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DRUG DEVELOPMENT
Steven Ryder and Ethan Weiner
INTRODUCTION 15 DECISION-BASED CONTINUOUS
THE DRUG DEVELOPMENT DRUG DEVELOPMENT 23
PROCESS 15 Discovery 23
PRINCIPLES GUIDING THE Candidate Nomination for
PROCESS 18 Development 23
Proof of Mechanism 24
DISCIPLINE- OR ACTIVITY-SPECIFIC Proof of Concept 24
GUIDANCE 21 Proceed to Confirmatory Clinical
Pharmaceutical Science 21 Trials 24
Nonclinical Safety
Registration 24
Assessment 21 Postapproval 24
Clinical Research 21
INTRODUCTION
Drug development is the process of translating drug discoveries into
new medical treatments. It begins with the planning of the program
that (i) will explore and study the drug candidate, (ii) will determine
whether it has the potential for becoming a new pharmaceutical treat-
ment, (iii) provides the information allowing the entry of the drug into
medical use, and (iv) continues to gather information on the drug
product until it is superseded by a safer, more well-tolerated, or more
effective treatment. The process builds information, and although it
has stepwise milestones, it is continuous.
This review discusses the principles guiding the process, their appli-
cation, and the ongoing improvement of the process. The chapter
discusses the development process for drug therapeutics (small mol-
ecules and biologic agents) and does not specifically discuss the devel-
opment process for medical procedures, devices or other nondrug
(e.g., herbal) agents. It should be noted that whereas small molecules
and biologics share much of the development process, biologics also
have some specifically different issues, such as particular manufactur-
ing issues or distinct issues around pharmacokinetics and pharmaco-
dynamics. The chapter restricts itself to the development process for
human therapeutics and does not discuss nonhuman (e.g., veterinary)
drug development.
The goal of drug development is to acquire and refine the information
necessary to determine the benefit-to-risk of using a potential new phar-
maceutical as a medical treatment. The ability to investigate and estab-
lish the benefit-to-risk of a new medicine is at the heart of the development
challenge, and the ability to effectively assess benefit-to-risk is directly
linked to the ability to effectively plan, acquire, and analyze information.
This is true in both nonclinical and clinical areas of study.
A rigorous scientific drug development process has allowed the
introduction of a remarkable number of drug treatments, with an
increasing amount of information and increasing precision in the
determination of benefit and risk. To exemplify the incredible progress,
it is worth reading the section from a 1951 medical text describing the
medical treatment of vascular hypertension1:
• Medical Therapy. ANTIHYPERTENSIVE AND DEPRESSOR
AGENTS. Tissue extracts, vegetable extracts, vaccines, hormones,
nitrites, sedatives, pyrogens, phlebotomies, thiocyanates, and sym-
patholytic agents have all been administered for hypertensive
disease, only to be abandoned.
• Within the therapeutic dosage range, the depressor activity of
thiocyanates in experienced hands has been dubious. A number
SPECIAL TOPICS 25
Japan 25
Elderly, Pediatric, and Special
Populations 25
Biologic Agents 26
Individual Assessment of Benefit-
to-Risk 26
Orphan Drugs 27
SUMMARY AND
CONCLUSIONS 27
of deaths have occurred, even though the blood level has been
carefully controlled. Serious toxic side effects, such as exfoliative
dermatitis, have occurred. The use of thiocyanates for therapy of
hypertension is to be discouraged except as a research procedure.
• The most powerful depressor substances belong to the Veratrum
viride group of alkaloids. In the acute hypertensions (acute glo-
merulonephritis and toxemia of pregnancy), veratrum alkaloids
have a real place in therapy. In chronic hypertension, on the other
hand, the dosage that lowers blood pressure is usually about the
same as that which produces nausea and vomiting. Until this
serious side effect can be eliminated, there is no indication for
their usage.
The text then goes on to describe dietary and surgical treatments in
more lengthy sections.
The reader is invited to compare this discussion with the treatments
currently available for hypertension, outlined in Chapter 27, Hyperten-
sion, or the antihypertensive treatment paradigm outlined in the
Seventh Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure (JNC 7) report.2 This report
emphasizes that systemic blood pressure must be aggressively con-
trolled, which usually requires multiple medications from among
the many classes of effective and safe antihypertensive drugs: thiazide-
type diuretics, angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, calcium channel blockers, β-blockers, α-blockers,
and others. In addition, each of these classes of antihypertensive drugs
includes many different individual molecular entities, each with a
specific pharmacokinetic, pharmacodynamic, efficacy, tolerance, and
safety profile. This remarkable change in the antihypertensive pharma-
copeia, and the corresponding change in many therapeutic areas, was
enabled and allowed because of a constantly improving drug develop-
ment process—beginning in the 1950s with the general introduction
of the controlled clinical trial paradigm and continuing to the present
with new adaptive study designs and data capture innovations. Along
with these improvements in drug development, the response to the
human immunodeficiency virus (HIV) epidemic, continued concern
over personal safety and health, and a heightened awareness of drug
withdrawals have increased the focus on drug development principles
and many of its key issues.
THE DRUG DEVELOPMENT PROCESS
Since the mid-20th century, the drug development process has become
more complex as understanding of the underlying biology has grown,
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