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5
Clinical Trials
5.1 Chapter Introduction
This chapter examines the process of conducting clinical trials with human subjects.
This is probably the most critical stage in the regulatory pathway, as the results estab-
lish the safety and ecacy of the drug in humans and ultimately determine whether
or not a successful marketing authorisation application can bemade. They also mark
the stage where extensive engagement with the regulatory authorities in respect of
the drug under development commences. There are considerable regulations gov-
erning the conduct of clinical trials, the underlying purposes of which are to ensure
that the safety, welfare and rights of subjects participating in the trials are protected
and that scientically useful and valid data is collected.
5.2 Clinical Trials
The overall objective of clinical trials is to establish a drug therapy that is safe and
eective in humans, to the extent that the risk–benet relationship is acceptable.
The International Council for Harmonisation of Technical Requirements for Phar-
maceuticals for Human Use (ICH) process has come up with an internationally
accepted denition of a clinical trial as:
● Any investigation in human subjects intended to discover or verify the clinical,
pharmacological, and/or other pharmacodynamic eects of one or more investi-
gational medicinal product(s), and/or to identify any adverse reactions to one or
more investigational medicinal product(s) and/or to study absorption, distribu-
tion, metabolism, and excretion of one or more investigational medicinal prod-
uct(s) with the object of ascertaining its (their) safety and/or ecacy.
The process of conducting clinical trials for drug approval may be broken down
into three consecutive phases. These are:
● Phase I,
● Phase II and
● Phase III.
Medical Product Regulatory Aairs: Pharmaceuticals, Diagnostics, Medical Devices,
Second Edition. John J. Tobin and Gary Walsh.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
86 5 Clinical Trials
Additional safety studies,termed Phase IV trials, may be conductedpost-approval.
Each phase may be distinguished in terms of its specic purpose and relative com-
plexity. A drug may not proceed to the next trial phase until the results of the current
phase have been analysed and reported, as the conclusions drawn will usually inu-
ence the study plan for the following phase. There are no absolute requirements as
regards specic studies that must be conducted in each phase, as these may vary
depending on the characteristics of the particular drug under investigation. Typi-
cally, however, studies progress in the following manner.
5.2.1 Phase I Trials
The primary objective of Phase I trial is to assess the safety of the drug in humans.
Studies are normally conducted in healthy male volunteers, although specic cat-
egories of subject may be used in certain cases. For example, to avoid the risk of
low blood pressure, subjects with mild hypertension would be more appropriate for
evaluation of antihypertensive drugs, while patients are likely to be used in the case
of drugs that are expected to produce signicant toxic eects, e.g. anticancer cyto-
toxic drugs. Remuneration may be oered for participation inthe study.The number
of subjects is normally between 10 and 100 people. The study will commence with
administration of low doses, as judged from the nonclinical data. As the study pro-
gresses, and provided there are no indications that it is unsafe to do so, dosage levels
may be increased past the anticipated therapeutic range. Subjects are closely mon-
itored for changes in vital signs (blood pressure, heart rate, body temperature, etc.)
and the emergence of side eects (nausea, drowsiness, pain, headache, irritability,
hair loss, etc.). Samples of blood and excreta are taken for laboratory analysis. It is
expected that at the end of this phase you will have a preliminary estimate of the
maximum dose that may be safely tolerated in humans and a basic prole of the
pharmacokinetic behaviour of the drug. Depending on the availability of appropri-
ate analytical indicators, pharmacodynamic and indicative ecacy data may also be
generated. Data must be carefully analysed and assessed so that based on the nd-
ings, appropriate Phase II trials can be planned. Phase I trials are relatively short and
are usually completed within a year.
5.2.2 Phase II Trials
The primary objective of Phase II trials is to explore therapeutic ecacy in patients.
The number of subjectsmay range from 50 to 500,and patients may be selectedbased
on specic restrictive criteria e.g.suer only from the condition under study, disease
stage, age, etc. An important goal for this phase is to determine the dosage level and
regimen for Phase III trials. Trials may commence with short-range-nding studies
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5.2 Clinical Trials 87
in a small number of patients before more extensive studies are conducted. Again
subjects will be monitored for any undesirable side eects or changes in vital signs.
However, the main thrust of the studies is to show that benecial therapeutic eects
may be obtained, and to determine the basic dose–response behaviour of the drug in
humans. The studies may also involve identifying or validating convenient markers
or endpoints that may be used as indicators of ecacy for later studies. To provide
objective evidence of benecial therapeutic eects, patient groupsreceiving the ther-
apy are compared against reference or control groups that have received either an
inactive placebo or the existing standard treatment. Phase II trials may last from one
to two years.
5.2.3 Phase III Trials
The purpose of Phase III trials is to conrm safety and therapeutic ecacy in a
broader range of subjects. This can involve studying groups that dier in terms of
age, sex, disease stage, additional medical or physiological conditions (e.g. kidney
or liver failure, pregnancy, breast-feeding), existing drug therapy or ethnic back-
ground. Thus, the number of subjects required will be signicantly greater than
Phase II trials, and depending on the specic drug, can easily approach or surpass
2,000 people. To obtain the number and diversity of subjects, multicentre or indeed
multi-country studies are common at this stage. This is also the phase where trials
involving extended exposure are normally conducted for drugs intended for admin-
istration over long periods.Thus, this phase may take fromthreeto ve years, or even
longer, to complete. The Phase III studies provide a comprehensive understanding
of the safety and ecacy of the drug, and at the end of this the developer should
have identied and conrmed:
● the type of patients/conditions that benet from the therapy (indications for
use),
● situations/conditions where the drug should not be prescribed (contraindica-
tions),
● the appropriate dosage regimen and
● possible side eects.
A summary of the clinical trial process is shown in Figure 5.1. Data from clinical
trials forms the most critical part of the submission for marketing authorisation. In
the case ofdrugs with multiple therapeuticuses, the developer may choose to submit
an application for just one indication for use, while continuing with trials to sup-
port other indications for use. Parallel to the clinical trials, outstanding non-clinical
studies will be continued. This may involve optimisation of the drug formulation
as dictated by clinical trial results and conducting stability studies on the nal drug
product.
88 5 Clinical Trials
Phase I
Purpose: Safety pharmacology
(pharmacokinetics,
side effects tolerance assessment,
evidence of toxicity, pharmacodynamics)
Subjects: 10–100 usually healthy males
Duration: ≤1 year
Phase II
Purpose: Explore therapeutic efficacy
(dose ranging and dose response curves,
pharmacodynamics,
identification/confirmation of efficacy indicators/endpoints)
Subjects: 50–500 patients
Drawn from well-defined narrow populations
Duration 1–2 years
Phase III
Purpose: Confirm therapeutic efficacy and safety
(indications for use, recommended dosage, contra
indications, long term administration and emergence of
additional side effects)
Subjects: up to 3,000 drawn from broad patient base
multi-site, multi-group
Duration: 3–5 years or longer
Figure 5.1 Summary of Clinical Trials conducted as a prelude to a marketing authorization
application.
5.3 Clinical Trial Design
A key element in planning and conducting clinical trials is to ensure that they have
scientic validity and objectivity. This is particularly relevant with respect to phase
II and III studies where it is desired to demonstrate a positive benet to risk out-
come. Responses to a drug among a patient population are rarely homogeneous and
clear-cut. Thus sound statistical principles must be applied to be able to distinguish
signicant eects from random events.
As a starting point, the objectives of each individual study should be clearly
dened. Studies can be broadly divided into two types, conrmatory studies which
set out to prove or disprove predened hypotheses on the basis of measuring dened
variables (indicators or endpoints), and exploratory studies where the outcome in
terms of indicators may not be clear in advance. Conrmatory trials can set out
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5.3 Clinical Trial Design 89
to show superiority of the treatment over a reference treatment/no treatment or
equivalence (non-inferiority) to an existing established treatment.
The number of participants must be chosen so that the trial will have sucient
‘statistical power’, particularly in the case of conrmatory trials. As a general princi-
ple, the greater thenumber of data, the greater the condence thereis in demonstrat-
ing that a statistical dierence between two groups exists or not. However, numbers
of participants willbe constrained by costconsiderations, availability of suitable sub-
jects, and above all, by the ethical principle that subjects should not be enrolled in
clinical trials unless they add scientic value.
Clinical trials should be designed so as to minimise potential sources of bias. It
is known that patients can demonstrate a positive response to treatments that they
believe will benet them, even if no pharmaceutical agent has been administered
(the placebo eect). Similarly, investigators may be biased in their observations by an
expectation of particular results. To avoid such bias, blinded trial designs are used.
In a single-blinded trial, test subjects receive the drug, while the controls receive
an apparently identical preparation that does not contain the active pharmaceuti-
cal ingredient under investigation. Subjects are not informed as to which treatment
they have received. In a double-blinded trial, this information is withheld from both
the subjects and the investigators that conduct the study. In contrast, an open-label
trial refers to one in which both recipients and researchers know which treatment
is being administered. A further source of bias may be introduced, when selecting
patients for control or test treatments. This can be avoided by using a randomised
procedure, where once a subject meets the basic study criteria, they are enrolled and
then assigned to control or test treatments according to a preset randomisation plan.
The most common clinical trial design for conrmatory trials is the parallel group
design, in which subjects are randomised between a control group and one or more
test groups. The results from the test groups are then compared to the control group.
An ethical issue may arise with this type of design in situations where the treatment
is very benecial and thus it would be unfair to withhold it from a control group
of patients. In such instances, it may be possible to use historical control data from
studies that were previously conducted, but caution must be exercised to ensure that
the data has relevance to the present day.
Crossover trial designs can be attractive in situations where availability of suit-
able patients is limited. In a crossover trial, patients act as their own controls as
they receive placebo and test at dierent stages over the course of the study. In the
simplest 2× 2 crossover design, each subject receives each of two treatments in ran-
domised order in two successive treatment periods (i.e. placebo-test-placebo-test or
test-placebo-test-placebo). These types of trials can yield statistically powerful data
with small numbers because aside from avoiding the requirement to have a sepa-
rate control group, they eliminate subject-to-subject variables that would be seen
in a parallel-group study. This type of study design is only suitable for drugs that
are intended for long-term treatment of chronic stable diseases as opposed to drugs
that can cure a condition. A washout interval between each treatment period is
usually required to ensure that drug carried over in the body is not aecting the
next phase.
90 5 Clinical Trials
Table 5.1 A simple factorial trial design
involving two drugs.
Treatment group Treatment
1DrugA+Drug B
2DrugA+Placebo
3DrugB+Placebo
4 Placebo + Placebo
Factorial trial designs are used to simultaneously evaluate two or more treatments
through the use of varying combinations of the treatments. An example of simple
trial to evaluate drugs A and B is illustrated in Table 5.1. They are particularly rele-
vant where multiple drug therapies are anticipated.
5.4 Good Clinical Practice
Clinical trials must be conducted in accordance with the principles of Good Clinical
Practice (GCP). GCP is an international ethical and scientic quality standard for
designing, conducting, recording, and reporting trials that involve the participation
of human subjects. Its purpose is twofold, (i) to ensure that the rights, safety, and
well-being of trial subjects are protected, in accordance with ethical principles that
were developed by the World Medical Organisation and set out in the Declaration
of Helsinki, and (ii) to assure that the clinical trial data are credible. A harmonised
guidance document on GCP has been developed by the ICH (ICH E6 R2). The core
principles of GCP as agreed in the guidance document are outlined in Table 5.2.
These principles of GCP have been incorporated into regulations that govern the
initiation and conduct of clinical trials. The process for undertaking clinical trials in
the EU and the US shall now be examined.
5.5 Clinical Trials in the EU
Approximately 4,000 clinical trials are authorized each year within Europe, of which
approximately 60% are sponsored by the pharmaceutical industry, with the remain-
ing 40% sponsored bynoncommercialconcerns (mainly academia). These trialseach
involve 2 EU Member States on average.
Harmonisation of the administrative provisions for the authorisation and supervi-
sion of clinical trials in the EU was initially introduced via Directive 2001/20/EC
on the approximation of the laws, regulations, and administrative provisions of
the Member States relating to the implementation of GCP in the conduct of clin-
ical trials on medicinal products for human use.
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5.5 Clinical Trials in the EU 91
This was supported by Directive 2005/28/EC laying down principles and detailed
guidelines for GCP as regards investigational medicinal products for human use,
as well as the requirements for authorisation of the manufacturing or importation
of such products.
Regulation (EU) No. 536/2014 of the European Parliament and the Council on clin-
ical trials on medicinal products for human use has now superseded Directive
2001/20/EC.
Table 5.2 Core principles of good clinical practice.
Helsinki declaration ethical
principles
Clinical trials shall be conducted in accordance
with the declaration of Helsinki on ethical
principles for medical research involving human
subjects
Primacy of subject’s rights The rights, safety, and well-being of the trial
subjects should prevail over the interests of
science or society
Favourable risk/benet balance Prior assessment should indicate that the
anticipated benets would outweigh any
foreseeable risks or inconveniences
Professional medical care
(investigator)
The medical care given to, and medical decisions
made on behalf of, subjects should always be the
responsibility of qualied medical personnel
Informed consent Freely given informed consent should be obtained
from every subject
Subject condentiality The condentiality of records that could identify
subjects should be protected to assure their
privacy
Independent ethics committee
oversight
The trials must be accepted by an Independent
Ethics Committee (IEC)/Institutional Review
Board (IRB) before commencing the study
Supporting data Each proposed trial should be supported by
existing nonclinical or clinical data
Scientically sound protocol Clinical trials should be scientically sound and
conducted according to a clear, detailed protocol
Qualied personnel Individuals involved in conducting a trial should
be qualied by education, training, and
experience to perform his or her respective task(s)
Record keeping All clinical trial information should be recorded,
handled, and stored in a way that allows its
accurate reporting, interpretation, and verication
Quality assurance Systems with procedures that assure the quality of
every aspect of the trial should be implemented
GMP manufacture of
investigational drug
Investigational products should be manufactured,
handled, and stored in accordance with applicable
good manufacturing practice (GMP)
92 5 Clinical Trials
A key requirement of the regulation was for the EMA to develop and maintain a
centralized Clinical Trials Information System (CTIS) through which clinical trial
sponsors, regulators, and the general public can interact with and access informa-
tion. This centralized EU portal and database are intended to streamline the admin-
istrative process and allow greater transparency for all interestedparties. As the new
IT system only went live on its own website from 31 January 2022, sponsors of new
trials have until 31 January 2023, to submit applications through CTIS while exist-
ing trials may continue under the provisions of the Directive until 30 January 2025.
Previously a EudraCT database for regulators was developed by the EMA for trials
operating under the directive. It is now maintained for interventional clinical trials
on authorized medicines that are part of a Paediatric Investigation Plan (PIP) Infor-
mation on the results of these trials is made available to the public via The Clinical
Trials Register, a subset of this database.
The legal instruments are quite general in nature but are supported by detailed
guidelines (ICH and EU specic) that may be accessed via the ICH website and The
Rules Governing Medicinal Products in the European Union, Volume 10 – Clinical
Trials. The main headings under which ICH ecacy guidelines are available are
shown in Figure 5.2. The following paragraphs examine the process and players
involved in conducting clinical trials.
E1 Clinical Safety for Drugs use for Long-Term Treatment
E2A-E2F Pharmacovigilance
E3 Clinical Study Reports
E4 Dose–Response Studies
E5 Ethnic Factors
E6 Good Clinical Practice
E7 Clinical trials in Geriatric Population
E8 General Considerations for Clinical Trials
E9 Statistical Principles for Clinical Trials
E10 Choice of Control Group in Clinical Trials
E11-E11A Clinical Trials in Pediatric Population
E12 Clinical Evaluation by Therapeutic Category
E14 Clinical Evaluation of QT
E15 Denitions in Pharmogenetics/Pharmacogenomics
E16 Qualication of Genomic Biomarkers
E17 Multi-Regional Clinical trials
E18 Genomic Sampling
E19 Safety Data Collection
E20 Adaptive Clinical Trials
Figure 5.2 ICH efficacy guideline headings.
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5.5 Clinical Trials in the EU 93
5.5.1 Sponsor
A sponsor initiates the process of conducting clinical trials. The sponsor may be an
individual, company, institution, or organisation, but is most usually the drug devel-
opment company or a contract research organisation that acts on its behalf. The
sponsor is responsible for the initiation, management, and/or nancing of a clini-
cal trial. The management responsibilities include making sure that the trials are
conducted according to the regulations and GCP principles and that the data are
documented, analysed and reported according to established SOP’s and appropriate
quality control and quality assurance measures. The sponsor or their legal represen-
tative must be located in the EU.
5.5.2 Investigator’s Brochure (IB)
As a rst step, the sponsor is required to prepare an investigator’s brochure (IB).
This must be an objective compilation of available clinical and nonclinical data on
the investigational medicinal product that are relevant to the study of the product in
human subjects. It should include a description of the physical, chemical and phar-
maceutical properties of the drug substance and product, as well as all the relevant
studies of its pharmacology, toxicology, pharmacokinetics and metabolism. At the
outset, in the case of a new drug substance, only non-clinical information will be
available, but clinical data or other relevant human experience should be included
for later trials. Its purpose is to provide the investigators, and others involved in the
trial, with sucient information to facilitate their understanding of the rationale for,
and their compliance with, many key features of the trial protocol, such as the dose,
dose frequency/interval, methods of administration: and safety monitoring proce-
dures, as wellas alerting themto the possible risks and adverse reactions that may be
encountered. The IB should be validated and updated at least once a year. Suggested
headings for an IB are shown in Table 5.3.
Table 5.3 Suggested headings for an investigator’s brochure according to ICH guidelines.
1 Table of Contents
2 Summary
3 Introduction
4 Physical, Chemical and Pharmaceutical Properties and Formulation
5
5.1
5.2
5.3
Nonclinical Studies
Nonclinical Pharmacology
Pharmacokinetics and Product Metabolism in Animals
Toxicology
6
6.1
6.2
6.3
Eects in Humans
Pharmacokinetics and Product Metabolism in Humans
Safety and Ecacy
Marketing Experience
7 Summary of Data and Guidance for the Investigator
94 5 Clinical Trials
5.5.3 Investigator
An investigator is responsible for the conduct of the trial at the trial site. The inves-
tigator must be a doctor, or other appropriately qualied medical personnel (e.g.
dentist), and should have adequate education, training, and experience appropriate
to the study. They manage the recruitment of subjects, administration of drugs, and
monitoring and recording of responses. Their overriding responsibility is to guard
the health and welfare of the subjects. Where multiple investigators are involved at
a trial site, a lead or principal investigator must be designated.
5.5.4 Trial Protocol
The sponsor with input from the investigator must prepare a trial protocol. The
document should describe the objective(s), design, methodology (including subject
selection criteria), statistical considerations, and organisation of the trial. Further
detail on the content of a trial protocol is to be found in Annex 1 of Regulation (EU)
No. 536/2014.
5.5.5 Investigational Medicinal Product Dossier (IMPD)
An Investigational Medicinal Product Dossier (IMPD), is intended to be more com-
prehensive than an IB, in that it should contain summaries of available quality data
in addition to the safety and ecacy information that constitutes the main part of
the IB. In total, it should provide information on the chemistry, manufacture, con-
trol and stability of the medicinal product together with the results of non-clinical
and clinical studies. To avoid repetition, the IB can be cross-referenced for nonclin-
ical and clinical results. Ideally, the IMPD should follow the same structure as that
which will be used later for the marketing authorisation application. For products
with existing marketing authorisations, the summary of product characteristics may
replace the IMPD to varying extents (see Chapter 6 for information on the summary
of product characteristics).
5.5.6 Informed Consent
All subjects enrolling on a trial must be informed in simple unbiased language of
the purpose, risks, benets, side eects, and any other information that could be
material to their decision to participate, including their right to withdraw at any
time. Then, if agreeable, subjects, or their legal representatives in the case of minors
or other persons unable to give informed consent, must sign and date an appropriate
informed consent form. Financial inducements, other than as compensation, are
prohibited in trials on minors or incapacitated adults. Trials involving such subjects
should be designed so as to minimise pain, discomfort, or fear.
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