BASICS OF

CLINICAL TRIALS
LAKSHMI MOHAN & PRIYANSHU MITTAL
B.Tech Bioinformatics(6th SEM)
CONTENTS
 History
HISTORY
According to WHO-
a clinical trial is any research study that prospectively
assigns human participants or groups of humans to one
or more health-related interventions to evaluate the
effects on health outcomes.

Clinical trial mean a systematic study of a new drug in human

subjects to generate data for discovering or verifying the clinical
claims or pharmacological and adverse effects with an aim to
determine the safety and efficacy of the drug in question.
 The procedure followed during the trails should comply with an elaborate code
known as ‘Good Clinical Practice(GCP)’ prescribed by the international
conference on Harmonization (ICH ) and declaration of Helsinki. The GCPs
provide details about designing the trial,collection of data, recording of
information , statistical analysis, documentation and reporting the results of
clinical trials.
 When the new compound passes the preclinical pharmacological screening the
manufacturer may file a ‘Preclinical New Drug’ or ‘Investigational New Drug’
application (IND application) to an authorized Drug control body of the
respective country. In UK it is to be submitted to the Committee on Safety Of
Medicine(CSM); In USA ,to the Food and Drug Administration (FDA), while in
India, to Drug Controller General, Govt of India, New Delhi
 IND APPLICATION MUST
CONTAIN
 a) The chemical structure, its source, its manufacturing data with details of its
purity.
 b) The preclinical data about pharmacodynamics, pharmacokinetics and
toxicological studies with ED, and LD, data.
 c) Specification of dosage forms in which it has to be administered to human
beings.
 d) A detailed description of the investigational protocol to be undertaken
(including the dose and route of administration).
 e) The names and qualifications of each investigator and the facilities available to
them.
 An agreement from the sponsors to submit annual progress report regularly.
 f) A certification that "informed consent" will be obtained from human volunteers
and that "ethics of research in human beings" will be strictly followed. The
sponsors have to also ensure that copies of all informational material have been
supplied to each investigator (through Investigator's Brochure).
 Primary and Secondary Outcomes of Clinical Trials
Outcomes in clinical trials are measurable events or endpoints used to
determine the effect of an intervention or treatment.
1. Primary Outcome:
The primary outcome is the main result that the clinical trial is designed to
assess. It answers the primary research question and determines the trial's
success.
 Characteristics: Usually a single, well-defined measure.Pre-specified before the
trial begins. Directly related to the main objective of the study. Guides the
sample size calculation and statistical analysis plan.
 Examples: Reduction in tumor size (oncology trials).Improvement in blood
glucose levels (diabetes trials).Time to disease progression (survival analysis).
2. Secondary Outcomes:
Secondary outcomes are additional measures used to evaluate other effects of the
intervention. They provide supplementary information beyond the primary outcome
 Characteristics: May address other research questions or broader impacts. Can
include safety, side effects, quality of life, and cost-effectiveness. Can be multiple
and exploratory in nature.
 Examples:

Improvement in quality of life (patient-reported outcomes).Reduction in

hospitalization rates. Changes in biomarkers or lab results.
 Endpoints in Clinical Trials
Endpoints are specific criteria or measurements used to evaluate outcomes in clinical
trials. They can be classified into various types:
 1. Clinical Endpoints:Direct measures of how a patient feels, functions, or survives.
These are considered gold standards.Examples:Overall survival (OS).Disease-free
survival (DFS).Symptom improvement
 .2. Surrogate Endpoints:Biomarkers or intermediate outcomes that predict clinical
benefit but do not measure it directly.Examples:Blood pressure reduction as a
surrogate for cardiovascular events.Viral load in HIV trials.
 3. Safety Endpoints:Focus on the adverse effects or toxicity of the
treatment.Examples:Incidence of side effects.Changes in liver enzyme levels.
 4. Composite Endpoints:A combination of multiple outcomes into a single
measure.Examples:Major adverse cardiovascular events (MACE), combining heart
attack, stroke, and death.
 5. Patient-Reported Endpoints:Reported directly by the patient to assess their
experience with the treatment.Examples:Pain scores.Quality of life questionnaires.
 Inclusion criteria
Inclusion criteria are the specific characteristics a person must have to
qualify for a clinical trial. These criteria vary based on the study’s focus. Some
trials need participants with a particular medical condition, while others
might look for healthy individuals. By setting these criteria, researchers
ensure that the right group of people is studied, which improves
the relevance and accuracy of results. For instance, a trial testing a new
cancer drug might only include people with a specific type of cancer, at a
certain stage, or with a genetic mutation that the drug targets. Other studies
might focus on participants within a certain age range or gender.
Common Factors in Inclusion Criteria
•Age: Some trials focus on children, while others target adults or the elderly.
•Gender: Certain studies may be limited to one gender, especially if the condition
affects only men or women.
•Stage of Disease: For disease-focused trials, researchers may seek participants at
specific stages.
•Previous Treatment History: Trials may require participants who have or haven’t
tried certain therapies.
•Genetic Characteristics: Some trials look for people with specific genetic markers.
 Exclusion criteria
Exclusion criteria identify characteristics that disqualify someone from joining a
trial. These criteria ensure that people who may face higher risks or might skew
results aren’t included. For example, someone with a health condition that could
worsen with the trial treatment might be excluded for safety reasons. Exclusion
criteria may also apply to those on medications that could interfere with the
treatment, helping prevent results from being affected by other factors.

Common Factors in Exclusion Criteria

•Pregnancy: Many trials exclude pregnant women to avoid potential risks to the
unborn baby.
•Pre-existing Conditions: Conditions like heart disease or diabetes might lead
to exclusion if the trial drug could worsen them.
•Use of Certain Medications: If a participant is on medication that may conflict
with the trial drug, they may be excluded.
•Risk Factors: A history of allergies or a weak immune system can also be
reasons for exclusion.
 The goal of clinical trials is to answer specific questions about new treatments.
By using inclusion and exclusion criteria, researchers can target the group
for which the treatment is designed, making the findings more relevant. For
instance, if a cancer drug trial includes only people with a specific
mutation that the drug targets, researchers can better assess if it’s effective.
Sometimes, broad criteria allow the study to include more diverse
participants, giving a fuller view of the treatment’s risks and benefits.
 Types of Clinical Trials
 The purpose of different trials varies depending on the question that is being
asked as part of the study. Different types of clinical trials include:1
• Preventive trials: These trials study ways to prevent a disease or a
complication of a disease from occurring.
• Screening trials: Screening trials look for ways to detect a disease at an
earlier, more treatable stage. For example, trying to find a way to
detect lung cancer at an earlier stage than it is usually diagnosed. They are also
called early detection trials.
• Diagnostic trials: These trials look for better and less invasive ways to
diagnose a disease.
• Treatment trials: People are often most familiar with treatment trials, the
studies that look for medications and procedures that work better or are
tolerated better with fewer side effects.
• Quality of life trials: Trials looking for better ways of providing supportive
care for people with a disease are very important and becoming more common.
DESIGN TYPES
OBSERVATIONAL
(non-experimental) EXPERIMENTAL
 Cohort • RCT
• Non-RCT
 Case-Control
 Cross-Sectional
PHASES OF CLINICAL TRIAL
PHASE 1
It is the phase of clinical pharmacological evaluation of the new drug and is
performed on a small number (25-100) of healthy volunteers. If the drug is
expected to have significant toxicity (as in the case of anticancer drugs or drugs
to be used in AIDS therapy), the volunteers with the particular disease are used
rather than healthy volunteers. The objectives of this necessary but cautious
phase of investigation are:
i) to check for safety (i.e., whether the drug affects any cardiovascular, hepatic or renal functions
adversely) and to check its tolerability (ie., does the drug produce any unpleasant symptom like
headache, nausea and vomiting).
ii) to determine whether humans and animals show significant pharmacokinetic differences. diii) to
determine a safe clinical dosage range in hu mans. The selection of an initial human dose is
difficult because the toxicological data on ani- mals are of limited usefulness (quantitatively) for
selecting such a dose. The common rule is to begin with 1/5th or 1/10th of the maximum tolerated
dose (mg/kg) in animals and calculating it for an average human body weight of 70 kg. The drug is
then given in small increments till the therapeutically effective dose is attained by clinical
observation.
iv) to determine the pharmacokinetics of the drug in humans so as to decide whether the
deficiency in drug effects, if any, is a result of its lack of absorption or its faster elimination.
v) to detect any predictable toxicity.
 These trials are NON-BLIND or OPEN LABEL; that means both the investigator and the subjects
know what is being given. Phase I trials are usually -performed by clinical pharmacologists in a
research centre especially equipped for pharmacokinetic studies.
 PHASE 2

In this phase, the drug is studied for the first time in patients with target disease, to determine its efficacy (i.e..
proof of claims). The main purpose of phase II trial is to gather evidence that the drug has the effects as
suggested by preclinical trials. Hence an end point is decided. It may be definitive end point (which measures
the drug effect directly, e.g., pain relief is the end point for testing an analgesic) or a surrogate end point (which
is predictive of the definitive end point, e.g., reduction in the tumour size is the surroga- te end point for survival
by anticancer drugs). These trials are divided into EARLY and LATE PHASES.
 In the EARLY PHASE II, a small number of patients (up to 200) are studied in detail to observe the potential
therapeutic benefits and side effects. The idea is to establish a dose range for more definitive therapeutic trials
to be undertaken in the late phase. It is usually a SINGLE BLIND design where only the subject does not know
whether he is taking an inert placebo (if used) or a positive control drug (i.e., an established standard
medicine) or the new drug (under trial).
 The LATE PHASE II trials are conducted on a larger number of patients (200-400) in a controlled DOUBLE BLIND
manner, where the investigator is also ignorant (besides the subject) whether he is prescribing a placebo, or a
positive control medicine or the new drug under trial. This is done to rule out the influence of preconvinced
notion or of benign communication by the investigator to his subjects.
 In such a design, a third party holds the code identifying each medication and this code is not deci- phered
until all the clinical data have been collected.
 In short, the phase II trials are carefully controlled blind studies (single as well as double) in a homogeneous
population to ensure safety and efficacy of the new drug in a specific disease.
 3. Phase III

 These are large-scale multicentered (heterogeneous population) randomized double-blind trials in

patients (1000-5000 plus) to further establish the safety and efficacy. These are designed to minimise
errors in the information gathered in Phase I and II trials. Therefore these trials are made using DOUBLE-
BLIND CROSS- OVER designs like those set out in Table 8.1.
 The term cross-over design means that the standard drug, the placebo and the new drug are given in
alternating periods and the sequence is systema- tically varied (as per Latin square rule) so that different
subsets of patients receive each of the possible sequences of the treatment (see Table 8.1). All the three
phases of clinical trial usually take 5. 6 years for completion.
 At the end of this trial, statistical analysis of the data is performed. Initially, relatively simple tests, like
the student t-test or the chi-square tests are applied to determine the significance of results. However,
complex statistical methods may also be needed like non-parametric tests, analysis of New Drug
Application. Once the phase III trials are completed satisfactorily the sponsors can file a "New Drug
Application" with the Drug Control authorities of that country. The new drug application usually contains
thousands of pages and includes complete detailed monograph of the product, the results of the trials,
the proposed registered name of this product and the package insert. The data are reviewed by the Drug
Control authorities and even by outside consultants who may require further information or clarification. If
the documentation is acceptable and is in compliance with the regulations, the drug control authorities
can allow the drug to enter the market with "New Drug Status".
 4. Phase IV
 Once approval is obtained to market the drug, phase IV of the trials begins. It is
the post-licensing phase- field trials. The phase IV has no fixed duration as it is
the surveillance phase during the post-marketing clinical use of the drug. The
performance of the drug is monitored for several years, immediately after
marketing, to discover relatively rare side effects (e.g., congenital effects) or
previously unknown drug
 interaction or even a previously unknown therapeutic use detected by a chance
discovery. During the "New Drug Status" period, the manufacturer is expected to
report any new information about the drug concerning its safety. Such Periodic
Safety Update Report (PSUR) is to be submitted every six months for first 2 years
and then annually for the next 2 years. The drug may remain in "New Drug
Status" (i.c., in controlled marketing) for several years until the Drug Control
authorities are confident about its release to unrestricted marketing.
REFERENCE
 Sharma&Sharma Pharmacology (3rd Edition) | PDF
 Inclusion and Exclusion Criteria in Clinical Trials | European Clinical Trials Inf
ormation Network
 SciencePharma | The History of Clinical Trials
THANK YOU