BASICS OF

CLINICAL TRIALS

LAKSHMI MOHAN
PRIYANSHU MITTAL
B.Tech Bionformatics(6th
sem)
CONTENTS
 INTRODUCTION AND HISTORY
 TYPES OF CLINICAL TRIALS
 INCLUSION AND EXCLUSION CRITERIA
 PRIMARY AND SECONDARY OUTCOME
 ENDPOINTS OF CLINICAL TRIALS
 NEED OF CLINICAL TRIALS
 PHASES OF CLINICAL TRIALS
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.
A properly planned and executed clinical trial is a powerful experimental technique for
assessing the effectiveness of an intervention.

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.
 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).
HISTORY
 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
 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.
 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.
 Primary and Secondary Outcomes: Example of Aspirin in the ISIS-2
Trial

The Second International Study of Infarct Survival (ISIS-2) was a major clinical
trial that tested the effects of aspirin and streptokinase in patients with acute
myocardial infarction (heart attack). This trial provides a clear example of primary
and secondary outcomes. Secondary Outcomes:
Primary Outcome:
In addition to vascular mortality, the
•The main research question was whether
researchers also examined other effects of
aspirin reduces vascular mortality in
aspirin:
heart attack patients.
1.Non-fatal heart attacks – Did aspirin
•The primary outcome was the
reduce the recurrence of heart attacks?
reduction in death from any vascular
2.Incidence of stroke – Did aspirin lower the
cause (such as heart attack or stroke)
chances of stroke in these patients?
within 5 weeks of treatment.
3.Incidence of major bleeding – Since
•This outcome was chosen because it
aspirin can increase bleeding risk, did it lead to
directly measured whether aspirin
more bleeding complications?
improved survival in heart attack patients.
4.Subgroup Analyses – Researchers
analyzed results based on factors like age,
sex, and pre-existing conditions to see if
aspirin worked differently in different patient
groups.
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.
 NEEDS OF CLINICAL
TRIALS
•Determining Treatment Effectiveness
Clinical trials are the most reliable way to assess whether a medical intervention works.
Without them, it is difficult to distinguish between real effects and random variations in patient
outcomes.
•Overcoming Uncertainty in Disease Progression
Diseases and conditions are not always fully understood, making it hard to predict how they
will progress in individuals. Clinical trials help establish reliable data on disease outcomes.
•Assessing Safety & Adverse Effects
Some interventions, like high oxygen therapy for premature infants or antiarrhythmic drugs,
were widely used before trials revealed their risks. Clinical trials identify side effects and
prevent harm.
•Avoiding Costly & Ineffective Treatments
Some expensive treatments, such as certain breathing therapies for lung disease, were used
without strong evidence. Trials help determine whether a treatment's benefits justify its costs.
•Providing Evidence-Based Decision Making
Clinical trials generate scientific data that guide doctors, policymakers, and
healthcare providers in choosing effective treatments.
•Influencing Clinical Practice & Public Health
Trials contribute to medical advancements, shaping guidelines for disease
prevention and treatment. Even though observational studies provide
insights, clinical trials offer stronger, controlled evidence.
•Addressing Ethical & Patient Expectations
While some patients with life-threatening conditions demand access to
experimental treatments, clinical trials ensure these interventions are
rigorously tested for safety and effectiveness before widespread use.
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 animals 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 surrogate 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 deciphered 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.
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".
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
 Fundamentals of Clinical Trials (4th edition)
THANK YOU