providers
EU, and WHO paediatric medicines initiatives. such as nurses and pharmacists). Paediatric clinical
Implementation of all the paediatric studies pharmacology is therefore a scientifically driven field
mandated by these initiatives requires well trained of endeavour that depends on a variety of skilled
investigators and other experts (eg research professionals with a training or special interest in
trained nurses, pharmacists, laboratory scientists) appropriate aspects of paediatric drug therapy.
which in many countries do not exist in numbers
sufficient to embrace the demands associated with I Scope of Practice in Paediatric
paediatric drug development. Accordingly, building Clinical Pharmacology
enhanced capacity and strength in paediatric clinical Practice environments for paediatric clinical
pharmacology across the world is essential to ensure pharmacology are diverse and can include patient
the success of these initiatives. care, research, teaching, drug development and drug
regulation. Paediatric clinical pharmacologists may
I Definition of Paediatric participate directly in the care of paediatric patients
Clinical Pharmacology as either primary care givers or consultants, or may
Paediatric clinical pharmacology is a scientific work in scientific and/or administrative capacities to
discipline that involves all aspects of the relationship improve the quality of medicines use irrespective of

the health care setting or the wealth of the country. At future, it is essential that their special needs with
the country level, paediatric clinical pharmacologists respect to the development and implementation of
can provide valuable service in the development safe and effective drug treatment be fully embraced.
of National Medicines Policies that consider the To this end, the enhanced availability of the expertise
special issues of the paediatric population. These and services that can be provided by paediatric
issues include the Rational Use of Medicines (RUM) clinical pharmacologists represents a critical need on
in paediatric drug therapy and measures to protect a global level.
the basic human rights of paediatric patients who
participate in medicines research. Their involvement I Training in Paediatric Clinical
often extends to the regulatory assessment of Pharmacology
paediatric medicines, the development of national Paediatric clinical pharmacology is a sub-discipline
treatment guidelines, proposing inclusion of of clinical pharmacology and paediatrics. It is a
paediatric medicines in reimbursement lists, and recognised paediatric medical sub-specialty in at
monitoring of the performance of medicines in least the UK (46) and Australia. Individuals in other
different clinical settings after regulatory approval professional groups can also receive training and
(eg through the application of pharmacoepidemiology, certification in specific areas related to paediatric
pharmacovigilance and pharmacoeconomic principles) drug therapy through their professional associations.
to assess impacts on health outcomes. Finally, it must be emphasised that training in
paediatric clinical pharmacology must extend beyond
It should also be recognised that, globally, more than the development of specialist paediatric clinical
a third of the population in developing countries, pharmacologists. It is vital that educational curricula
and almost half in the least developed countries are for all health care professionals involved in the
in the paediatric age range (less than 18 yrs). Close treatment of infants and children contain appropriate
to 9 million children die every year before their 5th components of the principles of paediatric clinical
birthday from diseases that are usually amenable pharmacology. Similar educational components
to treatment. In the area of priority diseases like should also be included in undergraduate medical
HIV/AIDS, malaria and tuberculosis, children lag programs and in paediatric medical and surgical
far behind adults in their access to appropriate sub-specialty postgraduate training programs.
medicines, especially where the large part of The continued development of programs and
the burden of disease is borne by the paediatric practitioners of paediatric clinical pharmacology is
population (eg malaria). Recognising that children essential for these broad educational goals to be
represent the hope of 100% of the world for its accomplished throughout the world.

Drug Therapy in Geriatric Patients 8
The most rapidly expanding age group world-wide research or educational needs, and attracting
is those 80 years and older (47). Multiple concurrent physicians and training them to do geriatric clinical
illnesses that may benefit from drug treatment pharmacology is a continuing challenge.
are the rule, not the exception, in this group. The
likelihood of adverse drug reactions increases Clinical pharmacology has an important role to foster
markedly as the number of concurrently administered the linkage of the principles of geriatric medicine and
drugs rises. This combined with the age-related disease-based therapeutics. In geriatric medicine,
decline in physiological functions (decreased cardiac advances in understanding the interplay of multiple
reserve, impaired baroreflex function, decreased concurrent illnesses and how these may result in a
immunological response, decreased renal function) common path to patient disability and death have
that in younger patients may reduce the severity of allowed definition of the frailty syndrome (50). In
an adverse drug reaction, make the older patient addition, the concept of competing morbidity such
particularly at risk for polypharmacy related adverse that in the older patient successful treatment of
drug reactions (48). However the benefits for the one illness may result not in restoration of health,
treatment of hypertension, coronary artery disease, but in the more obvious clinical presentation of
congestive heart failure, diabetes, arthritis, and other another concurrent illness, has advanced clinical
chronic illnesses associated with advancing age are decision making and end of life care. The clinical
well established. Clinical pharmacologists who focus pharmacologist has an important role in teaching
their research, teaching and clinical service toward about the changing balance of harm and benefit
older individuals have the opportunity to improve for specific drug therapy intervention in the context
RUM for this increasingly important segment of the of the individual older patient and their specific
worlds population. concurrent illnesses. The research opportunities in
this area for the clinical pharmacologist are both
During the past 30 years, clinical pharmacologists challenging and exciting. Research efforts by clinical
have conducted the research that has defined pharmacologists that have been translated into
the pharmacokinetics of aging (49). This work, improved clinical practice for older patients include
particularly in the area of drugs (or their metabolites) the development of expert opinion developed lists
that undergo renal clearance, has contributed of drugs to use such as the Wise List (27) and the
importantly to patient safety and well being. For Beers criteria (51). In addition, based on extensive
many drugs it is essential to assess renal function drug usage data, clinical pharmacologists in Europe
in order to choose the appropriate dosage. Looking have developed Unwise Lists of drugs that are
to the future, the research opportunities to define best avoided in older patients. Geriatric clinical
drug pharmacodynamics and altered drug harm/ pharmacologists also develop research tools such as
benefit relationships in older patients are abundant. the Drug Burden Index (52) that link anticholinergic
Similarly, teaching RUM for older patients and and sedative drug exposure to important clinical
placing this into a geriatric medicine perspective is functional outcomes in older patients.
an important role for the clinical pharmacologist.
The number of physicians trained as geriatric clinical Disease-based therapy focuses on the development
pharmacologists is inadequate to meet either the and implementation of treatment guidelines to

optimise treatment for a specific illness. Clinical concurrent illnesses. The clinical pharmacologist has
pharmacologists and geriatric medicine specialists a key role on this team, working closely with the primary
have pointed out that implementation of treatment geriatric medicine clinician, the clinical pharmacist, and
guidelines for each of the diseases of an older patient other members of the team to individualise and modify
leads to extreme polypharmacy when multiple complex drug therapy regimens as the clinical status
diseases are present. Often concurrent implemen- of the older patient evolves over time.
tation of multiple therapy guidelines result in
conflicts, contradictions, and the simultaneous use of As the population ages in developing countries, the
drugs that are known to have harmful pharmacokinetic role of the clinical pharmacologist assumes even greater
and/or pharmacodynamic interactions (53,54).The importance. Therapeutic decision-making for older
geriatric clinical pharmacologist brings the appropriate patients with multiple illnesses that may benefit from
training and knowledge base to either resolve these drug therapy must be considered in the context of
therapeutic dilemmas, or to conduct the research limited resources and the desire to provide effective and
needed to achieve optimal patient care. cost-effective treatment. Here too there are excellent
opportunities for the clinical pharmacologist to team
The multidisciplinary health care team is championed up with specialists in geriatrics and other health care
by geriatric medicine as the optimal means of providing team members to provide the best pharmacological
care for the complex older patient with multiple care to the largest number of older patients.

Teaching Clinical Pharmacology 9
I Increasing demands on There are more sources of opinion and

prescribers of drugs disinformation available to patients and
For most physicians, drug therapy is the main tool at prescribers, largely as a result of increasing access
their disposal to influence the health of their patients. to the internet.
New graduates are typically expected to start The marketing activities of pharmaceutical
prescribing drugs regularly as soon as they begin companies remain a potential threat to cost-effective
their first medical post. The prescribing demands prescribing decisions and are complicated by direct-
placed on this group in healthcare systems have to-consumer advertising in some countries.
progressively increased because of many important
trends: Prescribing drugs is a skilled task that always carries a
risk of significant harms as well as benefits. Although
The number of drugs available continues to rise so newly qualified physicians are usually protected
that physicians often have to prescribe drugs with from the requirement to undertake high-risk practical
which they are less familiar. procedures, they are often expected to prescribe
Patients are taking more drugs, increasing the powerful drugs from their first day of clinical work.
complexity of their treatment regimen and the Indeed, these inexperienced doctors typically write
potential for drug interactions. most hospital prescriptions in many healthcare
Medication errors and ADRs, many of which are systems. It is clear that all medical graduates should
avoidable, constitute a major challenge to public have a firm grounding in the principles of practical
health. prescribing, as underpinned by the science of clinical
Patients who receive drugs are older and sicker, and pharmacology, at the point of graduation, as the basis
more vulnerable to adverse events. for rational prescribing.
Patient throughput is increasing (matched by a
similar increase in prescribing episodes) imposing The primary determinant of the effectiveness of
higher workloads on individual prescribers. a prescriber in most areas of practice will be the
The expansion of evidence-based medicine and education and ability of a prescriber to respond
HTA has enabled the beneficial and harmful effects to changes in pharmacotherapy. The increasing
of drugs to be quantified more accurately, and this support of other healthcare professionals, such
knowledge has expanded the number of clinical as pharmacists, and the availability of prescribing
guidelines that define norms of acceptable drug support systems and electronic prescribing will help
use. the prescribers in their task but they are no substitute
Patients increasingly expect their physicians to for education and training.
provide information about the drugs they are being
given to inform their own choices about treatment. Several studies have shown that lack of training
Poor access to trained medical staff in developing and familiarity with drugs among prescribers is an
and emerging countries. important factor in serious medication incidents
Increasing problems with poor quality drugs and (6,55). New graduates rate prescribing as the most
combination therapies for chronic diseases such challenging aspect of their profession and the one
as HIV AIDS and tuberculosis in developing and for which they are least well prepared. Importantly,
emerging countries, in particular in Africa. educational interventions such as the WHO Guide
to Good Prescribing have been shown to improve
prescribing performance.

I Undergraduate education Drug Prescription (27) or the WHO Essential Drug
A key aim of undergraduate medical education List (34) but will normally contain far fewer drugs
should be to provide the learning opportunities than such lists. An extensive list of drugs should
that will enable all students to acquire the requisite be avoided as the professional prescription of
knowledge, skills and attitudes, and also to put drugs will be practiced several years later when the
in place appropriate assessments to ensure that prescribers have chosen their specialty. Specific lists
these outcomes have been achieved. As the rate of of drugs that should be familiar to the prescribers
drug development increased in the 1960s, Clinical will then differ between, for example general
Pharmacology and Therapeutics (CPT) emerged as practitioners, internists, psychiatrists and oncologists.
a new teaching discipline and many medical schools Postgraduate and continuing education in clinical
incorporated it into their curricula as a distinct pharmacology rather than undergraduate education
course. Most medical schools provide some teaching will thus determine the drugs that are commonly
in both basic and clinical pharmacology, the former prescribed. However, an understanding of the basic
during the early years and the latter during the principles of CPT should allow physicians to take a
later clinical years of the medical curriculum. When logical approach to learning about any of the drugs
students start clinical training, they have usually they will encounter during their practice.
passed examinations in basic pharmacology and are
expected to understand the principles of drug action The principal recommendations for the delivery of
(56-59). CPT in the undergraduate medical curriculum are
summarised below:
The core content of a curriculum in CPT can
be conveniently divided into knowledge and CPT and prescribing (or equivalent) should be
understanding, skills and attitudes with emphasis identified as an important component of the
on critical drug evaluation (see Addendum I). Most curriculum, visible to students in all years, either
of these outcomes are generic requirements for the as an identified course itself or a theme that
safe and effective use of drugs in all areas of clinical integrates with other modules.
practice. These core CPT learning objectives can be Core learning objectives in CPT should be clearly
linked to a number of specific drugs and therapeutic identified including knowledge and understanding
problems which might be used to provide relevant about drugs, skills related to the prescribing of
clinical examples of the principles of CPT in practice. drugs and attitudes towards pharmacotherapy.
Teaching about specific drugs is organised in different The factual burden posed by the large number
ways in different countries. of drugs should be eased by prioritising learning
around a core list of commonly used drugs (a
One model is to focus teaching on a selected student formulary), similar to the process used
list of the most commonly prescribed 50100 by the WHO in developing their Essential Drugs
drugs that will be influenced by the pattern of policy.
disease in the country concerned. These should be There should be an identifiable and robust
selected in such a way that their pharmacological assessment that indicates whether the main
properties reflect the important pharmacodynamic learning objectives have been met. This might form
and pharmacokinetic principles on which rational part of an integrated assessment but it should not
drug use should be based. The list could be close be possible to compensate for a poor performance
to a National Drug List (2), a regional list for Wise in this area by a good performance in other items.

I Student formulary in the production of a truly integrated curriculum,
Medical students are often overwhelmed by the often with an emphasis on problem-based learning.
large number of drugs that they encounter during In these circumstances, CPT learning objectives
their training. This can be demoralising and lead must compete simultaneously with many others,
to a lack of clarity and objectivity in learning. As usually dispersed across many different modules
suggested above, a potential solution is to develop and through several years of the course. This poses
a list of core drugs that could be considered as the practical difficulties for CPT teachers coordinating
student formulary that helps to prioritise study and learning opportunities across many modules over
provide learning objectives that are realistic and which they have limited influence. Nevertheless,
attainable. This has already been done in a number the importance of CPT should be emphasised in
of medical schools in Europe, the US, and elsewhere. all clinical modules in which there are continuous
The list should contain 50100 drugs that are opportunities to observe and appraise critically the
commonly prescribed and used to treat common patient drug charts, see the beneficial and harmful
diseases. For each drug or group of drugs, students effects of drugs and practice relevant skills (e.g.
might be expected to have an understanding of the prescribing, dose calculations, drug preparation
mechanism of action, recognise the appropriate and administration, and searching for good quality
indication and contra-indication, know about information to inform prescribing decisions).
potential interactions and adverse effects, know how
to monitor effects and be able to explain the salient I CPT leadership
features of all the above to the patient. The students A key factor in the successful implementation of the
should also learn about the principles for stopping CPT core curriculum, particularly in an integrated
irrational drug therapy. The list of core drugs can be course, will be strong and enthusiastic leadership.
organised by organ system and set alongside the All medical schools should be able to identify an
common therapeutic situations in which they are individual who will oversee delivery and ensure
used. This arrangement emphasises the suitability that the generic principles of safe and effective use
of a problem-based approach to develop learning of drugs are highlighted throughout the course.
about CPT and the ease with which CPT can be This role should ideally be undertaken by a senior
integrated within a system-based curriculum. individual with a background and training in CPT,
helped by colleagues in the discipline some of
I Delivering the core CPT whom may be trainees in CPT. In medical schools
curriculum without CPT departments, other specialists with an
Variability in the structure of medical courses will enthusiasm for ensuring that principles of CPT are
require local solutions for delivery of the CPT prominent throughout the curriculum should be
curriculum. Where there are traditional arrangements, identified.
there may be a preclinical phase containing scientific
disciplines that include pharmacology and later The coordination of CPT learning opportunities can
courses in CPT or pharmacotherapy and this model be devolved to many teachers across the course,
is straightforward. Delivery is more challenging often within organ-based specialties. They too
when the traditional barriers have been removed should be encouraged to emphasise these principles

and remind students about the effects of drugs over several weeks. Other approaches to CPT
beyond individual organ systems. Simply providing involve writing case reports containing discussion
a link between drugs and clinical conditions is about therapeutic aspects (e.g. portfolio cases),
insufficient to develop an appreciation of the complex discussing prescribing decisions with patients as
considerations that surround the decision to initiate part of communication skills, critiquing clinical trials
a prescription. involving drugs, appraising claims for new drugs and
searching for information about drugs.
All schools should ensure that, in each case,
students are helped to tackle the practical issues of I e-Learning
weighing the harms and benefits of drug therapy, Many CPT departments have now embraced web-
prescribing the drug and monitoring the impact based approaches as an opportunity to deliver
of therapy. Clinical pharmacists who are usually learning opportunities and self-assessment in
available in greater numbers than physician clinical CPT. Certainly, it is important that students should
pharmacologists also have an important role to play be exposed to and trained in the principles of
in reinforcing learning during clinical attachments, electronic retrieval of reliable drug information.
working with other pharmacotherapeutic experts. Computer-assisted learning packages are
constantly accessible. As the change from paper
I Learning styles to electronic prescribing spreads worldwide, aided
The successful delivery of the core curriculum may by advances in virtual reality environments, this
involve a variety of learning styles (e.g. lectures, approach will be able to provide increasingly
problem-based tutorials) depending on local realistic simulation of real-world therapeutics (60).
preference but the content should increasingly be An e-learning approach is foreseen to be of high
based around inquisitive rather than passive learning. relevance in resource-poor countries with chronic
There should be an appropriate balance of teaching lack of educated staff. Innovative teachers should be
in large groups and small groups, practical classes able to use the academic high-speed networks for
and opportunities for self-directed learning. The core provision of distance learning, interactive teacher
curriculum in CPT is well suited to take advantage student contact. This may also be applicable in many
of the increasingly popular style of problem-based developing countries.
learning.
I Assessment
Most prescribing episodes are a direct attempt to Assessment drives learning and is critical in
solve a clinical problem and require the appropriate emphasising the importance of CPT in the course
knowledge, skills and attitudes outlined in and ensuring that graduates are fit to practice.
Addendum I. Several schools have developed a All medical schools should have validated and
series of therapeutic case discussions that offer reliable schemes of assessment in place to ensure
students a case vignette and pose direct problems that students demonstrate that they have achieved
relating to prescribing and therapeutics. These can be the curricular outcomes. It is important too that
undertaken in live time, even within relatively large assessments should not simply be knowledge-
groups, or researched and discussed at intervals based but test the acquisition of practical skills

(e.g. writing a prescription, offering information The previous section outlines the importance
to a patient about a drug and spotting potentially of developing a firm platform on which to
dangerous prescriptions). The objective structured build postgraduate training. There should be
clinical examination (OSCE) is an ideal format for a progression from undergraduate training for
this kind of assessment. Relatively few schools now broad-based, supervised prescribing through to
have a traditional CPT examination as changes to the progressively specialised and less supervised work
curriculum bring the assessments of diverse learning during subsequent years. Curricula for specialist
objectives together in integrated examinations. training and related assessments will be critical in
Where this is the case, there should be a clear, promoting the importance of CPT principles and
identifiable and robust component devoted to knowledge. In the case of specialists in primary
the knowledge and skills that support rational care or hospital-based disciplines, arrangements for
prescribing. Furthermore, whether assessment continuing medical education (CME) (often known
is integrated or part of a collection of discipline- as Continuing Professional Development) will be
based assessments, it is normally not appropriate important in updating knowledge and skills and
for students to be able to compensate for a poor fostering reflective practice. The emergence of new
performance in prescribing or therapeutics with good prescribing groups (e.g. pharmacists, nurses) in
performances in other assessments. Students should some countries offers a further opportunity for CPT
also be provided with formative assessments and the education to be used to enhance health care.
chance for self assessment at regular intervals during
the medical course. There are several important challenges for
postgraduate CPT education. Perhaps the greatest
I Quality assurance is to find the necessary time in already busy clinical
All schools should have some form of external schedules. However, this problem is being increasingly
quality assurance to ensure that the CPT learning circumvented by the development of more flexible
opportunities and assessments they provide are fit web-based learning solutions and recognition within
for purpose, i.e. deliver graduates with sufficient the relicensingrevalidation process that all doctors
knowledge and skills. Such reviews might examine require protected time for CME. Another important
whether the goals outlined earlier in this section have challenge is to provide good quality non-promotional
been met. The appointment of external examiners education. Recent years have seen pharmaceutical
with CPT expertise might also help to ensure that companies play a well-resourced highly influential
appropriate standards are met. role in the delivery of unbiased postgraduate
education. Clinical pharmacologists should embrace
I Postgraduate Education the opportunity to contribute to the planning of non-
Education in CPT and prescribing should be a promotional educational events.
continuing process in postgraduate medicine, not
only because of the constant emergence of new
medicines but also rapid changes in the knowledge
base of those that are already established in clinical
practice (see Addendum II).

Research Domains
of Clinical Pharmacology 10
I Introduction I Pharmacokinetic,
In the first WHO report on clinical pharmacology in Pharmacodynamic and
1970 (1), the section on research emphasised the Pharmacogenetic studies in
need for studies that explored the mechanisms of Human Volunteers
action of drugs and identified their pharmacokinetics This research should lead to a fundamental
in humans. Improvement of the early studies of understanding of the mechanisms involved in the
new drugs in humans and conventional therapeutic actions of the drugs on the organism or the actions of
trials were also prioritised. Research in clinical the organism on the drugs. The research is particularly
pharmacology has now taken new paths and this focused on intra- and interindividual differences in
satisfies many principles of translational medicine pharmacokinetics and pharmacodynamics, an area in
defined as taking scientific data on drugs into rational which clinical pharmacologists have made important
patient care. contributions in the past. The mechanisms in such
variability usually involve inherited individualities in
However, we should be aware that not all research into the genes encoding drug targets, drug transporters
drugs falls within the remit of translational medicine. and drug metabolising enzymes. The perspective of
The endeavour of a pharmacologist working in a the research should not only be in understanding
clinical environment is to develop methods and the molecular mechanisms but also in designing
strategies that improve the quality of drug use in genotyping or phenotyping tests, which may be
individual patients and patient populations. Research applied to forecast drug response and to differentiate
in drug evaluation, drug utilization, pharmacovigilance between genetic and non-genetic modifiers of the
and pharmacoepidemiology areas that were only outcome of drug treatment . In vivo research is often
superficially mentioned in the 1970 document are combined with experimental studies in vitro and in
now the priority. All these research areas have great silico. The research aims to identify the routes of
potential for supporting healthcare personnel in their metabolism and excretion of drugs.
RUM. Rational use of medicines implies that drugs
should be chosen according to efficacy, ADRs and There are two separate approaches in pharmacoki-
cost as potentially equally important parameters. netic research, one based on several drug
Research in clinical pharmacology therefore also measurements over a fixed time schedule in a
includes studies that elicit new data about drugs few subjects and the other being based on sparse
in use, such as new indications and treatment of measurements in each subject of a large population of
neglected patient populations (children, elderly - see individuals (population pharmacokinetics). Such data
chapter 7 and 8). It also includes research into ADRs, may help to identify subpopulations with impaired
pharmacogenetics and drug interactions. Research in or enhanced elimination capacity. The population
clinical pharmacology is usually interdisciplinary and approach can also be applied to pharmacokinetic
hence often carried out in collaboration with other pharmacodynamic evaluation.
professionals: pharmacists, drug analytical chemists,
molecular biologists, statisticians, computer
specialists as well as clinical researchers from other
medical specialties.

I Clinical Drug Evaluation and I Therapeutic Drug Monitoring
Clinical Trial Phases IIII (see also Chapter 6)
Important research areas are to improve the Therapeutic drug monitoring (TDM) is a scientific
methods used to evaluate drugs in humans. The first medical technology where clinical pharmacology
examination of the effects of a new drug in humans has made major contributions. The measurement
(Phase I) is done with great care and in great detail, of drug concentrations in blood or plasma will often
few subjects being tested. These Phase I studies are help to achieve better understanding of the nature
often done by clinical pharmacologists working in of individual drug exposure, how this relates to
industry or in specialised clinical trial units. When expected exposure values at the given dose, and
the time comes to examine the effect of the drug recommended target ranges in plasma at which there
in patients with the disease to be treated (e.g. is an optimal therapeutic effect or an increased risk of
hypertension), again small numbers of patients will ADRs. Therefore, the clinical use of TDM is obvious
be studied in detail (Phase II studies). The training for drugs that have a narrow therapeutic window and
that clinical pharmacologists undergo gives them the for which individual exposure is difficult to predict
skills to do such studies. from the particular dose used owing to extensive
interindividual differences in pharmacokinetics. It
The randomised controlled trial (RCT) or its extension may provide direct guidance for individual dose
to meta-analysis or systematic reviews of several adjustments in cases of ADRs or therapeutic failure.
RCTs is considered to be the gold standard for TDM is based on the assumption that the plasma
documenting the efficacy of drugs. The RCT has concentration of the drug reflects the concentration
advantages but also disadvantages and other at the drug target, although this may not always
methods for the evaluation of clinical interventions be the case, for instance with some central nervous
are needed (61). Clinical pharmacologists have system (CNS)-active drugs or anti-infective agents
been the pioneers in introducing the RCT and in used to treat localised tissue infections.
particular in introducing the placebo as control.
The RCT is now mastered by clinical intervention TDM research into clinical routine samples has been
researchers in practically all medical specialties important for a safer use of specific drugs in subgroups
and is no longer solely the province of clinical of patients at risk: the elderly, children and patients
pharmacologists. The RCT is a method with which with renal or hepatic failure. TDM research has also
all clinical pharmacologists should be familiar as it helped to detect and manage drugdrug interactions
still forms the basis of most drug evaluations. One and to understand the clinical impact of genetic
area in which clinical pharmacologists could make a polymorphisms in drug elimination pathways.
difference is the detection of relatively frequent ADRs
that are predictable and understandable on the basis The mapping of the human genome and the
of the mode of action of the drug. Another area is the revolutionary developments in biotechnology and
evaluation of biomarkers as measures of drug action human molecular medicine have been of fundamental
in clinical trials. In the case of new drugs, the studies importance in this regard. Research at the beginning
described above are part of the Phase I clinical trials. of the 21st century mainly aims at understanding the
role of genetic variation in the capacity or function of

drug metabolising enzymes, drug transporters and routine algorithms and tools for finding such
receptors and their relationship to the clinical effects associations and patterns of associations between
of drug treatment. Many TDM laboratories now drug intake and adverse events.
offer genotyping services, in addition to TDM, and
medical input is crucial for an individualised, clinical I Drug Utilisation Studies
interpretation. Clinical pharmacologists play a key role in drug
utilisation research, which can be defined as an
Clinical pharmacologists need to understand the eclectic collection of descriptive and analytical
principles of the laboratory methods that are used, methods and theories for the quantification,
although they may not necessarily be able to understanding and evaluation of the processes
perform them. In experimental studies on TDM or of prescribing, dispensing and consumption of
pharmacogenetics, the main responsibility of the medicines. The subject is also concerned with the
clinical pharmacologist is to formulate a clinically testing of interventions to enhance the quality
relevant problem, design the study that will help of these processes. It is common to quantify drug
to bring further understanding to this problem, be utilisation by defined daily doses, which by definition
medically responsible for the study volunteers and is the typical maintenance dose of the drug in an
translate the results into clinical practice. adult for its main indication.
I Pharmacovigilance I Pharmacoepidemiology
When a new drug enters the market, it has been Sometimes an RCT is either unethical (e.g. in
tested in only 35000 patients. There ought to be detecting harmful effects on the foetus) or impossible
solid documentation that its actions are superior because hypothesis testing or signal generation
to placebo or comparable to or even better than will require very large numbers of patients. Clinical
the existing treatment. Its most common harmful pharmacologists have been pioneers in establishing
effects should be known, in particular those that pharmacoepidemiology, which may be defined as
are predictable from their basic pharmacological the science of studying the utilisation and actions of
properties or readily explained in the context thereof. drugs in large populations. Pharmacoepidemiology
However, at marketing, serious or even lethal but uses methods from both clinical pharmacology and
very rare ADRs that cannot be explained by the basic epidemiology. The purpose of the research may be to
pharmacology of the drug and that occur in, say, 1 detect a signal, to estimate the risk of an ADR or to
out of 10,000 patients or even less commonly, may test a hypothesis. The results of the research can be
not have occurred or been recognised. Spontaneous used to give advice to healthcare organisations and
ADR reporting is carried out in order to detect individual patients or to formulate a policy regarding
unknown potential drug toxicity. The method the optimal use of the drug.
consists of collecting individual case reports of clinical
suspicions of ADRs. Data mining in ADR research is Cohort studies are carried out by registering a drug
the search for structures and patterns in large ADR effect (cure, death, ADR) in a sample of patients
databases, manual inspection no longer being treated with a particular drug. A sample of patients
possible. Data mining involves the development, not treated with the drug is used as a control group.
testing and implementation of computer methods, Random allocation and blinding are not applied

and that presents problems with confounding and optimal outcomes and the allocation of healthcare
bias but methods have been developed to at least resources. Pharmacoeconomics incorporates health
partly overcome this. In case-control studies, drug economics, clinical evaluations, risk analysis,
use in patients with a symptom suspected of being technology assessment and health-related quality
an ADR is compared with drug use in a sample of of life, epidemiology, decision sciences and health
patients without the symptom. Thus, the odds ratio services research in the examination of drugs.
for developing an ADR can be calculated. Linkage Clinical pharmacologists are important in the field
studies are carried out by linking data from individual of pharmacoeconomics as they are best placed to
level prescription databases to health outcome formulate research questions of medical importance
databases. Pharmacoepidemiology is an important and to translate the research findings into effective
new development in clinical pharmacology. For treatment with sensible outcome measures for
the sake of the continued development of the the average patient. The main role of a clinical
scientific discipline, it is important that part of pharmacologist in this discipline is to assess the
pharmacoepidemiology be anchored in clinical quality and suitability of clinical trials data for
pharmacology. inclusion in the overall analysis, in order to determine
whether a new drug has any clinical advantage over
I Pharmacoeconomics the existing treatments. It is necessary to arrive at
Pharmacoeconomics is the scientific discipline that an objective quantitative evaluation of benefit or
evaluates the clinical, economic and human aspects of effectiveness to put into cost-effectiveness models
pharmaceutical products, services and programmes that health economists have developed. The clinical
as well as other healthcare interventions. The pharmacologist is uniquely able to do this evaluation
aim is to provide healthcare decision-makers, which may end up not conforming to the appraisal
providers and patients with valuable information for or claim submitted by manufacturers.

Emerging Roles of Clinical Pharmacology:
Biologics and Biosimilars 11
I Background Changes to the production process such as cell lines

The growing importance of biopharmaceuticals, is one used, vectors, culture media and conditions can lead
area in which the remit of the clinical pharmacologist to the formation of protein isoforms, alteration of
has expanded very significantly since the original glycosylation patterns and/or changes in the tertiary
WHO document appeared in 1970. In the last three protein structure. Therefore, unlike classical drugs,
decades, drugs produced or extracted from biological a medicine produced by such a process in order to
sources (e.g. recombinant products, monoclonal mimic an already licensed biologic (the reference
antibodies and recombinant vaccines) such as insulin, drug) is a product that is similar to but not the same
somatotropin, interferon, granulocyte-stimulating as the innovator drug. Therefore, such a product
factor, erythropoiesis-stimulating factors like epoetin is not called generic but biosimilar or follow-on
and tumour necrosis factor alpha (TNF-alpha) and biologic.
inhibitors like infliximab have been developed and
approved for therapeutic use. Biopharmaceuticals Because of the complex science involved, the EMA
are a rapidly growing segment of newly developed recognised that the usual approach to generic
drugs, with sales amounting to about $40 billion in medicines is scientifically not appropriate for these
2006 in the United States (62) . Today, 2030% of products. Clinical pharmacologists working in this
drugs are produced by biotechnological methods. field posess or need to acquire knowledge and skills
The patent on human insulin was filed in the early in molecular and cell biology rather different from
1980s and expired in 2002. Other patents have also those needed previously.
ended or are about to expire. Currently, about 400
biopharmaceuticals are under clinical development I Biosimilars Problems in
about half of which are used in treating cancers. Evaluation
As many of them are expensive, it is important that As biosimilars are different from existing biologics
generic products can be provided to make cost- in terms of their raw materials and manufacturing
effective treatment accessible to all those who need processes, biosimilars have the potential to cause,
them. for example, immunogenicity problems that were
not detected in clinical trials and did not occur with
In contrast to classical drugs, which are typically the original manufacturers product. Therefore, EMA
manufactured by chemical synthesis, biologics has stipulated that a regulatory framework should
(or biopharmaceuticals) are manufactured in a be established to minimise the risk to patients by
living system such as a micro-organism or plant requiring extensive testing before approval in order
or animal cells. Owing to their production process to ensure that biosimilars are safe and effective.
and mechanism of action, biologics have a different Moreover, biosimilars have to undergo post-
pattern of potential adverse effects compared with marketing monitoring like that required for new
chemically synthesised drugs, and these adverse biologics. Accordingly, EMA has taken a case-by-
effects deserve special attention (63). case approach to similar biological products, typically
requiring new clinical trials. The FDA is given some
Most biologics are very large, complex molecules flexibility in deciding how much data and testing are
or mixtures of molecules. The production is usually enough to establish the key standards of safety and
based on recombinant DNA technologies and the efficacy similarity and interchangeability - for follow-
process is often commercial-in-confidence (62). on biologics (64). In particular, the manufacturer of a

biosimilar has to provide a detailed pharmaceutical As the safety data from pre-authorization studies
dossier, including data on the manufacturing process, are never sufficient to get a complete profile of
manufacturing facilities, implementation of non- the immunogenic potential of a biosimilar, post-
clinical bioassays, toxicity studies, local tolerability authorization safety studies and the preparation of
studies, and Phase I to Phase IV studies compared risk management plans are obligatory for biosimilars.
with the reference product. Thus, for biosimilars of To illustrate the differences of approval for biosimilars
epoetin, EMA stipulated two double-blind studies of epoetin, Abseamed (Medice, Iserlohn, Germany)
in a parallel group design to investigate the efficacy and Binocrit (Sandoz, Kundl, Austria) were approved
of the new erythropoiesis-stimulating agent in in Europe except for subcutaneous injection in
patients with anaemia following renal damage. patients with chronic renal failure, as data on
Generally, it is permitted to extrapolate results on immunogenicity were considered to be insufficient
efficacy in a specific therapeutic area to others, e.g. for this indication. This exception does not exist for
from renal anaemia to the symptomatic treatment of the biosimilar Epoetin alfa Hexal (Hexal, Holzkirchen,
chemotherapy-associated anaemia. However, this Germany).
may vary between agencies and from time to time.
As mentioned above, immunogenicity is a major I Conclusions
problem of biologics. As they are proteins, an The extensive requirements of regulatory
immune response such as the formation of authorities concerning preclinical and clinical
antibodies is more likely than in conventional studies of biosimilars impose substantially higher
pharmaceutical products. Thus, in patients treated developmental costs than those for usual generic
with epoetin alpha, an isolated erythroblastopenia drugs. It is therefore expected that biosimilars may
(pure red cell aplasia) has occurred as a consequence save only 1520% of costs compared with the
of the generation of neutralizing antibodies against biopharmaceutical original (67).
erythropoietin (65). In general, the immunogenic
potential of biopharmaceuticals depends on the In summary, the assessment of the harm benefit
production process, and also on the mode of ratio of biologics and biosimilars is a challenge for
application, dosage, duration of treatment and physicians, manufacturers and regulatory authorities
specific characteristics of the individual patient. and requires translational efforts to consider the
Therefore, careful pharmacovigilance is needed, as needs of drug innovation on the one hand and patient
immunological reactions may be without clinical safety on the other hand (68). It requires the expertise
consequences, or may sometimes lead to a loss of of molecular biologists, immunologists and clinical
efficacy, without causing severe adverse reactions. pharmacologists in order to take advantage of these
According to EMA guidelines, at least 300 patients challenging new medications. The opportunities for
must be observed over at least 12 months in order clinical pharmacologists in this field are considerable
to assess possible immunogenicity and the profile provided the necessary training in molecular and cell
of adverse events of a biosimilar compared with the biology is taken on board in addition to the standard
reference substance (66). training that clinical pharmacologists undergo.

Clinical Pharmacology and the
Pharmaceutical Industry 12
I Overview and the Industry are meagre. There have also been highly visible
Environment failures of potential blockbusters at a late stage in
Pharmaceutical companies have until recently driven development and a number of high-profile safety-
the discovery, development and marketing of new related post-marketing drug withdrawals that have
and established drugs. They include a range of resulted in an increased regulatory focus on risk
organisations varying from big pharma global management during the drug development process.
companies such as Pfizer and GlaxoSmithKline, At another level, consumers, health insurers and
to smaller, usually disease-focused, specialised governments are increasingly focusing on paying for
companies, large (e.g. Genentech) and small health outcomes rather than drugs, and sales and
biotechnology companies, and companies focused marketing approaches used in the industry are being
on generic, over-the-counter (OTC) or complementary questioned with a resulting reduction in trust. What
medicines. The clinical pharmacologist has a changes are being driven by these factors?
broad perspective of all aspects of drug discovery
and use, and all of the sub-specialities of At the discovery level, there is recognition that
clinical pharmacology from pharmacokinetics diseases are complex and that a focus on single
pharmacodynamics to pharmacoepidemiology, targets may not be the optimal approach, resulting
pharmacovigilance (benefit harm management) and in a move back to disease models rather than
pharmacoeconomics are critical. More importantly, target-based R&D. The separate silos of discovery,
the clinical pharmacologist can integrate knowledge preclinical development and clinical development are
of the drug target, disease pathophysiology, context increasingly integrated vertically into development
and management and preclinical and clinical data to teams that include functions from early discovery
guide drug development in an ethical, informed and through to pharmacoeconomics and marketing.
efficient manner. Companies are emphasising translational research
to facilitate the efficient transition from in vitro and
Globally, pharmaceutical companies operate in a preclinical animal research to human applications,
complex environment where evolving economic, and medicines are developed for more tightly
regulatory, social and political influences constantly targeted patient groups who are identified as likely to
force change. Investment in R&D increases rapidly, respond using biomarkers and or pharmacogenomic
but is not matched by the rate of emergence of new approaches, thus improving the cost-effectiveness of
products onto the market. The high expectations the treatment (so-called personalised medicine).
of innovation models that involve combinatorial Companies increasingly market medicines coupled
chemistry, high-throughput screening, rational with related services and diagnostics to identify
drug design, pharmacogenomics, bioinformatics responsive patients, and there is recognition of
and disease and pathway modelling have not been developing markets and neglected diseases as targets
met despite the high level of investment. The risks for drug development and marketing. The focus
in a business model that concentrates on a few of payers on cost-effectiveness drives companies
blockbuster drugs are also apparent as patents towards development of medicines that produce real
expire or are challenged vigorously by generic health benefits, and the biotechnology paradigm
companies, and new drug pipelines to replace them replaces the chemical, with biologicals providing

high benefits coupled with high value and cost. drug metabolismPK, and toxicology partners
Big Pharma is accessing biotechnology medicines to synthesise all the available data, to plan the
through in-house R&D, licensing, sponsored R&D, optimal Phase I strategy for clinical development,
partnerships and the acquisition of small, vigorous, and eventual filing for marketing approval.
fast moving and innovative biotechnology companies Phase II proof of concept clinical trials to establish
that have often been started by academics. efficacy in a restricted patient population
Follow-up on PKPD studies exploring issues such
Despite the problems facing the industry, the as drug interactions, effects of disease states,
demand, and therefore the market, for medicines bioavailability and or bioequivalence of dosage
is likely to rise during the second decade of the forms used during early and late development,
21st century owing to ageing populations and the and special patient groups such as the elderly or
emergence and growth of new markets particularly in children.
developing countries. Companies are consolidating
through mergers and acquisitions and this trend is Specialised roles: Clinical pharmacologists have
set to continue. Paradoxically, they may become less diverse areas of special interest within the discipline,
homogeneous, with niche market, biotechnology and many of these roles and skills are needed by the
and generics companies all emerging as significant pharmaceutical industry (69-71). Given their broad
players. training and background, clinical pharmacologists
are well placed to integrate their special area of
I Roles for Clinical interest across functional and therapeutic area
Pharmacologists in Industry groups. Some examples are:
Clinical pharmacologists can work in a wide range
of roles across companies, but will need to develop Preclinical development
skills and expertise beyond those normally associated Pharmacogenetics
wit the discipline in the academic or hospital setting. Pharmacoepidemiology
The types of roles available, and the knowledge, Pharmacovigilance (benefit harm management)
skills and attitudes required are discussed below. Pharmacoeconomics
Late clinical development Phase III confirmatory
Traditional roles: The clinical pharmacologist in trials.
industry customarily has been involved at the early
stages of clinical drug development planning, Other activities: Clinical pharmacologists in
design, conduct, analysis, interpretation and industry contribute to greater or lesser extents in a
reporting of Phase I and Phase II studies in humans. range of other activities which may include:
These activities include:
Regulatory preparation of submissions,
First in human trials, involving the first exploration in interactions with regulatory authorities and
humans of dose, tolerability and pharmacokinetic regulatory strategy planning.
and (where appropriate) pharmacodynamic Outsourcing managing CRO and academic
parameters. The clinical pharmacologist works contracts.
with preclinical, translational medicine biomarker,

Advisory arranging and managing scientific Industry roles and needs. Pharmaceutical
and clinical advisory boards, interactions with key companies usually have distinct scientific and
scientific and clinical advisers to ensure appropriate management career streams. Clinical pharmacologists
product development. will normally start in the scientific stream, but are well
Intellectual property management assisting placed because of their broad background to contribute
with the preparation of patents, liaising with in both areas. Clinical pharmacologists are needed
patent lawyers and responding to queries from in roles including managing a project or product
patent offices around the world; involvement in IP development team, leading a therapeutic area such
protection strategies including decisions to patent, as CNS or cardiovascular system (CVS), or leading a
retain as in-house know-how or put in the public functional area such as clinical pharmacology, benefit
domain; scientific and clinical advice for patent harm management or pharmacoepidemiology. The
defence. broad perspective of clinical pharmacologists is ideal
Due diligence activities involvement in scientific for higher management roles with involvement in
and clinical analysis of data and the scientific, the companys overall discovery, development and
clinical and market potential of products or marketing strategies.
companies.
Management and financial activities human Knowledge, skills and attitudes. The clinical
and physical resources planning most efficient pharmacologist in industry normally has basic training
development paths quicker development gives as a physician with specialist training in clinical
higher net present value. pharmacology. Companies provide training in-house,
or externally, for necessary industry-specific skills such
Roles in small pharmaceutical or bio- as project management, but much is gained through
technology companies: hands-on experience. The areas involved may include:
The clinical pharmacologist is needed in this setting
to fulfil a much broader role, being involved in Intellectual property and knowledge management.
overall discovery, development and marketing. The Strategic planning and project management.
company will often function in a specific therapeutic Regulatory requirements international, regional
area with a small number of products in development and country-specific.
and or on the market. The role will usually involve Regulatory compliance GxPs, electronic and hard
a broader strategic planning, management and record data and information management.
financial focus. Clinical pharmacologists are needed Leadership and decision-making in complex
to contribute to many aspects of the overall business, organizations and cross-functional teams.
including raising funding on the financial markets, Core business skills including the structure of the
development strategies in relation to funds available, industry, a broad understanding of the business
and making decisions about developing to market issues and models in the industry, the differences
stage, or licensing or sale of the product at an earlier between industry sectors, and how product value
development stage. is created and measured.
E thical and societal perspectives and broad industry
issues attitudes and ethical practices in a company or
industry sector, medical versus marketing department
perspectives, values and activities.

The goal of drug development is to convert to influence industry practices along appropriate
intellectual and scientific creativity into medicines ethical, societal and medical lines, even though this
that are valuable in terms of both benefits to patients may be difficult in the context of a large, financially
and a sustainable business model for the company. driven organisation.
The clinical pharmacologist has the background

Governments: Essential Roles
for Clinical Pharmacology 13
The clinical pharmacologist is an individual who has to prepare guidelines to indicate how the ethical
had systematic training in the evaluation of drug principles that should guide the conduct of biomedical
therapy and drug products. This makes the specialty research involving human subjects, as set forth in the
suitable and valuable in a number of government- Declaration of Helsinki, could be effectively applied,
based public activities that relate, for example, to particularly in developing countries, given their
drug approval, post-marketing surveillance, drug socioeconomic circumstances, laws and regulations,
therapy selection, reimbursement decisions and and executive and administrative arrangements.
ethical review of research projects. Governments The most important of the publications of CIOMS
should be involved in the ethical, scientific and is its International Ethical Guidelines for Biomedical
developmental aspects of medicines. Activities in Research Involving Human Subjects, first published
all these three dimensions are complementary and in 1993. The updated version was published in
underpin the most important role of any government: 2002 (72) and is designed to be of use, particularly
to protect its citizens through support and promotion to resource-poor countries, in defining the ethics of
of public health. biomedical research, applying ethical standards in
local circumstances, and establishing or redefining
Governments and their respective institutions have to adequate mechanisms for the ethical review of
take all necessary measures to make sure that clinical research involving human subjects. Although
research involving its citizens is not doing them harm mainly targeting ethics committees sponsors and
or ignoring their basic human rights. This challenging investigators, the CIOMS guidelines, to which several
task involves making sure that the research to decide clinical pharmacologists have contributed, have
which medicines (or other healthcare interventions) influenced the thinking of governments concerning
are authorised for use in human beings provides clinical research, especially in resource-poor settings.
enough grounds to ensure safety. It also involves the Another important facet of research in human subjects
task of assessing whether planned clinical research is good clinical practice (GCP) which is a standard
follows scientific principles that can justify both the for the design, conduct, performance, monitoring,
harms and the expected benefits from this research. auditing, recording, analysis and reporting of clinical
This forms the ethical dimension of the role of trials. GCP provides assurance that the data and
governments. reported results are credible and accurate, and that
rights, integrity and confidentiality of trial subjects
I History are protected. Many GCP guidelines are based on,
Following the two world wars, several initiatives or refer to, the Declaration of Helsinki, including
were taken around human rights and these were WHO GCP Guidelines published in 1995 (73) and
embodied in the World Medical Associations the International Conference of Harmonization (ICH)
Declaration of Helsinki in1964. In particular, the GCP (E6) from 1996 (74).
Council for International Organizations of Medical
Sciences (CIOMS) was founded under the auspices of
WHO and the United Nations Educational, Scientific
and Cultural Organization (UNESCO) in 1949. In the
late 1970s, CIOMS set out, in cooperation with WHO,

I Ethics Committees and appropriate use; and ensuring the appropriateness
Regulatory Bodies of medicines information provided to the public and
A fundamental requirement for the application of health professionals.
ethical considerations is submission of a research
proposal to independent evaluation by an ethics The EMA which coordinates the work of the various
review committee. Nowadays, many governments national experts in Europe and has very far reaching
define procedural aspects of the work of ethics responsibilities, has a broader mission statement
committees in detail. For example, the European (76):
Commission has laid down strict timelines for To foster scientific excellence in the evaluation and
processing research applications which affect the supervision of medicines, for the benefit of public
work of ethics committees in all European Union and animal health by
Member States. Clinical pharmacologists are
particularly valuable as members of ethics review developing efficient and transparent procedures to
committees because of their knowledge of medicines- allow rapid access by users to safe and effective
related clinical research. In addition, governments innovative medicines and to generic and non-
have to ensure that only effective, safe, good quality prescription medicines through a single European
medicines are used to treat their citizens. Nowadays, marketing authorization;
all medicines are subject to marketing authorization controlling the safety of medicines for humans and
approval before they are prescribed. The approvals animals, in particular through a pharmacovigilance
are based on assessment of the quality, safety and network and the establishment of safe limits for
efficacy of the products. The safety monitoring residues in food-producing animals;
of medicines during their whole life cycle (from facilitating innovation and stimulating research,
marketing authorisation to potential withdrawal hence contributing to the competitiveness of EU-
from the market) is also a task for governments. based pharmaceutical industry; and
Usually, these and other medicines-related mobilising and coordinating scientific resources
regulatory functions are carried out by specialised throughout the EU to provide high-quality
governmental agencies national medicines evaluation of medicinal products, to advise on
regulatory authorities (NMRA) such as the US Food research and development programmes, to
and Drug Administration (US FDA) and in Europe, perform inspections for ensuring fundamental
the EMA. In a broad sense, the role of the NMRA GxP (GxP means good clinical practice (GCP),
is to cover multiple dimensions and is derived from good manufacturing practice (GMP) and good
their mission. WHO Policy Perspective on Medicines laboratory practice (GLP) collectively) provisions
No. 7 Effective Medicines Regulation: Ensuring are consistently achieved, and to provide useful
Safety, Efficacy and Quality (75) states the following: and clear information to users and healthcare
A clear mission statement, which includes the professionals.
national regulatory authority goals, is necessary to
guide its work. Goals usually include the protection These are two examples of mission statements.
and promotion of public health by ensuring the The one from EMA addresses the three aspects
safety, efficacy and quality of medicines, and their described above, namely ethical, scientific and

developmental concerns. It is very important that and Clinical Excellence in the United Kingdom. The
regulators involved in the evaluation of safety and activities of such bodies should be based on the best
efficacy of medicines have the best possible scientific possible scientific methods and knowledge and are
education and background. They should also be able part of the scientific dimension of the governments
to make a critical scientific evaluation of the clinical obligation to its citizens. Clinical pharmacologists
data and to understand what, at the time of the have proved themselves to be well prepared to
assessment, is known and what remains unknown meet the challenges of the complex assessment of
about each drug under review. Some NMRA also medicines.
have units focusing on clinical pharmacology. For
example, the U.S. FDA has in its Centre for Drug Working at the government level, clinical
Evaluation and Research (CDER), the Office of Clinical pharmacologists are well trained to work in the area
Pharmacology. Nowadays, safety surveillance and of HTA. Many of the assessments are very much
pharmacovigilance are also the responsibility of the in the field of new drug assessments, especially
regulators. the new molecular biology drugs, as well as in the
administration of drugs by new technologies. Recent
I Clinical Pharmacologists history gives evidence that not all the research
in Government necessary for developing and promoting public
In most countries, governments, directly or through health by medicines is possible using only private
their specialised agencies, are also involved in sector initiatives and funding. Thus, governments
taking decisions about the selection of medicines for may also be involved in delivering financial support
public procurement, developing national treatment for clinical research involving medicines. Clinical
guidelines and proposing inclusion of medicines pharmacologists are well positioned to make
in reimbursement lists. This work may also involve judgements about the scientific value of proposals
composing and updating national Essential for government funding of research projects. An
Medicines Lists as promoted by the WHO. Clinical important emerging issue is electronic patient health
pharmacologists are usually closely involved at the records which have been implemented or are on
government level in developing and delivering a their way in many countries.
National Medicines Policy. It is important that such
individuals work in an environment that has political Although these may be perceived as mostly
support but also where there is a good prospect of administrative tools, they include a huge scientific
continuity of support when governments change. potential for monitoring the safety and quality
The monitoring of the performance of drugs in of drug therapy. There is already evidence that
real life after regulatory approval, including cost- electronic health records can offer greatly added
effectiveness assessment in the wider context of value for research in pharmacovigilance (78). Clinical
Health Technology Assessment (HTA) needs highly pharmacologists should be actively involved in
qualified specialists. However, all these activities designing and using electronic patient health records
are linked to promotion of the rational use of because of the enormous potential for future clinical
medicines, sometimes also called quality use (77). research including monitoring of rational drug use
An example of governmental institutions involved and safety.
in such activities is the National Institute for Health

I Future Challenges institutions and necessary resource allocations to
A governments efforts to create a research-friendly support the infrastructure. One of the key resources
environment in its country should be composed is properly trained specialists, capable of taking
of functional legal and other systems which will decisions based on the best possible scientific
make government offices well informed about the methods and evidence. All these dimensions are
inter-related and interdependent. Good ethics
necessary scientific background, and thus help their
cannot do without good science; good science can
effective functioning.
be ethical, whereas bad science can never be.
Owing to the relative lack of new therapies
I Conclusions
and pressure from patient groups and industry,
The clinical pharmacologist is a specialist who,
governments have been pushed into granting early
working at government level, serves the public
market approvals under certain pre-conditions.
interest by helping to ensure that only safe and
However, effective methods for pharmacovigilance
effective medicines are authorised for use, as well as
and safety studies in the context of early market
facilitating cost-effective prescribing and improving
access need to be created and tested and clinical the RUM. The training of clinical pharmacologists
pharmacologists have an important role to play is ideal for these purposes and can be tailored to
(79,80). Clinical pharmacologists also contribute to meet the needs of various government services in
the topic of pharmacoepidemiology. This discipline order to ensure that the best scientific knowledge is
is being increasingly used and sometimes is the used to make decisions in public health. In particular
only available approach to assess the benefits and the governments of emerging economies and
harms of long-term pharmacotherapy. Similarly, developing countries will benefit from the applied
pharmacoeconomics attempts to give a financial cost expertise of clinical pharmacologists. However, few
and value to everyday drug use which may become have given the necessary priority to the development
the basis for rational reimbursement systems. of the discipline of clinical pharmacology, and many
In order to implement these various dimensions, have difficulty in creating positions that compete for
governments have to create laws and regulations, funds with disciplines that may be seen to be more
the necessary infrastructure in terms of governmental mainstream.

The Clinical Pharmacologist and
Traditional Medicines 14
Traditional medicine is a comprehensive term used From a clinical pharmacologists perspective there
to refer to various forms of indigenous medicine - are several issues surrounding traditional remedies.
including traditional Chinese herbal medicine, African Preparation from natural ingredients plant, animal or
traditional medicine, Ayurvedic and Unani medicine, mineral, is not necessarily standardised and quality
homeopathy, naturopathy and other administered may vary between suppliers and seasons. Safety of
treatments derived from natural sources (81). It also traditional medicines cannot be taken for granted
covers manipulative physical treatments which are and several have demonstrated significant toxicity
not considered here. even after many years of use, e.g., nephrotoxicity
and carcinogenicity of Aristolochia found in some
Clinical pharmacology arose in the universities of the traditional Chinese preparations (82). Many of the
western world where modern prescription and over- claims for efficacy have not been substantiated in
the-counter medicines were the sole entities studied adequate clinical trials although the spectacular anti-
and where the expectation was that trained clinical malarial activity of medicines derived from Artemisia
pharmacologists would teach, investigate, and have species should caution against dismissing activity
clinical expertise in, the use of such medicines. Most until the evidence has been fully investigated.
clinical pharmacologists in practice today will have Moreover, the taking of traditional and conventional
had little or no exposure to traditional medicines medicines together predisposes to potential adverse
unless they have sought it out for themselves. interactions, e.g., the co-administration of St Johns
Wort (an enzyme inducer) may reduce the efficacy of
In the 40 years since WHO published its first medicines metabolised by the cytochrome P450 3A4
Technical Report on Clinical Pharmacology (1), the enzyme sub-type (83).
use of traditional (complementary, alternative)
medicines has grown rapidly in developed countries All physicians need to be aware and knowledgeable
many of which have now created national regulatory about the side effects or toxicity of some common
bodies to set standards for their quality and safety. herbal remedies. Patients often use traditional
Although access to conventional medicines in medicines without being aware of the potential
developing countries has improved, it is still side effects or interactions with their other current
estimated that a third of the worlds population, medications, and fail to disclose this to their
which is almost exclusively in developing countries, physician. In fact, it is up to the physician to be
has inadequate access to Essential Medicines. proactive by inquiring about the use of traditional
Therefore, in the developing countries the majority medicines. In one report, approximately 20% of
of the population still relies on traditional medicines hospitalised patients used traditional medicines
and its practitioners. concurrently with conventional medicines without
informing their physicians (84). The reasons for
However, the involvement of clinical pharmacologists non-disclosure included patients anticipation of
in traditional medicines has so far been quite small the physicians disinterest or negative response, a
despite the remarkable increase in their use in both misconception that the physician would be reluctant
developed and developing countries. or unable to contribute useful information, and

complete ignorance of the potential risk of using Service: Adequate instruction is needed to ensure
traditional with conventional medicines (85). that the clinical pharmacologist is competent to
It is clear from these observations that the training advise on the value, potential risk and management
of clinical pharmacologists, and indeed of all of patients using traditional medicines. However, to
physicians, needs to be reviewed to ensure that have a broader influence on prescribing by traditional
traditional medicines are included. healers or practitioners, it is desirable that the
clinical pharmacologist undertakes further training
I The Undergraduate Medical in traditional medicine or even becomes a fulltime
Curriculum traditional medicine practitioner with specialisation
There is a need for instruction about traditional in the clinical pharmacology of these medicines-
medicines at some point in all undergraduate medical though at present this would be a rare occurrence.
curricula. This should provide an understanding of
the commoner traditional medicines that are used in I Resources
the particular society and that are therapeutically or In recent years, there has been a rapid expansion
toxicologically important in patient care. The aim is of evidence-based texts about traditional medicines
to enable the young doctor to advise and/or manage (86-88) and the scientific basis for these preparations
patients using these medicines, and to be vigilant will continue to be strengthened. The Cochrane
for any potential interaction with conventional library contains many systematic reviews of efficacy
medicines. Also, an opportunity to engage students of traditional medicines (89) and several excellent
in research involving traditional medicines might websites provide information with its accompanying
stimulate some to pursue working in this field at a evidence (90-93). Clinical pharmacologists should be
later stage. aware of, use and promote these resources.
I The Postgraduate Clinical

Pharmacology Curriculum
Research: It would be appropriate to provide
training in clinical research and evaluation of one
or more of the common traditional medicines in
the community for quality, safety and efficacy, using
scientifically acceptable guidelines for conduct and
evaluation of human studies.

Collaboration with Other
Drug Experts 15
The rise in clinical pharmacology in the 1960s and clinical pharmacists and Ph.D. scientists
was in a large part due to the realisation of basic trained in clinical pharmacology have increased in
pharmacologists that their discipline was too far numbers, contribution and collaboration among
removed from the practice of medicine, but also these somewhat differently trained individuals
due to the desire of prominent clinicians specialising has strengthened and extended the contribution
in pharmacotherapy to develop their science of medically trained clinical pharmacologists.
and improve the quality of drug therapy. Clinical This is particularly the case for multi-disciplinary
pharmacologists at the time had to have fruitful Drug and Therapeutics Committees and drug
collaboration with both pharmacology and internal information services. In pharmacoepidemiology
medicine and usually had considerable training in and pharmacovigilance, collaboration with
both disciplines. epidemiologists is necessary.
Clinical pharmacology at its best now requires a much In TDM, collaboration with drug analytical experts
broader view of all aspects of medicine in which is vitally important to maintain accreditation of the
drugs are used be it internal medicine, paediatrics, analytical methods used. Such experts are usually
psychiatry, anaesthesiology, geriatric medicine or trained in chemistry or pharmacy. Collaboration
oncology. The role of clinical pharmacology in all with persons knowledgeable in molecular
these areas should be to educate physicians, to biology is of increasing importance, particularly in
perform collaborative research and to disseminate pharmacogenetics. Many clinical pharmacologists
information about the principles of drug evaluation depend on their collaboration with trained nurses
and RUM. These roles are facilitated by having who fulfil valuable roles in areas such as drug
access to diversified methods for monitoring and utilization measurement and evaluation and assisting
improving drug therapy. As the field has evolved with clinical trials.

Organisation: Structural Models
for Clinical Pharmacology 16
I Introduction I Independent Department of

Historically, clinical pharmacology developed Clinical Pharmacology in a
either from departments of pharmacology or University Hospital
from departments of internal medicine. Clinical In some countries, clinical pharmacology has
pharmacology is now an independent medical developed to such an extent that a separate
specialty in many countries. In countries where department in a university hospital has been
it is not a separate medical specialty, clinical created. Such departments have sufficient staff for
pharmacology should be recognised as a scientific the manifold interests of clinical pharmacology in
and clinical discipline in its own right. Clinical research, teaching and clinical service. Such staff
pharmacology is usually organised in separate units will comprise both clinical pharmacologists and
headed by a clinical pharmacologist. Depending other multidisciplinary staff such as pharmacists
on local and national circumstances, the unit could and drug analytical staff and will often include basic
either be a division of clinical pharmacology in a pharmacologists.
clinical or in a pharmacology department. While
internal medicine is historically the base clinical The department may have beds, and the physician
department, increasingly clinical pharmacology units clinical pharmacologists are then fully responsible
are developing from other clinical specialties such as for the treatment of patients. The advantage of
paediatrics (see chapter 7), geriatrics,(see chapter 8), this arrangement is that the physician clinical
anaesthesiology or psychiatry. pharmacologist is fully integrated in the clinical work
of the hospital making it easier for them to relate
Irrespective of which model is used, the optimal to clinical colleagues. The disadvantage is that the
setting is in a university hospital as it supports all involvement of physician clinical pharmacologists in
three major functions of clinical pharmacology: direct health care will reduce their time availability
health care, teaching and research. County (or for other important clinical pharmacology activities
district) hospitals and primary health care also need (see chapter 6). Thus, in many countries, physician
experts in clinical pharmacology. Such expertise can clinical pharmacologists are not directly responsible
be provided from the university hospital if the local for patient care. As there are advantages and
availability of clinical pharmacologists is limited. In disadvantages in both models (see above) the
some cases, the discipline of clinical pharmacology model chosen should reflect the national and local
may justify only a small organisation and here the traditions, circumstances and needs.
terminology of Unit may be more appropriate than
Division. There are several models of organisation, Collaboration between basic and clinical pharma-
described below. cologists enables achievements to be made that are
rare when the disciplines work on their own. Finally,
the department will need staff with other skills such
as nurses, computer experts, statisticians, laboratory
technicians and secretaries to fulfil its role properly.

I Division or Unit of Clinical I Development of Clinical
Pharmacology in a Clinical Pharmacology Organizations
Department Many clinical pharmacology organisations start
In many countries, this model for clinical small, but as they grow over the years in response
pharmacology is more appropriate. It is likely to be to the healthcare needs of their communities, they
the pattern where it is impractical to have a fully develop new skills and require different staff groups.
independent department and this is the model most Thus, there are examples of clinical pharmacology
likely to be relevant in resource poor environments. organisations that have developed from basic
This may be the case where the range of clinical pharmacology but now have individual clinical
services required is significantly smaller than as listed pharmacologists who provide direct or consultative
in chapter 6 or where the number of staff employed health care to patients, e.g. by looking after
only permits the provision of a limited range of such patients who have taken a drug overdose, running
services. In either case, the long-term aim should a unit for clinical trials, or evaluating patients with
be to grow so that a full range of services, relevant pharmacotherapeutic problems such as therapeutic
to the needs of the community, can be provided. failure or ADRs.
This may result in the creation of an independent
department in due course. Equally, there are clinical pharmacology organisations
that have developed from providing direct patient
I Division or Unit of Clinical care to become more involved in the basic science
Pharmacology in a of pharmacology for example the use of molecular
Pharmacology Department biology skills to understand pharmacogenetic
In some cases, a clinical pharmacology unit (or variability and thereby to provide a more personalised
division) has been organised in close association approach to drug therapy. The training available
with (or has developed from) a department of for clinical pharmacologists will need to reflect this
basic pharmacology. The advantages of such an changing world (see Addendum II).
arrangement have been discussed above. There
will be a considerable disadvantage if the basic
pharmacology department is sited some distance
from the hospital.

The Central Place of Clinical
Pharmacology in Global Public Health 17
I Background These policies aim to ensure:

Since the first edition of the WHO Technical Report
in 1970 (1), the medical world has changed The quality, safety and efficacy of medicines
dramatically. New diseases have arisen (HIVAIDS), Equitable access to medicines for all the population
developments in molecular biology have generated The rational quality use of medicines
new biotherapeutic agents, communications have A viable and responsible local pharmaceutical
been revolutionised by the Internet and many of industry (quotation from the Australian National
the historically important diseases of the developing Medicines Policy, 2000). Clinical pharmacologists
world are receding and being replaced by non- have clear and demanding roles in the
communicable disease with the notable exceptions implementation of each of these key ingredients.
of malaria and multidrug- resistant tuberculosis.
However, more than 50% of countries that replied I Quality, Safety and Efficacy of
to a WHO survey in 2003 had no policies in place to Medicines
improve the use of medicines despite data showing Quality of medicines is threatened by counterfeiting,
around 50% of all medicines worldwide are being poor manufacturing practice or the unscrupulous
used inappropriately (38.) A prominent example is marketing of time-expired products each of
the excessive use of antibiotics which is a major factor these is a contemporary problem, especially in the
in the high prevalence of resistance to previously developing world (94). In many countries, clinical
first-line antibiotics for dysentery, pneumococcal pharmacologists contribute substantially to drug
pneumonia and hospital-acquired infections (38). regulation. The pre-marketing assessment of the
The World Health Assembly, recognising these quality, safety and efficacy of a new medicine
problems, urged member states to establish or demands critical skills possessed by the trained
strengthen multidisciplinary national bodies for clinical pharmacologist, including a capacity to
monitoring medicine use, and to implement national evaluate clinical trials performed in many different
programmes for the rational use of medicines (WHA clinical areas. The ability to assess the relevance and
resolution 60.16, May 2007). possible problems of a new medicine for a particular
With this as background, it can be argued that population also requires an understanding of local
the most important single development that has epidemiology (if only to establish whether or not
expanded the role of clinical pharmacologists in the country needs this particular medicine based
global public health has been the recognition by on an assessment of the prevalence and severity
many developed and developing countries of the of any particular medical condition) and possible
value of a National Medicines Policy. The initiative racial variations in, for example, the metabolism of
came to a focus in the WHO Guidelines for the medicines.
Development of National Drug Policies published in
1988 (2). More than 150 countries now have their Increasingly, pharmaceutical companies are
own policies in varying stages of implementation. conducting clinical trials in developing countries in

the expectation that this will be a cost- and time- right to health (97). Despite this assertion of principle
efficient way of recruiting large numbers of patients. and intent, WHO estimates that as many as two
The trial results feed into the regulatory system at billion people worldwide do not currently have access
the point of pre-marketing assessment. Clearly, this to essential medicines. For the poorest populations,
provides an opportunity to obtain country-specific lack of finances may be the major cause. An estimate
data, but it also raises the question of who takes of annual per capita income adjusted for within-
clinical responsibility for critically assessing trial country cost of living, expressed in international
protocols, who manages the necessary initial research dollars (so-called Purchasing Power Parities) was
ethics application and clearance, and who takes $41,674 for the United States in 2005, $3487 for Sri
responsibility for the clinical supervision of patients. Lanka and $1892 for Nigeria (98). With no regular
These are standard roles for clinical pharmacologists acceptance of the need for medicine prices to be
in developed countries and there is a strong case for proportional in some measure to national per capita
providing positions in less developed countries for income, the costs of many medicines are beyond
the same purposes. the limited resources of the poorer countries as the
figures above predict.
Safety cannot be fully appraised at the point of
marketing and only some form of post-marketing Many countries have or are developing systems
surveillance will permit the timely detection of less for pre-marketing economic evaluation of
common adverse effects not detected in the limited medicines. While the economic model chosen will
pre-marketing data. For many developing countries, influence the outcome, the starting point is always
limited resources mean that most new medicines evaluation of the clinical trials data from which
approved for marketing have already been used for the estimate of potential benefit is derived, to set
years elsewhere, and there is a greater probability alongside cost in the cost-effectiveness calculation.
that their safety has been more fully characterised, This requires clinical pharmacological skills and
allowing for differences in pharmacogenetic involvement of clinical pharmacologists as part of
variations from country to country. In whichever the pharmacoeconomic team to address these issues
context, the clinical pharmacologist has a major role specifically. In countries where the cost of medicines
in the setting up of spontaneous reporting systems, to the individual is subsidised by government, a list
in reviewing (and suggesting action on) reported of selected medicines is maintained.
adverse events, and in providing data not only to
guide decisions in the home country but also to This may be the same as the countrys Essential
contribute to the global database (95). Medicines List, and this is the case in many low
and middle income countries. However, subsidy of
I Equitable Access this type whether funded entirely by government,
The individuals right to the best possible standard partly by the patient as a co-payment or through
of health is set out in the Universal Declaration of some form of insurance scheme requires a rigorous
Human Rights (96). When challenged in the courts examination of not only the quality, safety and
of several countries, the right of access to essential efficacy of medicines but also measures of cost-
medicines has been upheld as an extension of the effectiveness and affordability.

Clinical pharmacologists are commonly involved in guidelines (below) that have been endorsed for a
this selection process in developed countries but country, hospital or community serve as the reference
much less so at present in the developing world, standard and help to define inappropriate practice.
partly because there are so few of them. Buying The clinical pharmacologist should be a member
only medicines that are cost-effective and affordable of the evaluating team and also in the design and
locally is a potent way of ensuring that limited implementation of interventions to mitigate problems
resources are used to best advantage. that are identified.
I Rational Use of Medicines Standard treatment guidelines

Having medicines of high quality that are accessible The introduction of evidence-based treatment
to all does not guarantee that they will be used in guidelines is one of the interventions that has a large
the best possible way. More money can be saved potential to improve the quality of use of medicines
and health objectives met by ensuring the highest (99). To have the necessary authority, the guidelines
standard of use. Over the past two decades, methods should contain the best available evidence, be put
for measuring and evaluating the quality of use of together with representative input from all end-users
medicines have been developed and implemented. and be sensitive to local conditions (e.g. storage
and transport problems for particular formulations of
Drug utilisation reviews medicines in remote countries with difficult climates
One of the first steps in improving the way medicines such as the isolated island communities of the Pacific
are used in any community is definition of the region). The guidelines should also be endorsed by
potential or actual problems. Measuring medicine use local opinion leaders (including government and
and relating it to clinical indication in a community, professional associations) and be revised regularly
hospital, clinic or at a national level is not the easy to maintain currency. Clinical pharmacologists
task it would be if there were databases that could commonly have a central role in developing
be linked (with proper attention to confidentiality of guidelines and their broad training fits them for this
the records). Supply is not the same as utilisation, task.
although in some circumstances, especially in
resource-poor settings, it may be the only surrogate Essential medicines lists
available. Commonly, utilisation has to be measured The essential medicines list should reflect, and derive
prospectively by data collection in a defined area for from, the national standard treatment guidelines.
an adequate time, to ensure representative results. Ideally, guidelines should be prepared first and
In many countries, this task has fallen to pharmacists the essential medicines list produced from their
who have had special training in the methods. recommendations. Whatever the sequence, the two
However, when the results are being interpreted, documents should always be harmonised at each
clinical input is required. Clinicians with specialty updating and review.
training are needed in order to judge whether
prescribing has been appropriate. Ideally this role is
best filled by a clinical pharmacologist with broad
clinical training and experience. Standard treatment

Objective information about medicines the adviser who helps to translate the information
(see also chapter 6) from medical to everyday language. Work in a Drug
In many developing countries, there is a dearth of Information Centre and Drug and Therapeutics
objective information for health professionals about Committees may be a natural extension of the tasks
medicines, the gap being filled by information listed above especially in larger teaching hospitals.
provided by pharmaceutical companies with,
not unexpectedly, a promotional bias. Many I The Clinical Pharmacologists
developed and some developing countries produce Job Description for Global
regular drug information journals. These deal with Public Health
topical issues about the use of medicines, review There is a wide job description for the clinical
the profiles of newly introduced medicines and pharmacologist working predominantly in the health
discuss adverse effects. Clinical pharmacologists system. It is good that we can now demonstrate
play a major role in the editorial processes and as that many of the strategies listed above have
authors for such publications. In some developed strong evidence that they are effective in increasing
countries, drug information centres staffed by knowledge, improving prescribing or the consumers
clinical pharmacologists, pharmacists and other use of medicines (99). However, while it appears
health professionals have been set up to provide intuitive, there is virtually no evidence to link
patient-focused information. Increasingly, medicines improved prescribing and use of medicines uniquely
information is being produced for consumers, written to improved health outcomes although there is
in non-technical language and in some countries the honourable exception of improved compliance
issued with all first prescriptions for medicines. adherence, reflected in better disease control
especially most recently in the treatment of HIVAIDS
Education of health professionals and of and some instances where antibiotic choice and
consumers (see also chapter 9 and Addenda I and II) adherence play the crucial role in patient recovery.
Clinical pharmacologists working within the
health system always have a responsibility to be The list of tasks above (and in chapter 6) reflects the
involved in undergraduate, postgraduate and clinical pharmacologists usual pre-occupation with
continuing education. Much evidence suggests that prescription medicines. A further, emerging role is
doctors prescribe less well than they might (6,38). in the evaluation and investigation of traditional
Undergraduate training, with continuation into post- medicines (see chapter 14) which provide first-line
graduate and continuing education, has the potential treatment for up to 80% of the worlds population.
to lift the level of prescribing beyond the mediocre Largely neglected by Western clinical pharmacology,
and provide a pattern for life-long learning as new these traditional preparations have the potential to
medicines, or new uses for old ones, are introduced. provide surprises. For example, it is arguable that the
Whose business is the education of consumers? Peer most important advance in the pharmacotherapy of
education is a powerful technique and several studies malaria in the last decade has been the introduction
have demonstrated its effectiveness in improving of the Artemisia derivatives which come directly
understanding and use of medicines. If this is the from the Chinese herbal tradition.
strategy chosen, the clinical pharmacologist may
not be the primary educator but often becomes Several developed and developing nations

have recently set up a regulatory framework for treatment or prophylaxis on such a scale in many
traditional complementary medicines. The concerns populations that they assume the same importance
that prompted these initiatives were the need to as other factors that influence public health has led
ensure quality control in the manufacture of these to the use of epidemiological methods to explore
products and to evaluate the potential for unexpected the impact of medicines on populations as a whole.
toxicity (as demonstrated, for example, by aristolochic The exploration of ADRs has led to fresh approaches
acids in some traditional medicines as a cause of for the linkage of events with medicines use. Case
renal impairment and renal cancer (82)). There is control studies (100) and health database linkage
also the difficult problem of assessing the efficacy of have raised hypotheses, and sometimes provided
products that have had little or no scientific study in hard causality evidence about events stemming
the past, and which are produced by an industry that from drug exposure. Record linkage is at present
has only limited options for patent protection. only feasible in countries that have the necessary
accessible databases but will undoubtedly spread
In addition, there are only limited funds available more widely as the technology comes within the
for the necessary clinical trials work and thus many reach of less well resourced countries.
problems remain to be solved. However, research
money is beginning to flow from both pharmaceutical I Conclusions
companies and from government sources in some The discipline of clinical pharmacology arose from the
countries. two imperatives of the need to be able to measure
the efficacy of medicines in patients and the equally
In several instances, clinical pharmacologists have urgent need to be able to monitor adverse effects.
been members of the national advisory committees However, the list of ingredients in a contemporary
making recommendations to government regulators, clinical pharmacologists work provides a menu too
and in both Australia and the UK these committees full for a single individual. In reality, and especially
have been chaired by a clinical pharmacologist. in resource-poor countries, clinical pharmacologists
Some preparations that have been in use for many will make the biggest contribution, working as part
centuries warrant investigation and evaluation a of a team, whether in the hospital, the community
further role for the clinical pharmacologist in relation or in an administrative position. Training of clinical
to global health. pharmacologists to meet these needs will have to
be rather different and much broader than envisaged
in 1970. It is covered in chapter 9 and in Addenda
I and II.
The recognition that medicines are used for

I Chapter 3. The Definition of contract in some countries there are now new signs
Clinical Pharmacology of optimism (see introduction).
Clinical Pharmacology is the scientific discipline that
involves all aspects of the relationship between
drugs and humans and involves the delivery of
health care, teaching and research as well as helping
to frame policy and giving information and advice
about drugs. It is a multidisciplinary science that
encompasses professionals with a wide variety of
scientific skills including medicine, pharmacology,
pharmacy, biomedical science and nursing. The
term clinical pharmacologist is also used in the
professional sense to refer to those physicians
who are specialists in clinical pharmacology.
They have usually undertaken several years of
postgraduate training focussing on important
aspects of clinical pharmacology including clinical
trials, drug evaluations, pharmaco-epidemiology,
pharmacoeconomics, pharmacogenetics, pharma-
covigilance and clinical drug toxicology. The primary
goal of clinical pharmacologists is the improvement
of patient care, directly or indirectly, by promoting
the safer and more effective use of drugs.
I Chapter 4. The History of

Clinical Pharmacology
Clinical Pharmacology is a relatively new medical
discipline having been developed extensively in
the middle of the 20th century. However it has its
roots in a much older tradition of materia medica
going back for centuries. After a period at the end
of the 20th century when the discipline was seen to

Overview 18
I Chapter 5. The Global Medicine

Scene The Place of Clinical
Pharmacology
Modern drug therapy has unquestionably improved
the health of peoples in developed countries over
the last 50 years and yet there is much more that
could be done in these countries quite apart from the
needs of developing and resource poor countries.
I Chapter 6. The Clinical

Pharmacologist in Patient
Care
The prime function of a clinical pharmacologist
in patient care is to deliver safe and effective drug
therapy in what is often termed the Rational Use
of Medicines (RUM). In some cases this is done
directly where a clinical pharmacologist has direct
responsibility for patient care, but more commonly
a range of services is offered to clinical colleagues
and their patients. Clinical pharmacologists are
trained particularly in the critical evaluation of both
new and old therapies and so may function on drug
and therapeutic committees or by delivering drug
information services (often in collaboration with
other health care professionals such as pharmacists).
Special skills are available in drug utilisation,
pharmacoepidemiology, and pharmacovigilance. In
addition many clinical pharmacologists are involved
in therapeutic drug monitoring services. These are
often combined with pharmacogenetic services
leading to a personalised medicine approach which
can result in more effective therapy with fewer
adverse drug reactions.

I Chapter 7. Drug Therapy in (Addendum I) a Model approach to the required Core
Paediatric Patients Knowledge and Understandings, Skills and Attitudes
The treatment of paediatric patients needs special is suggested.
skills since children are not just small adults. After a
number of drug disasters in children in the 1950s it Postgraduate teaching of Clinical Pharmacology is
was recognised that paediatric clinical pharmacology also covered (see Chapters 9 and 12 and Addendum
was a specialty in its own right which needed II) but the approach here is a more general one
development for a number of reasons but particularly mostly because there is far greater variability in the
because of the high death rate of children from availability of staff and resources as well as more
treatable diseases in under-developed countries. varying needs around the world in the postgraduate
scene than in the undergraduate one.
I Chapter 8. Drug Therapy in
Geriatric Patients I Chapter 10. Research Domains
The treatment of elderly patients is a real concern of Clinical Pharmacology
in todays world. The most rapidly expanding age Research is a fundamental part of the training and
group in the world is the over 80 age group. Elderly the work of virtually all clinical pharmacologists. The
patients have particular problems in drug therapy endeavour of a pharmacologist working in a clinical
as increasing age is associated with impairment of environment is to develop methods and strategies
several physiological functions particularly renal that improve the quality of drug use in individual
function which affects the excretion of drugs and their patients and patient populations. Research in drug
metabolites. In addition therapy with multiple drugs evaluation, drug utilisation, pharmacovigilance
leads to more problems from drug interactions. Thus and pharmacoepidemiology has become more
some specialists in the care of the elderly patients important than at the time of the 1970 WHO
have developed special skills in Geriatric Clinical report (1). The Rational Use of Medicines (RUM)
Pharmacology. implies that drugs should be chosen according to
their efficacy, adverse drug reactions and cost as
I Chapter 9. Teaching Clinical potentially equally important parameters. Research
Pharmacology in clinical pharmacology includes studies that
All clinical pharmacologists have a considerable elicit new data about drugs in use such as new
role to play in teaching, whether this is at the indications and treatment in neglected populations.
undergraduate, postgraduate or continuing It also includes research on adverse drug reactions,
professional development level. Most attention is pharmacogenetics and drug interactions. Research
currently directed at the undergraduate medical level in clinical pharmacology is almost always
because of the increasing demands being placed on multidisciplinary.
new prescribers and because of the evidence that
new prescribers are more likely to prescribe less
effectively and with more errors than their seniors.
A number of different approaches to this problem
are described and in a comprehensive Addendum

I Chapter 11. Emerging Roles I Chapter 13. Governments:
of Clinical Pharmacology: Essential Roles for Clinical
The Example of Biologics and Pharmacology
Biosimilars Governments need to develop systems to serve the
Biologicals play an emerging role in clinical public by ensuring that only safe and effective drugs
pharmacology. In contrast to common drugs, are authorised for use in their populations and the
which are typically manufactured through chemical clinical pharmacologist is well suited to this purpose
synthesis, biologics are made in a living system, as well as facilitating cost effective prescribing
so the usual generic approach is scientifically not and improving the rational use of medicines. The
appropriate for these products. Biosimilars require training of clinical pharmacologists is ideal to meet
a special regulatory framework in order to ensure the needs of various government services in order
that biological therapies are safe and effective, and to ensure that the best scientific knowledge is used
require post-marketing monitoring similar to that for in making decisions in public health. In particular,
new innovative biologics. Hence the assessment of the governments of emerging economies and
the harm/benefit ratio of biologics and biosimilars developing countries could benefit from the expertise
is a challenge for physicians, manufacturers and of clinical pharmacologists, although few have given
regulatory authorities and requires expertise across the necessary priority to the development of the
multiple disciplines. discipline and many would have difficulty in creating
positions that are seen to compete for funds with
I Chapter 12. Clinical other medical disciplines.
Pharmacology and the
Pharmaceutical Industry I Chapter 14 . The Clinical
The clinical pharmacologist has much to offer Pharmacologist and
the pharmaceutical and biotechnology industry Traditional Medicines
at all levels. The clinical pharmacologists broad Clinical pharmacologists conventionally have had
knowledge of all aspects of drug use combined with little exposure to traditional medicines and yet
the insights gained from clinical practice provides a these are widely used both in the developed and
unique platform to influence the effective and ethical in the under-developed world. It is clear that use
development and marketing of therapeutic drugs. of traditional medicines can cause harm as well as
Clinical pharmacologists contribute at many levels benefits. Clinical pharmacologists should be better
from broad high level management positions to a informed about traditional medicines and be more
focus on a special area of expertise within clinical involved in work to increase the scientific knowledge
pharmacology. They develop a range of skills and around traditional medicines.
knowledge not often encountered in academic
clinical pharmacology.

I Chapter 15. Collaboration I Chapter 17. The Central Place
with Other Drug Experts of Clinical Pharmacology in
Clinical pharmacology is a multidisciplinary activity Global Public Health
and close working relationships with a number of The development of clinical pharmacology has
different professional groups is critical. Some of the been centred on the developed countries of the
disciplines involved in various aspects of clinical world and yet the needs are arguably greater in the
pharmacology include medicine, pharmacology, developing and resource poor countries. The skills
pharmacy, biomedical science, nursing, social and resources available in such countries necessitate
and behavioural sciences, dentistry, economy, a different approach to developing the rational use
epidemiology, genetics, toxicology, mathematics and of medicines. The discipline of clinical pharmacology
computer sciences. arose from the two imperatives of the need to
measure the efficacy of medicines in patients, and
I Chapter 16. Organisation: the need to be able to monitor therapy and prevent
Structural Models for Clinical adverse drug effects. However the list of ingredients
Pharmacology in a contemporary clinical pharmacologists work
Clinical pharmacology services can be delivered provides a menu that is too full for a single individual
through a variety of different organisational or discipline. In reality, and especially in resource poor
arrangements. There is little doubt that the most countries, clinical pharmacologists make the biggest
effective system is for the clinical pharmacology contribution, working as part of a team, whether in
services to be delivered from a department or division the hospital, the community or in an administrative
based within a hospital, whether the hospital is a position.
university hospital or a district general hospital. The
needs of primary care are also important particularly Training of clinical pharmacologists to meet these
where these services are delivered outside the needs is rather different, and much broader, than
hospital setting. envisaged in 1970 when the initial WHO report was
published (1).

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Editors and Contributors 20
EDITORS ADDRESS
Prof Michael Orme University of Liverpool, UK , Lark House, Clapton-

Emeritus Professor on-the-Hill, Cheltenham, GL54 2LG, United Kingdom
Prof Folke Sjqvist Department of Clinical Pharmacology, Karolinska University

Emeritus Professor Hospital, Huddinge, S-141 86, Stockholm, Sweden.
Prof Donald Birkett Chairman of IUPHARs Clinical Division, Flinders University

Emeritus Professor of South Australia, 9 Raglan Street, Mosman, NSW 2088, Australia
CONTRIBUTORS
Prof Darrell Abernethy Assoc .Director for Drug Safety, Office of Clinical Pharmacology
Chapter 8 at the FDA, Washington USA.
Prof Donald Birkett Emeritus Professor, Flinders University of South Australia,

Chapter 12
Prof Kim Brsen Clinical Pharmacology, Institute of Public Health, University of

Chapter 10 and 16 Southern Denmark, JB Winslows Vej 19, DK-5000 Odense, Denmark.
Prof Ingolf Cascorbi Institute of Experimental and Clinical Pharmacology, University

Chapter 11 Hospital Schleswig-Holstein, Bld 30, Arnold-Heller Str 3,
D-24105,Kiel, Germany.
Prof Lars L Gustafsson Department of Clinical Pharmacology, Karolinska Hospital at

Chapter 6 Huddinge, S-14186, Stockholm, Sweden.
Prof Kalle Hoppu Department of Paediatrics and Clinical Pharmacology, University

Chapter 7 of Helsinki, Helsinki, Finland.
On behalf of the Section of Pediatric Pharmacology of IUPHAR *
Prof Simon Maxwell Clinical Pharmacology Unit, Clinical Research Centre,

Chapter 9 & Addendum I University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
Prof Michael Orme Emeritus Professor, Universiy of Liverpool, United Kingdom.

Chapters 1, 2 and 18

CONTRIBUTORS
Dr Lembit Rgo World Health Organisation, Avenue Appia, 1211 Geneva 27,
Chapter 13 Switzerland.
Prof Sir Michael Rawlins Chairman, National Institute for Health and Clinical
Chapter 5 Excellence, MidCity Place, London WC1V 6NA, United Kingdom.
Prof Marcus Reidenberg Clinical Pharmacology, Weill Cornell Medical College, 1300
Addendum II York Avenue, New York, NY10065, USA.
Prof Folke Sjqvist Emeritus Professor, Department of Clinical Pharmacology,

Chapters 4 and 15 Karolinska Hospital at Huddinge, S-14186, Stockholm, Sweden.
Prof Tony Smith Emeritus Professor, Clinical Pharmacology, Level 5,

Chapters 14 and 17 Clinical Sciences Building, Calvary Mater Hospital, Waratah,
NSW 2298, Australia
Prof Petra Thermann Philipp Klee-Institute of Clinical Pharmacology, Helios

Chapter 11 Klinikum Wuppertal, University of Witten/Herdecke, Germany.
Prof Andrew Walubo Department of Pharmacology, University of the Free State,

Chapter 14 & Addendum II P.O.Box 339 (G6), Bloemfontein, 9300, South Africa.
*The members of the Executive Board of the IUPHAR section of Pediatric Pharmacology are:
Gabriel Anabwani (Botswana), Facundo Garcia -Bournissen (Argentina), Madlen Gazarian (Australia), Kalle Hoppu (Finland),
Gregory L. Kearns (USA), Hidefumi Nakamura (Japan), Shalini Sri Ranganathan (Sri Lanka), Saskia N de Wildt (the Netherlands).

Addendum I.
Model Core Curriculum for Clinical Pharmacology, 21
Therapeutics and Prescribing for Medical Students
This addendum provides a list of knowledge and Clinical pharmacokinetics

understanding, skills and attitudes relevant to the
the mechanisms of drug absorption, distribution,
use of drugs that should be core content in the
metabolism and excretion
undergraduate medical curriculum. These represent
the concepts of volume of distribution, clearance
key learning outcomes that will enable all graduates
and half-life and their clinical relevance
to prescribe safely and effectively at the point of
how these factors determine the optimal
graduation. These core objectives are generic and
route, dose, frequency, and duration of drug
applicable to most areas of therapeutics. They
administration
should be considered in association with a relevant
list of core drugs and therapeutic problems to which
Factors that determine inter-individual variation in
they apply. Medical schools should be encouraged
drug response
to identify lists that are appropriate for their local
circumstances. For each drug, graduates should be adherence to therapy
expected to have an understanding of the mechanism pharmacodynamic variation
of action, recognise the appropriate indications for pharmacokinetic variation
use, know the appropriate route(s) of administration, pharmacogenetic variation
and know the important contra-indications and environmental variation
adverse effects. In some cases a drug class is listed pharmaceutical variation
with a commonly used member of the class as an
example. The list of drugs chosen might be viewed Monitoring Drug Therapy
as a student formulary. the importance of monitoring the effect of drug
therapy
I Core knowledge and the ways in which this can be achieved (e.g.
understanding, skills and measuring plasma drug concentrations or
attitudes required to support assessing pharmacodynamic responses)
rational prescribing
the variable relationship between drug dose,
Core Knowledge and Understanding plasma concentration and clinical effect
Basic pharmacology
the general mechanisms of action of drugs at a Adverse drug reactions
molecular, cellular, tissue and organ level the different types of adverse drug reactions
the ways in which these actions produce the frequency of adverse reactions in primary and
therapeutic and adverse effects secondary care
the receptor as a target of drug action and related recognition of common susceptibility factors and
concepts such as agonism, antagonism, partial how risks of harms can be minimised
agonism and selectivity the importance of reporting adverse reactions and
the development of tolerance to drugs other approaches to pharmacovigilance

Drug-drug interactions Developing new drugs
the potential for drugs to interact to cause drug development including clinical trials (Phase I
beneficial and harmful effects to Phase IV)
the mechanisms by which drugs interact the approval process and major regulatory
(pharmaceutical,pharmacokinetic, pharmacodynamic) authorities in the relevant country
the ways in which interactions can be predicted the requirements of good clinical trial design
and avoided consent, ethics, bias, statistics, dissemination of
information
Medication errors
Understanding the principles and pitfalls of clinical
the different types of medication errors
drug trials
the common reasons medication errors occur in
practice Aims of the trial
the ways in which individual prescribers can Relevance of the trial for health care
reduce the risk of medication errors Selection of patients, diagnostic criteria and
sampling procedure, criteria for inclusion and
Clinical drug toxicology exclusion
Controls: crossover, separate control group,
the assessment, recognition and treatment of
untreated, other therapy, placebo
common intoxications (e.g. paracetamol)
Design: double blind, single blind, open
the principles of removing or counteracting the
Randomisation of treatment
effects of toxic substances after ingestion
toxicokinetics and toxicodynamics
Concentration-effect studies, biomarkers
Prescribing for special patient groups with altered Drug interaction
physiology, pharmacokinetic handling and Recording of effects (subjective and/or objective)
pharmacodynamic responses Recording of adverse effects
Statistical planning
elderly patients
The authors conclusion: adequate, questionable,
children
irrelevant or impossible?
women who are pregnant, breast-feeding, or of
child-bearing potential
Managing the prescribing of medicines in the health
patients with renal or liver disease
service
Legal aspects of prescribing drugs the role of local formularies
the role of drug & therapeutics committees
categorisation of drugs as over-the-counter
the influences that affect individual prescribing
preparations, prescription-only medicines,
choices
controlled drugs
the rational assessment of new drugs based on
the prescribing of unlicensed preparations
safety, efficacy and cost-effectiveness
the responsibilities associated with prescribing
controlled drugs

Ethics of prescribing Prescription writing
informed patient consent and adherence to therapy choosing a safe and effective drug and an
appropriate dose
Commonly used drugs writing accurate, legible, and legal prescriptions
including controlled drugs
the mechanism of action, the indications for use,
keeping accurate records of prescriptions and
the appropriate route, frequency and duration
response
of administration, and the important contra-
calculation of drug doses based on patient weight
indications and adverse effects of commonly used
or a nomogram
drugs
calculation of the strength of an infusion based on
the required rate of drug administration
Common therapeutic problems
prescribing oxygen (flow rate, delivery) and
the management of common acute and chronic intravenous fluids
therapeutic problems
Drug administration
Alternative therapies and traditional medicines
selecting the appropriate route of administration
the motivations that lead patients to seek administering subcutaneous, intra-muscular and
alternative therapies intravenous injections
some common indications and appraisal of the preparing drugs for parenteral administration
evidence for their efficacy including mixing and dissolving drugs
how such therapies interact with prescription preparing and administering drugs by an infusion
drugs that patients are receiving pump
preparing and administering nebulized drugs
Drug information retrieval advising patients about special modes of drug
Retrieval of drug information for prescribers and delivery e.g. inhaled, topical, insulin
other health care staff
Acquisition of knowledge and practice in how to Prescribing drugs in special groups
assess the value and reliability of drug information elderly, children, pregnancy and breast-feeding,
sources renal and liver failure
Core Skills Prescribing drugs to relieve pain and distress

Taking a drug history
palliation of pain and other distressing symptoms
taking accurate information about current
prescription and non-prescription drugs
making an assessment of adherence to a
medication regimen
recording current and past adverse drug reactions
and allergies

Adverse drug reactions and interactions Obtaining accurate objective information to support
safe and effective prescribing
assessing drugs as a possible cause of symptoms
and signs using National Formularies
recognising the potential for adverse interactions accessing reliable drug information from medical
reporting adverse drug reactions and interactions journals and medical databases
accessing Poisons Information Services
Drug allergy assessing the reliability of varying sources of
evidence and opinion
recognising allergic drug reactions and taking a
history of allergic reaction
Obtaining informed consent to treatment
treating allergic reactions, emergency treatment of
acute anaphylaxis providing patients with enough information about
drugs to allow them to make informed decisions
Clinical pharmacokinetics about their treatment
discussing benefits and harms of drug therapy

using core knowledge of pharmacokinetics to
with the patients
inform safe prescribing
exploring patients own views and wishes in
relation to drug treatment
Monitoring Drug Therapy
identifying which therapeutic effect to observe Core Attitudes
using measurements of plasma drug concentrations A rational approach to prescribing and therapeutics
appropriately (which and when)
identifying the correct clinical diagnosis
acting appropriately with the results
understanding the pathophysiological processes
involved
Analysing new evidence
knowing the drugs that might beneficially influence
practising evidence-based prescribing these processes
assessing the validity of evidence presented on establishing the end-points with which to monitor
new drugs or therapies therapeutic response
reading, assessing and criticising clinical studies assessing the potential harms and benefits of
spotting methodological flaws including sources treatment
of bias communicating with the patient in making the
recognising the difference between clinical and decision to treat
surrogate end-points

Assessing the balance of benefit to harm Responding to the future
recognising that there are harms and benefits recognising the need to update prescribing
associated with all drug treatments practices
recognising these may differ between patients ensuring that patients benefit when possible from
depending on a variety of factors advances in medical knowledge
recognising that doctors should monitor the effects recognising the need to assess the benefits and
of the drugs they prescribe harms of new therapies
knowing the limitations of applying clinical trial
Recognising the responsibilities of a doctor as part of data to individual patients
the prescribing community
Recognising the Effect of Drugs on the Environment
avoidance of wasteful prescribing and consumption
of limited resources
recognising the need to report adverse drug
reactions for the common good
controlling the availability of restricted drugs
adhering to therapeutic guidelines and drug
formularies as appropriate
avoidance of indiscriminate prescribing of
antibiotics
Recognising personal limitations in knowledge

recognising the need to seek further information
about drugs when faced with unfamiliar
prescribing problems

Addendum II.
Model Curriculum for Medical 22
Specialisation in Clinical Pharmacology
I Introduction However admission requirements will vary

A medical clinical pharmacologist is a physician with depending on national needs and agreements.
an advanced knowledge of pharmacology and the We recognise that the above scheme represents the
skills needed to achieve the rational use of medicines ideal for the training of clinical pharmacologists but
(RUM) in individual patients and in the population in many parts of the developing world it may be
at large. The former may include the direct care of necessary, for practical reasons, to reduce the scope
patients and also includes consultations on patients of the training in order to see health care delivered by
with complex drug problems such as therapeutic health care professionals with a relevant knowledge
failure, adverse drug reactions and drug interactions. of clinical pharmacology. Other entry requirements
This pattern will vary from country to country. in the form of preparatory/orientation training for
Improving drug therapeutics more broadly includes, general Medical Officers or general physicians are
but is not limited to, work on drug development, determined according to local conditions.
drug utilisation (both analysis of current practices
and research on ways to improve it), teaching and I Other Interests
providing information about drug therapy, working A physician starting the program after initial medical
in Drug and Therapeutics committees from local registration or licensure may wish to acquire
(hospital formulary) to regional, national, and additional specialty training. This can be interspersed
international organisations, and other problems that with clinical pharmacology training by special
arise during the practice of clinical pharmacology arrangement with the directors of both programs or
(see below). following the clinical pharmacology training.
I Aim Syllabus Overview

This Model Curriculum is designed to enable the The formal clinical pharmacology training program
aspiring clinical pharmacologist to obtain the is normally a 3 year activity but can vary from 2
knowledge and skills needed to carry out this 5 years depending on the country concerned. The
professional activity in an efficient and satisfying activities include:
way. It is deliberately set to be broadly based and
thus applicable to as many countries as possible. 1.
Formal instruction for the trainee to acquire
the specialist fund of knowledge of a clinical
I Admission Requirements pharmacologist which often involves working
Physicians are usually admitted to a clinical closely with basic pharmacology.
pharmacology training program after they have 2. Clinical experience caring for patients with drug
completed the requirements for registration as a problems.
practising physician in their geographic area. In 3. Research experience that advances therapeutics
addition they will often have completed 2-3 years of more broadly. In some countries CPT is a research
work as a practising doctor under supervision in one intensive discipline entailing the production of a
of the specialties in which drug therapy is the major thesis.
means of treatment.

1. Formal instruction should include: The specific subject matter should be covered at the
appropriate time in the complete curriculum.
A review of the broad field of pharmacology
including the topics covered in a medical school 2. Clinicalexperiencecaringforpatientswithdrug
pharmacology course but at an appropriately high problems
level. It is often of great benefit for the trainee to The trainee should get substantial clinical experience
spend time in a basic pharmacology department consulting about or caring for patients with serious or
and to experience work in such a laboratory complex drug problems with increasing responsibility
including work with animals. as the trainees knowledge and skill levels increase.
Pharmacological topics of special relevance to the Ideally, experience with infants and children as
discipline are: well as elderly patients should be included. This
experience may be concentrated in one part of the
i. Critical evaluation of drug effects, both desired program or spread throughout it.
and adverse;
ii. Principles of research methods in humans, 3. Researchexperiencethatenhancesknowledgeof
both experimental and observational ,eg drug therapy more broadly
clinical trials methods; The trainee should be encouraged to identify,
iii. Informed voluntary consent and ethics of by the end of their first year of training, an area
research in humans; of drug therapy in which information could be
iv. Data management and biostatistics; improved, with benefit to future drug therapy.
v. Absorption, distribution, metabolism and The trainee will then plan the research to be done,
excretion (ADME) of drugs in humans; write the protocol, and obtain any necessary ethics
vi. Pharmacogenetics; committee approval for the work to proceed.
vii. Additional sources of variation among people This work will be done under supervision and the
in their dose-response, such as age, gender, results reported in such a way that they can then be
pregnancy, liver and renal disease, drug communicated to others, preferably by publication in
interactions and environmental factors; a learned journal or monograph. Trainees with talents
viii. Drug concentration measurement and in research should be encouraged to complete a PhD
techniques for monitoring drug therapy; thesis (or equivalent) in clinical pharmacology.
ix. Drug intoxications and poisoning, both This research experience has been discussed in the
intentional and accidental; broadest terms and should be applicable anywhere.
x. Drug tolerance, dependence and addiction; What is important is for the trainee to develop the
xi. Pharmacovigilance and pharmacoepidemiology attitude that gaining new knowledge to improve
(including drug utilisation); drug therapy for an identifiable group of patients,
xii. Pharmacoeconomics; no matter how few in number or how small the
xiii. The process of drug discovery, development and geographic area in which these patients live, is part
regulation; of the practice of clinical pharmacology.
xiv. Adherence to medication regimens;
xv. Drug information;
xvi. Other topics of local relevance.

I Required Training Resources A training program can be at a single institution with
A clinical pharmacology training program must all the resources needed or through a consortium of
have resources for the curriculum to be carried out. institutions committed to the training program, their
This requires an adequate number of trained and combined resources being adequate.
committed staff, a sufficient number of patients
with a variety of illnesses for adequate clinical Further details of training programmes can be found
pharmacology experience for the trainee, supporting in the literature (see references 101-106).
clinical services including the ability to measure
concentrations of drugs in human body fluids, and
research facilities for the resident to carry out a
research project.

Council for International Organizations of Medical Sciences
20, Avenue Appia
CH-1211 Geneva 27
Switzerland

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Clinical

The World Health Organisation

The Council for International Organizations of Medical Sciences

The International Union of Basic and Clinical Pharmacology

The British Pharmacological Society

The Swedish Foundation for Clinical Pharmacology and Pharmacotherapy

For WHO Lembit Rgo

For CIOMS Gunilla Sjlin-Forsberg

IV Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 1

2 Clinical Pharmacology in Health Care, Teaching and Research

I Definition individual patients and for patient populations

I The Clinical Pharmacologist I Teaching Clinical

Clinical Pharmacology in Health Care, Teaching and Research 3

4 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 5

6 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 7

Clinical Pharmacology in Health Care, Teaching and Research 9

10 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 11

12 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 13

I Key clinical pharmacology - aims of the trial

Critical drug evaluation assists the practicing physician

14 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 15

16 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 17

18 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 19

20 Clinical Pharmacology in Health Care, Teaching and Research

I Increasing demands on There are more sources of opinion and

Clinical Pharmacology in Health Care, Teaching and Research 21

22 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 23

24 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 25

Clinical Pharmacology in Health Care, Teaching and Research 27

28 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 29

30 Clinical Pharmacology in Health Care, Teaching and Research

I Background Changes to the production process such as cell lines

Clinical Pharmacology in Health Care, Teaching and Research 31

32 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 33

34 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 35

36 Clinical Pharmacology in Health Care, Teaching and Research

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38 Clinical Pharmacology in Health Care, Teaching and Research

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40 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 41

I The Postgraduate Clinical

42 Clinical Pharmacology in Health Care, Teaching and Research

Clinical Pharmacology in Health Care, Teaching and Research 43

I Introduction I Independent Department of

Clinical Pharmacology in Health Care, Teaching and Research 45

46 Clinical Pharmacology in Health Care, Teaching and Research

I The Clinical Pharmacologist I Teaching Clinical

I Key clinical pharmacology - aims of the trial

I Increasing demands on There are more sources of opinion and

I Background Changes to the production process such as cell lines

I The Postgraduate Clinical

I Introduction I Independent Department of

I Background These policies aim to ensure:

I Rational Use of Medicines Standard treatment guidelines

I Chapter 4. The History of

I Chapter 5. The Global Medicine

I Chapter 6. The Clinical

103. Folb PI. The future of clinical pharmacology in

I Introduction However admission requirements will vary

I Aim Syllabus Overview