1

Introduction to Drug Development and

Regulatory Decision-Making
Lawrence J.Lesko and
Chandrahas Sahajwalla
Food and Drug Administration
Rockville, Maryland, U.S.A.

The science of contemporary drug development is a tremendously complex

and costly process but it has successfully advanced our understanding of
modern diseases and has improved public health significantly by providing
society with many valuable drug treatments. A crucial step in the drug
development process is the submission of nonclinical and clinical data and
information in a New Drug Application (NDA) to the Food and Drug
Administration (FDA) by a sponsor seeking marketing authorization. A
typical new molecular entity (NME) that is the subject of a NDA has most
likely been studied preclinically for 57 years and has been in clinical trials for
67 years. The average cost of bringing an NME to market is somewhere
between 500 and 800 million dollars including the costs of lost opportunities
and lead-compound failures [1]. With this investment of time and money,
many scientists involved in drug development have explored various ways to
make drug development as efficient, and yet informative, as possible [2].
1
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Lesko and Sahajwalla

Despite its successes, the drug development process, including regulatory

decision-making based on benefit/risk assessments, can be improved in three
areas.
1.

2.

3.

Provide a greater understanding of human health and the

causes of diseases at a genomic or molecular level. This would
address the well-known heterogeneity of disease states that
underlies the wide interindividual variation in efficacy
observed with many common treatments. For example,
incomplete or absence of response occurs in 3050% of eligible
patients with hypercholesteremia who are treated with
statins. With greater insights into health and disease,
sponsors would be more likely to identify a target protein or
receptor and to find the best NME to provide preventive,
curative, or palliative treatment for patients.
Improve the safety of medicines. Adverse drug reactions (ADRs)
have had a major impact on morbidity, mortality, and health
economics. In studies going back to 1974, up to the present time,
approximately 1520% of hospitalized children and 2530% of
hospitalized adults have experienced drug-related adverse events
[3, 4]. The overall incidence of drug-induced adverse events in
nonhospitalized patients is thought to be around 7% [5]. The
economic cost of drug-related morbidity and mortality to society
has been estimated to be almost 200 billion dollars [6]. While
there are many reasons, some of them unknown, for the
relatively high incidence of ADRs (e.g., medication errors, drug
interactions), it is thought that the majority of the risks
associated with drug therapy are known and most drug-related
adverse events are preventable [7].
Optimize drug doses and dosing schedules. Approximately 70%
of drug-related adverse events are due to extended
pharmacological actions. Thus, there is growing evidence to
suggest that drug doses approved for marketing may be higher
than is necessary and may be contributing to the high frequency
of serious drug side effects. A recent study that examined the
doses of 354 prescription drugs recommended in the label and
released between 1980 and 1999 found that approximately 17%
of these drugs had a reduction in dose or a new restriction for use
in special populations such as patients with renal or hepatic
disease [8]. Furthermore, it has been reported that prescribers in
their practice frequently use doses which are lower than the
FDA-approved label dose [9]. In an informal survey, it was also
found that doses approved in other countries, e.g., Japan, are

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Drug Development and Regulatory Decision-Making

lower than those approved in the United States and most often
there are no apparent scientific rationale for these differences.
These three areas of improvement should be viewed as a challenge to the
scientific community in industry, academia, and the regulatory agencies to
engage in dialogue and scientific collaboration to optimize the drug
development process. This is especially important in light of the emergence
of new genetic technologies and our understanding of the human genome
that provides us new ways to ask important questions during the drug
development process. Indeed, the promise of personalized or predictive
medicine that stems from pharmacogenetics and pharmacogenomics means
that the benefit/risk ratio of drugs is systematically optimized by identifying
and selecting the right drug target, developing the right drug, and delivering
the right dose to the right patient.
ROLE OF CLINICAL PHARMACOLOGY
At the core of the drug development process is a fundamental understanding
of the clinical pharmacology of the drug substance. Clinical pharmacology
can be thought of as a translational science in which basic information
about the relationship between a drugs dose, local or systemic exposure and
response (related to either efficacy or safety) is applied in the context of
patient care. Knowledge of this relationship, which is a key to successful
therapeutics, and how it is altered by the intrinsic (age, gender, renal
function, etc.) and extrinsic (diet, drugs, life-style) factors of an individual
patient is one of the major contributions of clinical pharmacology to drug
development and regulatory decision-making.
Once a lead compound with the intended pharmacological action is
identified, the step-wise process to characterize and potentially optimize
its pharmacokinetic (PK) properties (i.e., absorption, distribution,
metabolism, and excretion), as well as to minimize its pharmacokinetic
limitations (e.g., poor absorption), begins in humans as part of phase I
human clinical trials. Soon after, other principles of clinical pharmacology
[e.g., pharmacokinetic-pharmacodynamic (PD) relationships] become
critical to the evaluation and selection of the most appropriate dosing
regimen of the drug in a carefully selected target population enrolled in
phase II clinical trials. These trials form the scientific rationale for
subsequent dose selection in large-scale phase III clinical trials where the
primary goal is to provide adequate evidence of efficacy and relative safety
of the drug. Phase III trials are the most expensive and time-consuming
component of the overall drug development process and many believe that
paying careful attention to doing clinical pharmacology homework has

Copyright 2004 by Marcel Dekker, Inc.

Lesko and Sahajwalla

the greatest potential to reduce the failure rate of new drugs at this nearfinal stage of development.
Often, in parallel with phase III clinical trials, a group of clinical
pharmacology studies, such as those in special populations, are conducted
in human volunteers to develop a knowledge database of factors influencing
drug exposure. These data are crucial for an understanding of when, and
how much, to adjust dosage regimens. Because these studies typically focus
on changes in systemic exposure, as a surrogate marker for either efficacy or
toxicity, the availability and the intelligent use of exposure (e.g., dose, PK
measurements)-response (e.g., biomarkers, surrogate clinical endpoints,
clinical outcomes, PD) relationships to interpret the results of these studies
become critical to information for various sections of the product label.
These studies can be broadly classified into two broad categories: (1) those
dealing with patient-intrinsic factors that include gender, age, race, diseases
states (primarily renal and/or hepatic impairment), and genetic (e.g., activity
of cytochrome P450 enzymes) factors, and (2) those dealing with patientextrinsic factors that include drug-, herbal- and nutrient-drug interactions,
environmental variables (e.g., smoking, diet), and lifestyle factors.
ROLE OF BIOPHARMACEUTICS
Related to the science of clinical pharmacology, biopharmaceutics can be
thought of as the body of scientific principles applied to convert a wellcharacterized drug substance to an appropriate, and potentially optimized,
drug product. At the heart of biopharmaceutics is a thorough understanding
of the physical, chemical and biological properties of the drug substance
related to absorption (e.g., solubility, stability and intestinal permeability)
and how to utilize these data to decide on the best route of administration
and to develop a successful dosage form. The development of an initial
formulation for a drug substance entails the study of drug product
dissolution under a variety of environmental conditions (e.g., pH), and
linking the resulting rate and extent of dissolution to the subsequent rate
and extent of absorption (i.e., bioavailability or BA). These so-called in
vitro-in vivo correlations (IVIVC) are important to early optimization of
formulation performance in order to achieve systemic plasma drug
concentration-time profiles later in human clinical trials with the greatest
chance for therapeutic success.
Not infrequently, the final, to-be-marketed formulation of the active drug
substance is different than the initial formulations used in either early or late
clinical trial phases of development. Biopharmaceutics plays a critical role in
linking the in vivo performance or BA of each of the early formulations (i.e.,
reference formulations) to the final (i.e., test formulations) formulations.

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Drug Development and Regulatory Decision-Making

The standard study to assess comparative BA of the test and reference

formulations is the bioequivalence (BE) study. Often, the results of BE
studies are expressed as measures of exposure, such as area under the
plasma concentration-time curve (AUC) and peak or maximum plasma
concentration (Cmax). The ratio of these in vivo measurements (test/
reference) are usually statistically reported as 90% confidence intervals (CI).
BE is declared if the 90% CI is between 80 and 125% (goalposts).
However, if the 90% CI is either partially or completely outside these
goalposts, therapeutic equivalence is determined by integrating the
clinical pharmacology information about exposure-response relationships
into the regulatory decision-making process.
REGULATORY REVIEW
Within the Center for Drug Evaluation and Research (CDER) of the FDA,
the regulatory review of clinical pharmacology and biopharmaceutics
studies is the responsibility of the Office of Clinical Pharmacology and
Biopharmaceutics (OCPB). The mission of OCPB has patient care and
therapeutics as center stage, and this is reflected by the scientific goals of
clinical pharmacology and biopharmaceutics, that is, to critically study,
thoroughly understand, and successfully identify (1) the right dose, in (2)
the right dosage form, for (3) the right patient. The final step is to
responsibly translate this knowledge to the product label with appropriate
information about the use of the drug/drug product in the clinical
pharmacology, precautions, warnings, contraindications, and/or dosage
and administration sections of the package insert. This is indeed a critical
step in the review process, since labeling a drug for use in the manner that is
intended for patients to use it (or not use it) is one of the most important
ways of risk management for ADRs.
OCPBs review process is based on a paradigm known as the QuestionBased Review, or QBR [10]. It recognizes that it would be unreasonable to
expect that everything will be known about the clinical pharmacology (CP)
and biopharmaceutics (BP) of a drug/drug product at the time of NDA
submission. Accordingly, the QBR emphasizes the importance of the
reviewers responsibility to ask the right questions related to the efficacy and
safety of new medicines based on the clinical pharmacology and
biopharmaceutics database provided by the sponsor in a NDA, and also to
identify what is important but not known about the drug. The latter may be
the basis for postmarketing studies (phase IV commitments). There are
many critical principles in applying the QBR but two stick out the most
when reviewing CP and BP studies: (1) analyzing study results and
integrating knowledge thoughtfully across studies, and not just reviewing

Copyright 2004 by Marcel Dekker, Inc.

Lesko and Sahajwalla

studies in isolation from one another, or necessarily in the chronological

order in which they were conducted, and (2) interpreting results of CP and
BP studies in the overall context of what is also known from the nonclinical
chemistry, pharmacology and toxicology data, and the clinical efficacy and
safety information, and not just to focus on providing a narrow-focused CP/
BP report to medical officers. To meet these responsibilities, reviewers are
strongly encouraged to act credibly and to communicate extensively with
other professionals during the review process.
VIEW TOWARD THE FUTURE
Clinical pharmacologists and biopharmaceutical scientists have an
opportunity, as much as any professional, to lead the pharmaceutical
industry and regulatory agencies in leveraging their science and technology
for achieving future breakthroughs in therapeutics. The process of marrying
comprehensive biopharmaceutical information to clinical pharmacology
data, and integrating that knowledge into what is known about drug
efficacy and safety, will bring the drug development enterprise a step closer
to realizing the dream of individualized medicine. Part of this process will be
leveraging several existing fundamental technologies and new scientific
discoveries to a greater extent.
Pharmacogenetics (PGt) and Pharmacogenomics (PGx)
While no consensus on definitions is at hand, for the purpose of this chapter
PGt can be thought of as the study of the genetic variability in PK among
individuals, affecting liver enzymes that metabolize drugs and transporters
that determine BA and drug distribution. PGx, closely related to PGt, may
be defined as the study of genetic variability, including that of drug receptors
(PD), among individuals, affecting the rest of the genome that regulates drug
response. Many believe that PGt and PGx are at the core of future drug
development processes with applications ranging from new knowledge
about the molecular basis of diseases to identification of new genes or gene
products (e.g., protein) that serve as novel drug targets. There are several
significant industry examples of the impact of PGt and PGx. These include
(1) the comarketing of trastuzumab (Herceptin, Genentech) and a
diagnostic test (HercepTest) for patients with breast cancer whose tumors
have overexpressed HER 2 activity [11], (2) a gene-based diagnostic marker
that has the potential to identify at-risk patients with HIV for
hypersensitivity to abacavir (Ziagen, GSK), (3) haplotypes that have the
potential to be used as diagnostic tests to optimize the selection of approved
HMG Co-A reductase inhibitors (statins) in patients with

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Drug Development and Regulatory Decision-Making

hypercholesteremia, and (4) potential genetic markers to identify patients

with rheumatoid arthritis who are responders to IL-1 and TNF-inhibitors. A
regulatory perspective on PGt and PGx has recently been published and
regulatory agencies worldwide generally are optimistic that these sciences
will, in time, profoundly transform the drug development and regulatory
review processes [12].
However, closer attention needs to be paid to what is already known
about PGt with an eye toward how this information can be integrated into
current standards of patient care to reduce the incidence of ADRs. For
example, it has been reported that of the top 27 drugs frequently cited in
ADR reports, 59% are metabolized by at least one enzyme having poor
metabolizer (PM) genotype. Eleven of the 27 drugs (38%), mainly used for
cardiovascular and CNS diseases, are metabolized specifically by cytochrome
P450 (CYP) 2D6 [13]. Despite the strong suggestion that knowing a patients
CYP 2D6 genotype (or phenotype), and adjusting doses downwards or
upwards depending on the genotype, would positively influence benefit/risk
of therapy, CYP 2D6 genotyping is not recommended in any package insert
of approved products. There are a variety of reasons for this, but as genotyping
tests for CYP enzyme activity become more widely available and cost-effective,
clinical pharmacologists will have the responsibility to ask the right questions
about genetic polymorphism and to act responsibly on the information during
drug development and regulatory review.
In the broad world of PGx, there will be greater reliance on global DNA
sequencing and candidate gene studies to discover genes and genetic
biomarkers that play a role in assessing disease progression and variability
in drug response. Clinical pharmacologists will have opportunities to
explore associations between gene variants, in the form of single nucleotide
polymorphisms (SNPs) or combinations of SNPs (haplotypes), to better
understand variability in drug response and dosage requirements. In
addition, complementary PGx technologies, such as gene-chip microarrays
and quantitative polymerase chain reaction (PCR), will provide additional
insights into the genetic basis of disease and drug response which will
impact clinical therapeutics in terms of measuring disease- and druginduced differences in expression profiles and providing multiple biomarker
panels to associate with drug therapy.
Assay Development
It is well known that chemical assays of high quality (i.e., adequate
sensitivity, selectivity, and reproducibility) are essential to obtaining credible
data in clinical pharmacology studies (e.g., PK) and biopharmaceutics
studies (e.g., BE). However, in the future, assay development that includes
more sophisticated technologies and more attention to detail will be needed.

Copyright 2004 by Marcel Dekker, Inc.

Lesko and Sahajwalla

For example, there are many pharmacological or physiological biomarkers

of drug activity which are used in analyzing exposure-response relationships
for the purpose of making decisions in drug development or regulatory
review, where evidence of validation of the measurement of the response
component is incomplete or missing. In addition, with the evolution of PGt
and PGx, principles of validation of new technologies such as mass
spectrometry (proteomics), high-throughput DNA sequencing, and
expression profiling (microarrays) will need to be established to ensure
credible interpretation and use of these data. Each of these newer
technologies, in contrast to traditional technologies, will provide a
tremendous amount of information about changes in gene expression and
potentially useful biomarker panels. The bioinformatics software used to
mine these data sets is not standardized at the moment, and as a result
various association algorithms, cluster analyses, and SNP and haplotype
identification methods are used from company to company. The potential
for interlaboratory differences in interpretation is enormous and consensus
on how to use these tools reliably will be important in clinical pharmacology
and biopharmaceutics studies of the future.
Modeling and Clinical Trial Simulation (CTS)
Development and validation of models for exposure-response datasets have
been widely used by clinical pharmacologists during drug development and
regulatory review to understand the nature of dose-response and PK-PD
relationships and to predict alternative clinical scenarios. There are many
examples of the value of modeling in terms of improving drug development
and regulatory review [14]. In the future, modeling of biological systems at
the cellular level, disease progression models, and models for quantitative
assessment of risk will take on greater importance in CP studies. More
recently, CTS or computer assisted trial design (CATD) methodologies have
been advanced as tools to use phase I and phase II exposure-response
information to design phase III trials, predict trial outcomes in terms of
efficacy and safety, and allow for more informed decisions on benefit/risk
analysis and the economics of drug development programs [15]. CATD,
while not routinely used in drug development and regulatory review, is likely
to take on more importance as our understanding of the causes of disease,
disease progression, molecular drug targets, and drug pharmacology/
toxicology increases through the co-evolution of genetics and genomics.
Diagnostic Tests and Kits
As PGt and PGx mature, it is highly likely that gene-based diagnostic tests
and kits using genetic markers will significantly influence drug

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Drug Development and Regulatory Decision-Making

development and regulatory review. These tests and kits will not only be
used on patient blood or tissue samples to diagnose diseases when they are
present, but will also be able to (1) predict the probability of developingdiseases in the future, (2) identify patients who are most likely to be
responders or nonresponders, (3) select the most appropriate dose for a
given individual, and (4) select the best drug in a class once a decision is
made to institute drug therapy. To date, there are relatively few diagnostic
test kits approved by FDA, although in the future this would be desirable.
HercepTest (Dako Corporation) and PathVysion Her-2 DNA FISH (Vysis)
have been approved by FDA to measure HER 2 activity prior to making a
medical decision to administer Herceptin to women in advanced stages of
breast cancer, and HIV-1 TruGene Assay (Applied Sciences/Visible
Genetics) has been approved to measure HIV resistance and to provide
drug treatment options for patients with AIDS. FDA approval of genebased diagnostics would provide many advantages such as assuring high
quality reagents, validated reference standards, standardized assay
procedures and protocols, and greater acceptance of these tests by patients
and physicians. Interpreting the test results for physicians, by bridging this
information to package inserts, is likely to become an important
responsibility of clinical pharmacologists in the future.
Knowledge Management (KM)
For the purposes of this chapter, KM is defined as the marriage of science,
bioinformatics, and computer technology to more effectively assess and
utilize the ever increasing amounts of clinical pharmacology and
biopharmaceutics data arising from drug development. As an example,
modern NDAs may contain more than 60 CP and BP studies, and each
study contains many more pieces of data than ever before. In order to
conduct a meaningful and thorough analyses of these data and to learn as
much as possible about the drug/drug product, industry and regulatory
scientists will need the capability that computer visualization and analysis
software can offer. Applying web-based data management will enable
endusers to (1) use information across studies better, (2) make more
efficient and informed decisions about benefit/risk, and (3) create learning
databases that can be effectively queried to compare CP and BP attributes
across drugs and therapeutic areas. Visualization software is also a
powerful way to communicate important CP and BP information to those
in other disciplines in order to make maximum use of the scientific data at
hand.

Copyright 2004 by Marcel Dekker, Inc.

10

Lesko and Sahajwalla

SUMMARY
The current mission and goals of clinical pharmacology and
biopharmaceutics is highly likely to expand and be transformed in the future
as the new tools, technologies, and expectations (as described above and in
the following chapters) become reality. Many of the questions about
efficacy, safety, benefit/risk, drug dosing, and drug product performance
will be tailor made for the scientists in CP and BP. These scientists will have
to integrate their knowledge with other disciplines more broadly to take a
leading role in drug development and regulatory decision-making. The
efforts of clinical pharmacologists and biopharmaceuticists, if future
challenges are accepted by the profession, will have the potential to
introduce innovation and ultimately impact the standards of medical care.
How CP and BP data is interpreted and applied in the future will affect risk
assessment, risk management plans, and drug development and regulatory
decisions. The quality of CP information in drug product labels and the
setting of standards and specifications based on BP data to assure consistent
drug product performance over time in the marketplace will likely impact
the effectiveness and, perhaps most importantly, the safety of new
medicines. This is, without a doubt, a common and meritorious goal shared
by clinical pharmacologists and biopharmaceuticists whether they practise
in industry or in regulatory agencies.
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