CORRELATION BETWEEN DEVELOPMENT

PHASES AND TYPES OF STUDY

Therapeutic
Use
PROGRESS

Therapeutic
Confirmatory

Therapeutic
Exploratory

Human
Pharmacology

TYPE
Phase I Phase II Phase III Phase IV
PHASE

TIME
FREQUENTLY DONE

SOMETIMES DONE 23
IMPORTANT GUIDELINES
ICH AND GCP

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IMPORTANT GUIDELINES – ICH
 ICH (International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human use) is a unique undertaking that brings together the drug regulatory
authorities and the pharmaceutical industry of Europe, Japan and the United States.

 Regulatory harmonisation offers many direct benefits to both regulatory authorities and the
pharmaceutical industry with beneficial impact for the protection of public health. Key benefits include:

 Preventing duplication of clinical trials in humans and minimising the use of animal testing without
compromising safety and effectiveness;

 Streamlining the regulatory assessment process for new drug applications;

 Reducing the development times and resources for drug development.

 This regulatory harmonization is achieved by developing guidelines. These guidelines are divided into
four categories as follows:

 Q – Quality Guidelines: Defining relevant thresholds for impurities testing and a more flexible approach to
pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.

 S – Safety Guidelines: ICH has produced a comprehensive set of safety guidelines to uncover potential risks
like carcinogenicity, genotoxicity and reproductive toxicity.

 E – Efficacy Guidelines: The work carried out by ICH under the Efficacy heading is concerned with the
design, conduct, safety and reporting of clinical trials.

 M – Multidisciplinary Guidelines: Those are the cross-cutting topics which do not fit uniquely into one of the
Quality, Safety and Efficacy categories. It includes the ICH medical terminology (MedDRA) and the Common
Technical Document (CTD)
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EFFICACY GUIDELINES

 Clinical Safety E1 – E2F

 Clinical Study Reports E3

 Dose-Response Studies E4

 Ethnic Factors E5

 Good Clinical Practice E6

 Clinical Trials E7 – E11

 Guidelines for Clinical Evaluation by Therapeutic Category E12

 Clinical Evaluation E14

 Pharmacogenomics E15 – E16

 Joint Safety/Efficacy Topic M3

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PRINCIPLES OF GCP (GOOD CLINICAL PRACTICE)
 Clinical trials should be conducted in accordance with the ethical principles that have
their origin in the Declaration of Helsinki, and that are consistent with GCP and the
applicable regulatory requirement(s).

 Before a trial is initiated, foreseeable risks and inconveniences should be weighed

against the anticipated benefit for the individual trial subject and society. A trial
should be initiated and continued only if the anticipated benefits justify the risks.

 The rights, safety, and well-being of the trial subjects are the most important
considerations and should prevail over interests of science and society.

 The available nonclinical and clinical information on an investigational product

should be adequate to support the proposed clinical trial.

 Clinical trials should be scientifically sound, and described in a clear, detailed

protocol.

 A trial should be conducted in compliance with the protocol that has received prior
institutional review board (IRB)/independent ethics committee (IEC)
approval/favourable opinion.

 The medical care given to, and medical decisions made on behalf of, subjects should
always be the responsibility of a qualified physician or, when appropriate, of a
qualified dentist.

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PRINCIPLES OF GCP (CONTD.)

 Each individual involved in conducting a trial should be qualified by education,

training, and experience to perform his or her respective task(s).

 Freely given informed consent should be obtained from every subject prior to
clinical trial participation.

 All clinical trial information should be recorded, handled, and stored in a way
that allows its accurate reporting, interpretation and verification.

 The confidentiality of records that could identify subjects should be protected,

respecting the privacy and confidentiality rules in accordance with the
applicable regulatory requirement(s).

 Investigational products should be manufactured, handled, and stored in

accordance with applicable good manufacturing practice (GMP). They should
be used in accordance with the approved protocol.

 Systems with procedures that assure the quality of every aspect of the trial
should be implemented.

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DESIGN OF STUDIES
BASIC CONSIDERATIONS

29
DESIGN – BASIC CONSIDERATIONS
The basic considerations that need to be kept in mind while designing a trial are as follows:

 Objective of the Trial: The medical questions that need to be answered should be clearly
formulated so that necessary resources such as the number of subjects, study duration, study
endpoints for evaluation of the study drug, facility/equipment, and clinical personnel can be
determined in order to provide an accurate and reliable statistical/clinical inference for
addressing these questions. The objectives may be more than one and may be segregated into
primary and secondary as demonstrated by the example of Lung Cancer trial below:

 Primary Objectives - This is a randomized, parallel-group trial to demonstrate that the one-year survival of
the patients with pre-treated advanced (Stage IIIB/IV) non-small-cell lung cancer (NSCLC) receiving the oral
investigational drug is not inferior to those receiving intravenous (IV) docetaxel.

 Secondary Objectives - Secondary objectives of the trial are to evaluate overall survival, time to
progression, response rate, time to response, improvement in quality of life, and qualitative and
quantitative toxicities.

 Target population and patient selection: In clinical trials a set of eligibility criteria is usually
developed to define the target patient population from which qualified (or eligible) patients can
be recruited to enrol the studies. Typically a set of eligibility criteria consists of a set of inclusion
criteria and a set of exclusion criteria. The set of inclusion criteria is used to roughly outline the
target patient population, while the set of exclusion criteria is used to fine-tune the target
patient population by removing the expected sources of variability. To be eligible for the
intended study, patients must meet all the inclusion criteria. The next slide shows an example
of the eligibility criteria required for a trial involving an anti-infective agent.

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 ELIGIBILITY CRITERIA FOR ANTI-INFECTIVE AGENTS
A. Inclusion Criteria

1. Hospitalized patients aged 18 years or older.

2. An oral temperature greater than 38.5°C once or greater than 38°C on two or more occasions during a
12-hour period.

3. Fewer than 500 absolute neutrophils (polymorphonuclear and segmented) per mm3, or patients
presenting with between 500 and 1000 absolute neutrophils per mm3, whose counts are anticipated
to fall below 500 per mm3 within 48 hours because of antecedent therapy.

B. Exclusion Criteria

1. History of hypersensitivity to a cephalosporin or penicillin.

2. Pregnant or breast-feeding.

3. Requiring other systemic antibacterial drugs concomitantly except for intravenous vancomycin.

4. Creatinine clearance 15 mL/min or requiring hemodialysis or peritoneal dialysis.

5. History of positive antibody test for HIV.

6. A severe underlying disease such as meningitis, osteomyelitis, or endocarditis.

7. Patients undergoing bone marrow transplantation or stem cell harvesting and infusion.

8. Any other condition that in the opinion of the investigator(s) would make the patient unsuitable for
enrollment.
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DESIGN – BASIC CONSIDERATIONS (contd.)
 SELECTION OF CONTROLS: In clinical trials, bias and variability can occur in many ways
depending on the experimental conditions. These bias and variability will have an impact
on the accuracy and reliability of statistical and clinical inference of the trials.
Uncontrolled (or non-comparative) studies are rarely of value in clinical research, since
definitive efficacy data are unobtainable and data on adverse events can be difficult to
interpret.

FDA requires that adequate well-controlled clinical trials be conducted to provide an

unbiased and valid evaluation of the effectiveness and safety of study medicines. The
purpose of a well-controlled study is not only to eliminate bias but also to minimize the
variability, and consequently to improve the accuracy and reliability of the statistical and
clinical inference of the study.

 STATISTICAL CONSIDERATIONS: At the planning stage some statistical considerations

regarding the manner in which the data will be tabulated and analyzed at the end of the
study should be carefully considered. These considerations include the primary and
secondary response variables, the criteria for efficacy and safety assessment, sample size
estimation, possible interim analysis and data monitoring, and statistical and clinical
inference.

 OTHER CONSIDERATIONS: In addition to these considerations, some other issues are

dependent on individual trials e.g. treatment duration, patient compliance, missing value,
and drop outs.

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 DIFFERENT DESIGNS OF TRIALS
 Parallel Group Design: A parallel group design is a complete randomized design in which each patient
receives one and only one treatment in a random fashion. Basically there are two types of parallel group
design for comparative clinical trials, namely, group comparison (or parallel-group) designs and matched
pairs parallel designs. The simplest group comparison parallel group design is the two-group parallel design
which compares two treatments (e.g., a treatment group vs. a control group). Each treatment group usually,
but not necessarily, contains approximately the same number of patients.

TEST

RANDOMIZATION
RUN IN
PATIENTS CONTROL A

Run-in Periods CONTROL B

Before patients enter a clinical trial, a run-in (or lead-in) period of placebo, no active treatment, dietary
control, or active maintenance therapy (e.g., diuretic and/or digoxin in heart failure studies) is usually
employed prior to randomization. The inclusion of a run-in period prior to the active treatment has the
following advantages:

1. It acts as a washout period to remove effects of previous therapy.

2. It can be used to obtain baseline data and to evaluate if patient fulfils study entry criteria.

3. It can be used as a training period for patients, investigators, and their staff.

4. It helps in identifying placebo responders.

5. It provides useful information regarding patient compliance.

6. It can be used to estimate and compare the magnitude of possible placebo effects between groups.
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 DIFFERENT DESIGNS OF TRIALS - CONTD
 Crossover Design: In the crossover design, each subject is randomised to a sequence of two or more
treatments, and hence acts as his own control for treatment comparisons. This simple manoeuvre is
attractive primarily because it reduces the number of subjects and usually the number of assessments
needed to achieve a specific power, sometimes to a marked extent. In the simplest 2×2 crossover design
each subject receives each of two treatments in randomised order in two successive treatment periods,
often separated by a washout period. The most common extension of this entails comparing n(>2)
treatments in n periods, each subject receiving all n treatments. Numerous variations exist, such as
designs in which each subject receives a subset of n(>2) treatments, or ones in which treatments are
repeated within a subject.
PERIOD
I II
TEST CONTROL
RANDOMIZATION

SEQUENCE A

WASHOUT
PATIENTS

SEQUENCE B CONTROL TEST

STANDARD TWO-SEQUENCE, TWO-PERIOD CROSSOVER DESIGN

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 DIFFERENT DESIGNS OF TRIALS - CONTD
TITRATION DESIGNS

For phase I safety and tolerance studies, Rodda et al. (1988) classify traditional designs as follows:

1. Rising single-dose design.

2. Rising single-dose crossover design.

3. Alternative-panel rising single-dose design.

4. Alternative-panel rising single-dose crossover design.

5. Parallel-panel rising multiple-dose design.

6. Alternative-panel rising multiple-dose design.

FACTORIAL DESIGNS:

In a factorial design two or more treatments are evaluated simultaneously through the use of varying
combinations of the treatments. The simplest example is the 2×2 factorial design in which subjects are
randomly allocated to one of the four possible combinations of two treatments, A and B say. These are: A alone;
B alone; both A and B; neither A nor B. In many cases this design is used for the specific purpose of examining
the interaction of A and B. The statistical test of interaction may lack power to detect an interaction if the
sample size was calculated based on the test for main effects. This consideration is important when this design
is used for examining the joint effects of A and B, in particular, if the treatments are likely to be used together.

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RANDOMIZATION
AND
BLINDING

36
 RANDOMIZATION
 Randomization is a process in which the study subjects, after assessment of eligibility and
recruitment, but before the intervention to be studied begins, are randomly allocated to
receive one or other of the alternative treatments under study.

 Some ethical considerations may arise as some subjects receive the treatment under study
while the remaining receive the standard treatment or the placebo. But it is to be noted that
before the study data is analyzed, no one knows whether the treatment under investigation is
more effective than the standard treatment or less effective compared to the placebo, as the
case may be for the individual trial under consideration.

 The benefits of randomization are as follows:

 It eliminates selection bias .

 It eliminates confounding by adjusting for co-variates.

 It facilitates blinding of the identity of treatments from investigators, participants, and assessors.

 It permits the use of probability theory to express the likelihood that any difference in outcome between
treatment groups merely indicates chance.

 Different randomization procedures are there like simple randomization, restricted

randomization and adaptive randomization.

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 CONSORT 2010 FLOW DIAGRAM
Assessment for eligibility

Enrollment
Excluded

Randomization

Allocation TEST CONTROL

Allocated to Intervention Allocated to Intervention

Did not receive Did not receive

Received Intervention Received Intervention

Follow-Up Lost to Follow up Lost to Follow up

Followed Up Followed Up

Not Analyzed Not Analyzed

Analysis
Analyzed Analyzed

CONSORT - Consolidated Standards of Reporting Trials

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 BLINDING / MASKING
 Blinding is defined as an experimental condition in which various groups of the individuals involved with
the trial are withheld from the knowledge of the treatments assigned to patients and corresponding
relevant information. The blinding is also known as masking by some research organizations such as
NIH.

 The purpose of blinding is to eliminate bias in subjective judgment due to knowledge of the treatment.
Although the concept of randomization is to prevent bias from a statistically sound assessment of the
study drug, it does not guarantee that there will be no bias caused by subjective judgment in reporting,
evaluation, data processing, and statistical analysis due to the knowledge of the identity of the
treatments. Since this subjective and judgmental bias is directly or indirectly related to treatment, it can
seriously distort statistical inference on the treatment effect. it is therefore imperative to eliminate such
bias by blocking the identity of treatments.

 Blinding in clinical trials can be classified into four types: open label, single blind, double blind, and triple
blind.

 An open-label study is a clinical trial in which no blinding is employed.

 A single-blind trial is a trial in which only the patient is unaware of his or her treatment assignment.

 A double-blind trial is a trial in which neither the patients nor the investigator (study centre) are aware of patient’s
treatment assignment.

 In addition to the patient’s treatment assignment, the blindness also applies to concealment of the overall results of
the trial.

 A triple-blind study with respect to blindness can provide the highest degree for the validity of a
controlled clinical trial.

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THANK YOU
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