2

Evolution of Drug Development and its

Regulatory Process
Henry J.Malinowski and
Agnes M.Westelinck*
Food and Drug Administration
Rockville, Maryland, U.S.A.

The history of clinical pharmacology over the past 100 years may be thought
of as a gradual progression from the use of potions and other sometimes
dubious concoctions to the complex drug development process seen today
[1]. The future of clinical pharmacology has been described as academia,
industry, and government working together to advance science, develop new
drugs, and improve the quality of life of mankind [2]. Efforts such as the
International Conference on Harmonization (ICH) have promoted unification
of regulatory policies, including those related to clinical pharmacology. More
than 35 harmonized ICH Guidelines are available [3] and the recently
harmonized Common Technical Document provides for a common format
for new drug and biological regulatory submissions. Following are
perspectives from Europe and the United States on the progress of clinical
pharmacology over the years, in these two major regions of the world.
* Current affiliation: Barrier Therapeutics, Princeton, New Jersey, U.S.A.

13
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DRUG DEVELOPMENT IN EUROPE

Early Days
Clinical pharmacology, the science of drug actions in humans, started its
development in the 19th century. Test animals were increasingly used in
pharmacology research. In France, Francois Magendie (17831855) played
a prominent role. He is known to many for his description of the foramen of
Magendie in the brain but could be thought of also as one of the most
important founders of modern pharmacology. Czech Jan Evangelista
Purkinje (17871869), whose name is linked to large nerve cells in the brain
(Purkinje cells) and to conducting tissue in the heart (Purkinje fibers), was
one of the first to study drugs in healthy subjects, an unusual step, to avoid
interference by illnesses when studying drug characteristics [4]. In 1805,
German pharmacist Friedrich Serturner isolated the pure active ingredient
in opium. He named this chemical morphine, after Morpheus, the Greek
god of dreams. Serturners discovery was the first isolation of an active
ingredient. For many years he experimented on himself and others to
explore the effects of the alkaloid.
In the 17th century, a controlled study design was described. Jan Baptista
van Hellemont (15781644), a physician in Brussels, had proposed to his
opponents to settle a dispute about wound treatments. Several hundred
patients were to participate in an experiment, with vitriol or bloodletting
treatments assigned by lottery to each individual patient. Results were to be
judged by the number of funerals on each side. It is only in the 20th
century that the randomized controlled study design became generally
accepted. The double blind randomized study conducted in the late 1940s
by the British Medical Research Council confirming the effect of
streptomycin on tuberculosis was to become a classical example. With the
emergence of the chemical industry in the second half of the 19th century,
drug manufacturing by chemical synthesis became possible and a number of
pharmaceutical companies emerged.
Several drugs to treat serious diseases were discovered. Due to
insufficient pharmacological knowledge those drugs were probably too
easily introduced. The American government realized an important role to
play. Legislation in 1938 and later in 1962 required manufacturers to show
respectively safety and efficacy of drugs. The American example was
followed in Europe with some delay. In the Netherlands the first such
legislation was introduced in 1958. But it was only after the thalidomide
tragedy in the 1960s that an official agency to evaluate drugs started to
operate efficiently in this country. Similarly, in the United Kingdom it was
not until the Medicines Act was introduced in 1972 that evidence of efficacy
as well as safety was required as a condition for granting a product license.

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Drug Development and its Regulatory Process

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The legal obligation to demonstrate safety and efficacy before market

introduction stimulated the development of clinical pharmacology as a new
scientific discipline. The development of clinical pharmacology is a logical
consequence of the pharmaceutical revolution in the beginning of the 20th
century and the increasing contribution that drug treatments have made to
medical practice in the second half of the century [4, 5].
Clinical Pharmacology
Clinical pharmacology, the science of interactions between men and drugs,
was forged as an established medical discipline in the late 1950s and early
1960s in the United States, the United Kingdom, and Scandinavia. By 1970,
it had been recognized by World Health Organization (WHO) and in the
same year the Clinical Pharmacology section of the British Pharmacological
Society was formed. In 1974 the British Journal of Clinical Pharmacology
was launched. Clinical pharmacology has developed unevenly within the
European region and indeed throughout the world. It has developed rather
at a faster pace in some countries (e.g., the United Kingdom, Scandinavia)
but slower in others. The functions of clinical pharmacology were defined
30 years ago in a WHO report as research, teaching and service functions to
enhance the scientific study of drugs. Pharmacological service functions
are referred to functions aiming to solve problems in drug therapy, not to
traditional clinical work. In retrospect it is felt in Europe that most clinical
pharmacology groups who lived up to the recommendation of this WHO
report have evolved favorably, while many of those who did not, have
disappeared [6].
There are different descriptions of clinical pharmacology. It is considered
as both a research discipline (interdisciplinary) and a clinical specialty
(specified training of MDs). Under ideal circumstances they work closely
together, and there is a career ladder for both. At times, there has been
tension between a conservative clinical specialist approach, at the cost of
isolation, and a broader multidisciplinary-in-touch approach. However, to
meet various challenges in Europe, old barriers divided along traditional
subject lines, are being replaced in both academia and industry by
interdisciplinary teams [6].
Four decades of clinical pharmacology research (19602000) have
emphasized different aspects of the discipline (see Table 1) from controlled
clinical trials and drug metabolism during the early 1960s to molecular
pharmacogenetics and pharmacoeconomy during the late 1990s [6] (also
see Section 2 of this chapter).
In Europe, clinical pharmacology continues to be driven by a thriving
pharmaceutical industry, much of which is West-European based. Its

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TABLE 1 Four Decades and Different Aspects of Clinical Pharmacology [8]

development has been underpinned by the recognition that newly available

drugs must be assessed in unbiased controlled clinical trials designed,
conducted, and analyzed to the highest possible standards. Meanwhile,
understanding of potential mechanisms of drug actions has improved,
increasing the number of target sites for new drug development. Improved
measurement techniques of both drugs and their metabolites, and the bodys
response to them, have increased the understanding of pharmacokinetics
and pharmacodynamics [7].
Evolution in Clinical Drug Development
Globalization
Drug development is undertaken today mostly in a globalized industry
where companies tap international sources of technology. European
companies nurture U.S. as well as European scientific bases and vice versa.
Traditional domestic companies are mostly less innovative and rather
persist through marketing based strategies and protection [8]. Current
trends in drug development are therefore global in nature. The items
described in this section however reflect insights and opinions from
European sources.
New Needs and Concepts
The implementation of genomic research combined with progress in
discovery techniques has significantly increased the number of potential
drug candidates for a series of diseases for which there are currently no or
only insufficient treatments. Due to the present system, many of these
candidates never reach the patient because of bottlenecks in, and limitations
to, the drug development process (see Table 2). In the early 2000s, an

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TABLE 2 Bottlenecks in Traditional Drug Development [6]

apparent downturn in productivity in pharmaceutical R&D has been

observed. This is illustrated by the fact that the European Medicines
Evaluation Agency (EMEA) has willingly given back part of its approved
budget in 2002 because the anticipated number of new drug applications
had not been forthcoming. European scientists from industry, academia,
and drug regulators have been discussing the so-called crisis. Many share
the opinion that the rational way to reverse the trend of dwindling
productivity is to introduce new faster methodologies and modern
technology at every step of the development process [912].
To address new needs, a series of new concepts and techniques have been
introduced in European drug development:
The need to predict the developability in the selection of potential drug
candidates to go forward to full drug development. Early testing is
expected to be discriminating while predictive of potential future
problems, especially with respect to toxicity in humans [11].
The need to predict the probability of therapeutic and commercial
success. Due to increasing costs of drug development and marketing
competition, companies need an early answer to the likely clinical and
commercial success with abandonment of the compound if the target
profile is not likely to be met, ideally after the first human study [13].
In the end, economics are key considerations in drug development
[14].
The increasing use of well-established techniques of PK modeling and the
evaluation of dose-concentration-effect relationships (PK/PD) for both
desired and undesired effects.
The use of rapidly evolving computer modeling and simulation
techniques especially into difficult areas such as cancer and pediatric
studies [11].
The need to optimize the dosing regimen early in clinical development.
Traditional drug development, based on the maximal tolerated dose

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Malinowski and Westelinck

approach or fractions thereof, has often resulted in overdosing.

However, clinical trials at too high a dose may attribute an
unacceptable safety profile to an otherwise good drug [13]. Moreover,
European regulatory authorities typically require an appropriate dosefinding study and demonstration of both the maximal tolerated and
minimal effective dose.
Clinical development divided into two parts. Exploratory
development or proof-of-concept which may require as little as one
study and typically covers Phase I and Phase II (typically, Phase I
studies conducted in healthy volunteers and Phase II in patient
population) in the traditional theme, followed by full development
and completion of the registration dossier. This approach is
particularly important to innovative biotechnology companies which
are considered of great value for the future. The probability of
attracting a partner, and the value of partnership to the initial
company, will depend heavily on whether the proof-of-principle
point has been reached [13].
The use of well-validated surrogates which can substantially shorten
clinical development time or time to reach a critical decision point.
Biomarkers (less validated) may be useful in decision making,
although a larger amount of data is usually required to offset the
uncertainty. New biomarkers are explored in preclinical development
and link preclinical pharmacology and toxicology with the design and
interpretation of early human studies [13].
Pharmacogenetics gives researchers a powerful tool in the understanding
of how genetic variation contributes to variations in response to
medicines [15, 16]. Many individual and ethnic variations in drug
metabolism have already been shown to be due to genetically
determined variations in metabolic enzyme activity, particularly
cytochrome P450 enzyme subtype polymorphisms. European
regulators therefore require the testing of relevant drugs in target
groups of poor or extensive metabolizers [17].
Integration of Knowledge
Projected needs of the pharmaceutical industry are related to the need for
broad expertise to deal with increasingly complex projects and the
integration of specialist knowledge. Optimization of the drug development
process requires technical and scientific expertise in many areas. In some
disciplines, such as genetics (human polyphormism), mathematics
(modeling, simulation), bioinformatics (prediction), and information
technology (including pharmacometrics and information management),
there is a lack of well-trained experts. Moreover, due to the

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Drug Development and its Regulatory Process

19

multidisciplinary nature of drug development, knowledge covering a range

of disciplines is required [9].
An expected central challenge of the pharmaceutical industry in the
coming years is the management of complex information. Many
shortcomings in drug development can be attributed to insufficient use of
available knowledge. The interfaces between the various phases of the R&D
process have to be eliminated and a seamless discovery-development process
established, ensuring that all knowledge and data are maintained and put to
maximum use throughout (Fig. 1). New standards for handling complex
data and standardization of the format for knowledge-exchange are
required (A.Cohen, personal communication, 2001). This involves,
developing IT-supported information data management and
decisionmaking process [9]. For example, very promising new standards are
to be used in view of the International Harmonization (ICH) initiatives, the
Common Technical Document (CTD), and the Electronic Common

FIGURE 1 Integration of functions. Courtesy of A.Cohen, Center for Human Drug

Research, Leiden, The Netherlands, Phase I studies tailored towards proof-ofconcept. Personal communication, 2001.

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Malinowski and Westelinck

Technical Document (e-CTD). The aim is to provide a harmonized format

and content for new product applications to be used with regulatory
authorities in different regions of the world.
New Approaches in the Real World
The initial goals of drug evaluation have been modified to include new
questions directed at goals other than drug safety and efficacy. For example,
testing a drug in a population representing the real world setting has
become a major basis for phase III trials and for establishing evidencebased pharmacotherapy.
Other new questions that have been asked are How should the
physician and patient be advised to use the drug? and Is the drug better or
similar to a drug already available? In a sense, clinical trials have evolved
from a role in drug development to physician education and competitive
marketing [18].
A frequently forgotten aspect of drug development, which in some
respects is the most important of all, is defining the drug labeling, the
European Summary of Product Characteristics (SmPC). This document
should provide essential information for the health care professional and is
the basis for patient instructions and prescribing guidelines. This document
must be accurate but needs also to be easily understood [5].
Risk and Benefit
The standards of safety expected for an agent which may be lifesaving and
one which relieves minor symptoms should not be the same. Perceptions
on the appropriate balance of risk and benefit however vary widely,
including nationally. Based on evidence of efficacy, which may be
uncertain, together with limited safety data, licensing decisions may need
to be made on as much a judgmental as a scientific basis [5]. While formal
analysis of risk and benefit for a particular drug can be carried out,
comparative risk assessment with similar drugs is also considered useful
(see next paragraph).
Efficacy and safety have traditionally been the most important
influential bases to make decisions. In the future, priorities may also be
more influenced by costs and expected benefits of drugs on the market. At
present pharmacoeconomic data are required for requesting
reimbursement in countries such as Netherlands, United Kingdom,
Denmark, Finland, Norway, and Portugal. In the future more information
regarding the efficiency of the drug as compared to available drugs may be
needed, thus magnifying the social value of the resources invested on drug
expenditure [19].

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At the end, drug development should contribute to the use of the most
appropriate drug to the right patient in an optimal dosage schedule with the
right information and at a reasonable cost.
Considerations on Study Design
During the 1990s, the importance of properly designed early trials (Phase I
and II) has led to dramatic changes in their design. These changes have
included both proper randomized, double blinded designs and increased
sample sizes. Although there are different opinions on how best to use data
from Phase II in the present process, there is little doubt concerning the high
level of information likely to be available at the end of Phase II and the
conduct of too many Phase III and IV trials may be considered redundant or
unethical [18].
There are global concerns that activities carried out during the later
stages of clinical trials are balancing on the edge of inappropriate activities.
Regulatory authorities in Europe have in a sense addressed these issues by
their request, in specific situations, for comparative trials of marketed drugs.
As the goal of these trials is often to show equivalence, they, however, tend
to be more difficult to conduct and to require larger number of patients.
Occasionally, global pharmaceutical companies have sought approval on
the basis of placebo-controlled trials in the United States and have added
active control comparative trials to register in Europe [18].
Problem Solving by the Entire Community
Mistakes in the design of a drug trial are usually reported as drug failure
rather than insufficient expertise, marketing influence, inadequate
regulatory management, or improper patient enrolment and follow up. The
assumption has been made that these are problems for the pharmaceutical
companies to solve. The regulatory role is simply to identify them and reject
the failed studies. This might be considered false. It might be considered a
problem created by the process of clinical trials, which should be solved by
the entire healthcare community [18]. To address this and to reinforce the
success of the European Agency, specific changes have been proposed to the
European Commission to enlarge the scope of the Agencys activities beyond
the evaluation of medicinal products, by strengthening its role as a scientific
adviser.
New Safe Medicines Faster in Europe
Competitiveness of the Industry
Pharmaceutical companies based in Europe have traditionally played a
leading role in developing new drugs, the industry making a significant

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TABLE 3 Objectives of New Safe Medicines Fast in Europe [7]

contribution to the health and economy of European Union (EU)

communities. Many of the top pharmaceutical companies reside in the EU
and Switzerland and the European pharmaceutical industry has
traditionally held a world-leading position. The trend in the late 1990s,
however, indicated that U.S. companies have perhaps taken over the
leadership role, showing the U.S. industrys superior ability to translate new
technologies into marketable medicines [9].
However, initiatives to improve the EU competitive situation are the topic
of agendas and programs of EU professional and trade organizations and a
New Safe Medicines Faster initiative has been recognized for support by
the European Commission [11]. Within Europe, medicinal development
may still be hampered by barriers put up by the legislation of individual
nations, by fragmentation and by suboptimal cooperation among the
industry, academia, and authorities. The need for new revised European
standards and for pan-European interdisciplinary networks is recognized
and addressed [9].
Initiatives to Exploit Huge Opportunities
Proposed key actions are to promote basic research, new leading
technologies, and new interface research, including management of the
enormous quantity of diverse data that the development of drugs delivers.
Networking is considered essential and the creation of centralized databases
and database networks at a European level is suggested. New European
platforms for regulators and researchers are recommended to design the
necessary changes to the drug development process in partnership and bring
about improvements in capacity, efficacy, and speed (Table 3). The purpose
is to exploit the enormous opportunities created by the genomic revolution
and modern drug discovery for the generation of new medicines to the
benefit of the European citizen [9].

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The European System for Approving Medicines

Coordinating Scientific Resources
The role of national regulatory authorities in Europe has changed since the
EMEA came into operation in 1995, after several years of cooperation
among national authorities at a European level. The EMEA is a technical
agency coordinating the scientific resources made available by the national
authorities to provide high quality drug evaluations, to advise on
development programs and to provide useful and clear information to the
users. In addition to their country specific responsibility, national
authorities now also investigate medicines for decisions at the EU level, in
close collaboration with the drug regulatory authorities in other European
countries [20].
To Promote Public Health and Free Circulation of Medicines
The European System offers two routes for granting authorizations. A
company can or must, depending on the type of product, seek centralized
approval, which means an authorization valid for the whole EU. The
centralized procedure is compulsory for biotechnology products and
optional for innovative conventional products. In this case the application is
dealt with administratively by the EMEA. Independent evaluations are
conducted by two selected members of the European scientific committee
(named CPMP, Committee for Proprietary Medicinal Products).
Multidisciplinary teams, coordinated by the selected members, perform
those evaluations and discuss their conclusions with the other members. The
European Commission makes final decisions after the CPMP has expressed
an opinion following its scientific debate.
For innovative conventional products a company can instead choose the
route based on mutual recognition of national decisions. The European
System affords many advantages. New medicines come to market faster,
which of course benefits patients and industry. Also, by utilizing the
collective competence of several national drug authorities, the quality and
objectivity of evaluations can be improved, duplication of work is avoided,
and harmonized opinions and labeling throughout the EU becomes
available.
An important part of this European-oriented work also revolves around
developing new standards and requirements in the face of rapid scientific
discoveries and development of new medicines. The intended end result is to
promote public health and free circulation of medicines [20].
Broad Level of Satisfaction
In 2000, an extensive consultation [21] was carried out on behalf of the
European Commission to review the operation of the new European System

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Malinowski and Westelinck

since 1995. It has revealed that there is a broad level of satisfaction about
the system from ministries, patient and professional associations, regulatory
authorities, and industry, although improvements can be made and new
challenges exist.
There is a general feeling that the system has contributed to the creation
of a harmonized EU market for medicinal products and that it provides a
strong foundation for an efficient regulatory environment. There is also a
general perception that assessment of products to date has provided a high
degree of protection to the public health. This is despite the fact that there
have been withdrawals from the market of products already authorized.
This is considered consistent with increasingly effective pharmacovigilance
procedures and the bias toward products developed on the leading edge of
science.
Comparative Observations
From the same consultation in Europe, comparative observations upon the
regulatory frameworks in the EU and United States have revealed a
perception that the EU is taking a more risk-adverse approach to assessment
as compared with the FDAs policy of risk management. Specific instances
would exist where products were removed, or threatened with removal,
from the EU market because of perceived safety concerns, while the same
products were dealt within the United States by the imposition of specific
warnings in the label [21]. Comments were made about a similar level of
conservatism in the EU in the approach to the review of products in
specialist areas such as oncology and a greater willingness to embrace new
therapies in the United States [21].
Analysis of Outcomes
An analysis of outcomes of applications in the Central Procedure from 1995
to 1999, published by the EMEA [21], has shown 72% (97/135) positive
outcomes, i.e., drug approvals. For applications with a negative outcome,
methodological concerns over study design, choice of endpoint, comparator,
and selected population were raised more frequently than over those with a
positive outcome. FDA had authorized 13 (34%) of the 38 applications that
had a negative outcome in the EU. This may be explained by a different
attitude toward data requirements e.g., requirements for controlled data, by
the availability to FDA of additional regulatory tools, e.g., conditional
approvals, and by the limited use of EMEA scientific advice (11%) prior to
submission [22].
It is expected that the Reform of EU Pharmaceutical Legislation,
proposed in 2001, will influence the regulatory environment
significantly [23].

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DRUG DEVELOPMENT IN THE UNITED STATES

The modern uses of clinical pharmacology data in the United States may be
thought of as having several phases, beginning with early efforts in the
1970s, which related to the increased availability of sensitive and specific
analytical methods around that time. This was followed by application of
these capabilities to various areas such as the study of specific
subpopulations. Further implementation has emphasized the link of
pharmacokinetic data to clinical safety and efficacy data. Most recent
emphasis has included better understanding of drug interactions and
optimal dose adjustment for various sub-populations. Communication of
information and recommended approaches has been facilitated by the
preparation of FDA Guidances as well as ICH Guidelines.
Era of Pharmacokinetic Studies
The modern era of drug development related to clinical pharmacology
studies may be thought to have begun in the 1970s. A key component was
the development of bioanalytical methods needed to accurately detect
plasma concentrations of administered drugs. This aspect has continued to
improve until it is now possible to measure plasma levels for nearly every
drug under development. This is an important factor in the study of the
relationships of dose, exposure, and effect.
An important regulatory milestone was the creation of the distinct Human
Pharmacokinetics and Bioavailability Section of NDAs [24]. This established
a section in each NDA in which are contained all clinical pharmacology and
biopharmaceutics studies. Prior to what is called the NDA rewrite, NDAs
were not very consistent in content, and information to be included was not
very precisely defined or well organized. When this Format and Content
Guideline was first introduced in 1987, the types of studies were identified as:

Pilot or background studies carried out in a small number of

subjects as a preliminary assessment of ADME.
BA/BE studies.
Pharmacokinetic studies.
Other in vivo studies such as those using pharmacological or
clinical endpoints in humans or animals.
In vitro studies such as dissolution and protein binding studies.

While the original focus was on in vivo studies in healthy subjects, this has
expanded to include plasma sampling in patients as part of population
pharmacokinetic studies, exposure response studies and pharmacokinetic/
pharmacodynamic studies.

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There are numerous types of clinical pharmacology studies conducted

during the development of a new drug. These include both studies on
healthy subjects without the disease intended for treatment (Phase I) and
studies involving patients (Phase II and III).
Studies in healthy subjects primarily focus on safety aspects of the drug,
in establishing dose-toxicity relationships. These studies also investigate the
pharmacokinetics for the drug under development, dose proportionality,
absolute bioavailability, mass balance, effect of food, different formulations,
as well as special populations.
Studies conducted in patients primarily relate to establishing efficacy and
dose/response. In addition, optimal dosing interval, effect of severity of
disease, tolerance, and adverse reactions are determined.
One significant example from this era involved a once-a-day extended
release theophylline product which was shown to have a significant change
in bioavailability when administered with a high fat meal. This important
safety information resulted in the following precaution being added to the
products labeling:
Drug/Food Interactions Taking (this product) less than one hour before a highfat-content meal, such as 8 oz whole milk, 2 fried eggs, 2 bacon strips, 2 oz
hashed brown potatoes, and 2 slices of buttered toast (about 985 calories,
including approximately 71 g of fat) may result in a significant increase in peak
serum level and in the extent of absorption of theophylline as compared to
administration in the fasted state. In some cases (especially with doses of 900
mg or more taken less than one hour before a high-fat-content meal) serum
theophylline levels may exceed the 20mcg/mL level, above which theophylline
toxicity is more likely to occur.

A CDER Guidance [25] is available which describes current

recommendations related to food effect studies and labeling based upon
the results of such studies. Drug administration relative to meals is
sometimes of great importance. The labeling for atovaqone serves to
illustrate a situation where drug must be taken with food for optimal
efficacy:
Failure to administer (atovaquone) with meals may result in lower plasma
atovaquone concentrations and may limit response to therapy.

Era of Special Populations

With the ability to conduct pharmacokinetic studies well established,
attention advanced to additional applications. One such area was the study
of various sub-populations, including the elderly, males compared to

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Drug Development and its Regulatory Process

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females and possible racial differences in pharmacokinetics. These aspects

have continued to be emphasized and currently, it is expected that all NBAs
will include analysis of data related to age, gender, and race.
CDER has used numerous methods to move forward the science of drug
regulation. This includes involvement in Workshops to discuss current drug
regulatory issues and the development of Guidances to put forward
recommendations to sponsors as to how to proceed in many areas including
clinical pharmacology studies. These Guidances include both
CDER-developed documents [26] and ICH Guidelines [27].
The importance of age-related differences in response to drugs is
discussed in a CDER Guidance [28]. A pharmacokinetic screen [29] is
recommended, consisting of obtaining blood samples from patients in Phase
II and Phase III clinical investigations. This is a means of identifying
subgroups of patients, such as the elderly, in whom the drug may have
unusual pharmacokinetic characteristics. Procedures such as the
pharmacokinetic screen have evolved into current methods of population
pharmacokinetics [30].
An example, from about 20 years ago, of a drug which proved to have
serious toxicity among some elderly patients was benoxaprofen, a nonsteroidal anti-inflammatory drug, used to treat arthritis. It was
promoted as perhaps capable of arresting the disease process in
rheumatoid arthritis. While it was certainly effective for labeled
indications, for certain elderly patients it was associated with fatal
cholestatic jaundice among other serious adverse reactions. If the
pharmacokinetics of benoxaprofen had been studied in the elderly, it is
possible that a dose adjustment for elderly could have been
recommended and withdrawal of benoxaprofen from the market, which
occurred in 1983, might have been avoided [31].
While for most drugs, males and females can safely receive the same dose,
for a few drugs, differences in pharmacokinetics related to gender can be
important. In 1993, the Guideline for the Study and Evaluation of Gender
Differences in the Clinical Evaluation of Drugs [32] was published. This
recommended inclusion of patients of both genders in drug development,
assessment of clinical data by gender, assessment of potential
pharmacokinetic differences between genders, and the conduct of specific
additional studies in women, when appropriate.
Patients with impaired renal or hepatic function are also important subpopulations. Consideration of the need for dosage adjustment in
situations of renal or hepatic impairment has received considerable
attention. Guidances [33, 34] addressing these topics are available from
FDA.

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Era of Drug Interactions and PK/PD Relationships

In 1991, a Workshop was held to discuss current thinking related to the
rational integration of pharmacokinetics, pharmacodynamics, and
toxicokinetics [35]. This was an important milestone along the path of
closer relationships between clinical data and pharmacokinetic data.
In CDER, a reorganization establishing the Office of Clinical
Pharmacology and Biopharmaceutics in conjunction with increased
resources related to User Fees, promoted communication among medical
reviewers and clinical pharmacology reviewers. Co-location of these
reviewers provided for increased discussions, data sharing, and
consultations.
The importance of the relationship of changes in pharmacokinetics to
drug safety and efficacy is a continuing topic of much discussion. One
related area is drug interactions, which sometimes are extremely
important.
The interaction of fluorouracil and sorivudine, which caused a
number of deaths in Japan [36] in the 1990s, served as an important
reminder of the potential consequences of drug-drug interactions.
Sorivudine was withdrawn in Japan after 15 patients who were
prescribed both sorivudine and fluorouracil died. They had developed
aplastic anemia, after taking sorivudine with fluorouracil. Knowing the
situation that had occurred in Japan, sorivudine was not approved in the
United States because of this potentially fatal drug interaction and the
fact that alternative drugs to sorivudine were available, without the
serious drug interaction potential.
Serious interactions between mibefridil and certain cholesterol lowering
statin drugs resulted in the removal of mibefridil from the market.
Mibefradil is a potent inhibitor of the metabolism of lovastatin and
simvastatin and if either of these drugs is taken together with mibefridil,
they can cause potentially life-threatening rhabdomyolysis related to much
higher exposure to the statin drug due to inhibited metabolism caused by
mibefridil [37].
In response to the significance of drug interactions, Guidances for the
study of potential drug interactions, both in vitro [38] and in vivo [39], are
available from FDA. Study continues on establishing in vitro/in vivo
correlations for metabolically related drug interactions, in order to increase
the predictability of in vitro drug interaction data.
An important new law went into effect in 1997. The Food and Drug
Administration Modernization Act (FDAMA) [40] contained many new
provisions including a section describing the number of required clinical
investigations needed for approval. If the Secretary determines, based on
relevant science, that data from one adequate and well-controlled clinical

Copyright 2004 by Marcel Dekker, Inc.

Drug Development and its Regulatory Process

29

investigation and confirmatory evidence (obtained prior to or after such

investigation) are sufficient to establish effectiveness, the Secretary may
consider such data and evidence to constitute substantial evidence. The
confirmatory evidence described can be obtained from earlier clinical trials,
pharmacokinetic data, or other appropriate scientific data. This indicates
further reliance on pharmacokinetic data in conjunction with clinical
studies in the overall development of a new drug.
Year 2000 and Onward
As we continue to move forward in the area of clinical pharmacology
aspects of drug development, we are faced with worldwide pharmaceutical
companies, an explosion of data, and increased knowledge of the
importance of optimal drug administration and the consequences of less
than optimal drug use. In this context, computer-based systems increasingly
provide an essential means of communication, as well as an effective tool for
modeling and simulation. From the internet to personal information
managers and Pocket PCs, we are nearly always close to a source of drug
information. An increasingly common utterance is that there is so much
information available but there are also increasing difficulties in sorting
through this avalanche of information to find what is useful and thereby
translating information into useful knowledge. But, there can be no
question that computer-based information will continue to expand and
progress as one of the most important means of communication and sources
of information.
Clinical trial simulation [41] has matured to a point where all available
information about a drug under development can be used efficiently to
promote more rapid drug development. The entire process of drug
development has been estimated to take up to 12 years and cost upwards of
$350 million. About one-third of this cost and half the time is spent on
clinical development. Simulation techniques can provide valuable
information related to optimal dosing schedule, expected range of response,
effects of changes in exclusion criteria on expected outcome, optimal
frequency to measure response, and the impact of compliance.
Effective labeling has become an important topic, as large amounts of
information become available for newly approved drugs. Drug interactions
studied for a new drug have implications for the other drugs involved in the
interactions and keeping labeling up to date for all drugs is a difficult task.
As difficult is the task of healthcare providers being aware of all patient
situations where dose adjustment may be appropriate, related to age,
gender, race, renal or hepatic function, or drug interactions. FDA has
proposed a new labeling format [42] in the effort to present important
dosing and other safety information more clearly and obviously.

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30

Malinowski and Westelinck

The use of population pharmacokinetics [30] allows for the study of

differences in safety and efficacy among population subgroups. This
approach, which involves obtaining plasma samples from patients
participating in clinical studies, can permit the identification of important
factors, such as age, gender, weight, renal function, hepatic function, and
concomitant medications which can affect the safe and effective use of a
drug.
A topic of interest and considerable discussion recently is the Global
Clinical Trial. Clinical trials conducted in the United States. Europe, or
Japan often need some type of bridging study to allow the existing clinical
data to be used in the approval process in a different region of the world. A
Global Clinical Trial would include patients from the three ICH regions and
might allow the results of the trial to be directly applicable for approval in
all three regions and thereby speed worldwide drug approval.
Risk management is a frequently heard term in the current and future era
of a complex healthcare environment, with many potent new drugs being
approved, and an emerging global market. The FDAs Task Force on Risk
Management [43] has recommended that a new framework for risk
management activities is needed. The current system, which involves not
only the FDA but also pharmaceutical manufacturers, healthcare
practitioners, and patients, is more fragmented rather than part of an
integrated systems effort. One important recommendation relates to risk
confrontation, which involves community-based problem solving and
involves all stakeholders in the decision-making process. Regarding postmarketing surveillance and risk assessment, it has been suggested that new
approaches be considered such as increasing reliance on computer-based,
perhaps global, health information databases, as well as gathering data
from identified sentinel facilities where staff are trained to recognize rapidly,
and report accurately, adverse reactions.
In conclusion, one of the most striking developments in this area over
the past 30 years has been the change from independent clinical studies
conducted in patients with the goal of determining safety and efficacy, and
independent pharmacokinetic studies conducted in healthy subjects, to the
current situation where these studies are viewed together. Over the years,
these two sources of data have become increasingly associated and utilized
together in numerous approaches to efficient drug development. By
obtaining some additional plasma samples from patients in clinical
studies, all studies in humans can be viewed as a continuum and a more
complete evaluation of a drug can be obtained. By the integration of all
available drug development data, dose can be better optimized for each
patient, thereby minimizing adverse reactions and promoting effective
treatment of diseases.

Copyright 2004 by Marcel Dekker, Inc.

Drug Development and its Regulatory Process

31

ACKNOWLEDGMENT
Dr. A.Cohen, Center for Human Drug Research, Leiden, The Netherlands
and Dr. P.Neels, Member of the Commission for Proprietary Medicinal
Products, Brussels, Belgium.
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Copyright 2004 by Marcel Dekker, Inc.