COMMENTARY
Clinical Trials in New Drug Development
J. Rick. Turner, BSc, PhD;1 Theo J. Hoofwijk, MD2
From Clinical Communications, Quintiles, Durham, NC;1 and Therapeutic Strategy Development, Quintiles B.V., Hoofddorp, The Netherlands2
The November 2012 issue of this journal contained a
commentary entitled “The 50th Anniversary of the
Kefauver-Harris Amendments: Efficacy Assessment and
the Randomized Clinical Trial” that explained the
importance of the amendments in the development of
the randomized clinical trials (RCTs) that are used to
provide compelling evidence of a new drug’s efficacy.1 It
also emphasized the relevance and importance to
practicing physicians of a fundamental understanding
of the role of clinical trials in new drug development.
Clinical research informs clinical practice and evidence-
based medicine. Preapproval clinical trials bring new
drugs to market and provide the information contained
within each drug’s prescribing information (label). This
information concerning the drug’s safety and therapeu-
tic benefit, which is the best available information at the
time of approval, guides treatment decisions at the
individual patient level. Clinical trials also generate the
evidence contained within treatment practice guidelines,
which have a broader reach across populations of
patients. Clinical trials conducted after the drug’s
approval, along with spontaneous safety reporting and
active postmarketing surveillance, provide additional
information that may lead to changes to the drug’s label
over time as the drug’s use in clinical practice increases.
This paper provides an overview of clinical trial
categorization in new drug development and the nature
of trials falling within each category. Specific examples
focus on antihypertensive agents.
SAFETY, EFFICACY, AND BENEFIT-RISK
BALANCE
When a regulatory agency reviews the marketing
application for a new drug, it will determine whether
there is compelling evidence that the drug is safe and
effective for its intended use. It is therefore appropriate
to discuss the meaning of these terms in the context
of biopharmaceutical medicine. Defining efficacy is
straightforward: Assessments measure the degree to
which the drug accomplishes its intended effect, eg, the
degree to which an antihypertensive agent lowers blood
pressure. Statistical analysis will reveal whether a trial
has provided compelling evidence of statistically signif-
icant efficacy, where the term compelling is operation-
alized by a set of statistical conventions that all
interested parties have agreed to honor. Equally impor-
Address for correspondence: J. Rick Turner, BSc, PhD, Senior Scientific
Director, Clinical Communications, Quintiles, 4820 Emperor Boulevard,
Durham, NC 27703
E-mail: rick.turner@quintiles.com
Manuscript received: January 17, 2013; revised: January 21, 2013;
accepted: January 29, 2013
DOI: 10.1111/jch.12085
306 The Journal of Clinical Hypertension Vol 15 | No 5 | May 2013
tantly, medical judgment will be guided by additional
statistical analyses employing confidence intervals to
determine whether the magnitude of the efficacy is great
enough to warrant the drug’s approval, ie, there is
evidence of clinically significant efficacy.2,3
Defining safety is less straightforward. One might
initially think that safety is synonymous with the
absence of risk; however, this is not the case. A useful
operational definition of safety was provided in 2008 by
the US Food and Drug Administration’s (FDA’s) Senti-
nel Initiative:4
Using medical products brings benefits and risks.
Although marketed medical products are required by
federal law to be safe for their intended use, safety
does not mean zero risk. A safe product is one that
has acceptable risks, given the magnitude of benefit
expected in a specific population and within the
context of alternatives available.
While the words “acceptable risks” may at first sight
seem disconcerting, we simply cannot guarantee that a
drug carries no risk to anyone. This is not a new realization.
For example, in 1986, Herxheimer5 wrote as follows:
If we want to benefit from medicine, we must accept
some risks. We first need to consider the risks when
deciding whether or not to use the medicine. When
we have decided to take the medicine, because the
likely benefit sufficiently outweighs the risks, we have
to understand how to minimize these risks. The user
thus needs two quite separate kinds of information
about possible harm: first, a realistic assessment of
benefits and risks when the drug is properly used;
second, what precautions and circumspections
“proper use” requires.
It is the responsibility of those of us conducting clinical
research to design, execute, analyze, interpret, and
present the results of clinical trials to the highest
standards to provide robust data to regulatory agencies.
Regulators then examine these data to assess the drug’s
benefit-risk balance when making their approval deci-
sion. The benefit-risk balance must be favorable, ie, the
benefits must be considered to outweigh the risks. If a
drug is approved, a summary of benefits and risks will be
provided in the drug’s label. Prescribing physicians such
as readers of this journal then have the responsibility to
use appropriate “precautions and circumspections”5
when prescribing a given drug, making benefit-risk
judgments at the individual patient level.
REGULATION AND CLASSIFICATION OF
CLINICAL TRIALS
Piantadosi6 provided the following succinct definition:
“A clinical trial is an experiment testing a medical
Official Journal of the American Society of Hypertension, Inc.

treatment on human subjects.” Since the term human
subjects can be uncomfortable to some readers, we have
used the term participants. The participation of humans
means that we must execute every aspect of clinical
research to the highest ethical standards, and protection
of participants’ welfare is our paramount concern.7
Regulatory agencies worldwide govern how trials are to
be conducted. These agencies include the FDA,8 the
European Medicines Agency (EMA),9 and the Japanese
Pharmaceuticals and Medical Devices Agency
(PMDA).10 While not a regulatory agency itself, the
International Conference on Harmonisation of Techni-
cal Requirements for Registration of Pharmaceuticals
for Human Use (ICH)11 brings together regulatory
agencies and biopharmaceutical industry representatives
from Europe, Japan, and the United States “to discuss
scientific and technical aspects of drug registration,” ie,
marketing approval. Its mission is “to achieve greater
harmonisation to ensure that safe, effective, and high
quality medicines are developed and registered in the
most resource-efficient manner.”11
Biopharmaceutical clinical trials are typically classi-
fied into various phases, with any given trial being
identified as belonging to one of them. A common
system includes four temporal phases: phases I, II, III,
and IV. However, as ICH Guideline E812 noted, “It is
important to recognise that the phase of development
provides an inadequate basis for classification of clinical
trials because one type of trial may occur in several
phases.” The guideline provides an alternate 4-item
system, one that employs more informative nomencla-
ture relating to study objectives. This system includes
human pharmacology, therapeutic exploratory, thera-
peutic confirmatory, and therapeutic use trials. Guide-
line E8 hence combines these systems as indicated by the
headings of the next 4 sections.
Phase I (Most Typical Kind of Study: Human
Pharmacology)
An enormous amount of work spanning several years is
completed in the new drug development process before
clinical trials commence. This work comprises a drug’s
nonclinical development program. Nonclinical develop-
ment comprises in silico,13 in vitro, ex vivo, and in vivo
testing, including investigations conducted at the intra-
cellular, cellular, isolated tissue, isolated organ, and
intact animal levels.14 No animal model is a perfect
predictor of the precise effects of a drug in humans, but
these data nonetheless constitute the rational basis for
determining what drug doses we administer to the
individuals participating in first-in-human clinical trials.
Human pharmacology trials assess the safety of the
drug, obtain a thorough knowledge and understanding
of the drug’s pharmacokinetic profile and potential
interactions with other drugs (drug-drug interactions),
and estimate pharmacodynamic activity. These trials are
typically conducted by clinical pharmacologists. They
include relatively small numbers of participants, but a
lot of assessments are completed for each one.
Official Journal of the American Society of Hypertension, Inc.
Commentary
Acute single-dose studies are conducted first. Short-
term studies of various doses are then conducted,
followed by longer-term studies of various doses.
Eventually, dose-finding studies are conducted to deter-
mine the maximum tolerated dose of the drug. Human
pharmacology trials are informative with regard to
providing answers to questions concerning any side
effects, their characteristics, and whether they are
consistent to any notable degree across participants.
Phase II (Most Typical Kind of Study: Therapeutic
Exploratory)
Participants in these trials have the disease or condition
of clinical concern, eg, hypertension, thus facilitating
initial assessments of a drug’s safety and efficacy in the
intended patient population. They are conducted by
researchers trained in clinical trial methodology and
operational execution.
Often, several hundred participants take part in these
trials. Some of them receive the drug being developed
(the investigational drug), and some receive a control
treatment, which can be a placebo or an active
comparator. The nature of these trials is therefore
comparative, since responses to the drug are compared
with responses to the control treatment in order to
investigate the drug’s comparative efficacy.
Some authors have voiced the opinion that these trials
provide the most accurate assessment of efficacy, since
they are conducted in an extremely tightly controlled
manner. While we agree, however, this environment is
not typical of those in which the drug will eventually be
used if approved. Therapeutic confirmatory and thera-
peutic use trials provide more realistic assessments with
regard to the drug’s benefit to large numbers of patients
in real-world therapeutic settings.15
Phase III (Most Typical Kind of Study: Therapeutic
Confirmatory)
Therapeutic confirmatory studies are conducted as
RCTs, as discussed previously in this journal.1 Several
thousand participants with the disease or clinical
condition for which the drug is being developed take
part. These trials are often required to specifically
include certain subgroups of participants that are
representative of patients who will receive them in
clinical practice if the drug is approved. For example,
EMA’s 2010 guideline for the development of new
antihypertensive agents states that the number of
participants 75 years and older “should be sufficient
to assess both efficacy and safety in this group and
specific attention should be paid to them.”16
As for therapeutic exploratory trials, the nature of
these trials is comparative. The drug’s treatment effect,
the representation of the drug’s efficacy, is calculated as
“mean response to the drug treatment minus mean
response to the control treatment.” An example of a
therapeutic confirmatory study in the field of hyper-
tension was published by Bakris and colleagues.17 This
study was an RCT comparing the single-pill
The Journal of Clinical Hypertension Vol 15 | No 5 | May 2013 307
Commentary
combination of azilsartan medoxomil and chlorthali-
done vs coadministration of azilsartan medoxomil and
hydrochlorothiazide in participants with stage 2 pri-
mary hypertension. It was conducted as part of a phase
III program in support of a marketing application for
the single-pill combination. Additional safety data are
also gained from trials like this, adding to the safety
data portfolio already accumulated.
Upon completion of therapeutic confirmatory trials,
sponsors submit a marketing application to regulatory
agencies. If an agency determines that there is compel-
ling evidence of beneficially balanced safety and effi-
cacy, it will approve the drug for use in its jurisdiction.
Phase IV (Variety of Studies: Therapeutic Use)
Therapeutic use studies are conducted once the drug is
on the market. They may be optional studies, or studies
required by a regulatory agency as a condition of
approving the drug for marketing. In the former case,
the biopharmaceutical company sponsoring a trial may
wish to know more about the drug’s performance in
patients who were not well represented in preapproval
trials, eg, patients with compromised liver function and
patients taking several concomitant medications. In
addition, other sponsors such as an institute within the
National Institutes of Health may want to explore a
drug’s place in current treatment practice guidelines,
comparing its safety and/or efficacy with other treat-
ment options or combinations of various treatment
options. In the latter case, the regulatory agency
approving the drug for marketing felt that, based on
the drug’s benefit-risk balance as indicated by the data
they had to review at that time, the drug could be
marketed and hence offer immediate benefit to patients,
but it also felt that it would be advantageous to require
the sponsor to provide additional safety and/or efficacy
information that could be used to refine the drug’s label
if necessary. In these cases, the drug often receives a
restricted initial label.
THE SHEP, ALLHAT, AND ACCOMPLISH
TRIALS
Readers of this journal will be familiar with these trials.
Of specific relevance in the present context is that, while
they were all therapeutic-use RCTs, the designs of the
trials differed such that the most appropriate control
treatment was employed in each case to best answer the
research question of interest. The Systolic Hypertension
in the Elderly Program (SHEP)18,19 was conducted as
a multicenter, randomized, double-blind, placebo-
controlled trial of chlorthalidone for isolated systolic
hypertension. The Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT)20
employed a multicenter, randomized, double-blind,
active-controlled design to compare chlorthalidone with
each of 3 alternative antihypertensive treatments with
regard to the incidence of nonfatal myocardial infarc-
tion and coronary heart disease death in hypertensive
patients with at least one other risk factor for coronary
308 The Journal of Clinical Hypertension Vol 15 | No 5 | May 2013
heart disease. The Avoiding Cardiovascular Events
through Combination Therapy in Patients Living With
Systolic Hypertension (ACCOMPLISH) trial21 was also
a multicenter, randomized, double-blind, active-
controlled clinical trial, but one that differed from
ALLHAT in that the combination therapy benazepril
plus amlodipine was compared with benazepril plus
hydrochlorothiazide with regard to reduction of cardio-
vascular events in high-risk hypertensive patients.
POSTMARKETING SURVEILLANCE
A landmark report from the Institute of Medicine of the
National Academies22 emphasized the importance of
postmarketing evaluations, commenting as follows:
The approval decision does not represent a singular
moment of clarity about the risks and benefits
associated with a drug – preapproval clinical trials
do not obviate continuing formal evaluations after
approval.
The limited sample size of even the largest preap-
proval clinical trials means that there is a (very) low
probability of observing (very) rare but potentially
important events. The “rule of threes” is instructive
here.23 The sample size, ie, the number of individuals
participating in a clinical trial, that would be needed to
be 95% confident that a single case of an identified
adverse event of interest would be seen is approximately
3 times the reciprocal of the frequency of the event in
the general population. That is, for an event that occurs
in 1/1000 individuals, a sample size of 3000 participants
would provide 95% confidence of observing at least 1
event. For adverse events that are considerably more
rare (eg, rhabdomyolysis, Torsades de Pointes), much
larger sample sizes would be needed (30,000 and
300,000 for events with frequencies of 1/10,000 and
1/100,000, respectively), and trials of this magnitude are
infeasible from both cost and time perspectives. There-
fore, it is probabilistically (very) unlikely that adverse
events with a (very) low frequency of occurrence will be
observed during these trials. They are much more likely
to surface once the drug is widely used by very
large numbers of patients; hence, the critical role of
therapeutic use clinical trials and postmarketing
surveillance.
CONCLUDING COMMENTS
New drug development is a lengthy, expensive, and
complex endeavor. While precise quantification of time
and cost differs on a case-by-case basis, meaningful
estimates at this point in time are 10 to 15 years and US
$ 1 billion. There are therefore many ongoing initiatives
to increase the speed and reduce the cost of drug
development. New drug development is a very mean-
ingful pursuit: biopharmaceutical medicines have
improved health and quality of life on a global scale
that is unrivaled by any other medical intervention.15
There are still many unmet medical needs, however, and
many new drugs to be developed. We hope that
Official Journal of the American Society of Hypertension, Inc.

physicians who have not previously been investigators/
principal investigators at sites running clinical trials
might consider doing so in the future.
Disclosures: The authors report no specific funding in relation to the
preparation of this paper. No editorial support was used.
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