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Medisetty. Greeshma
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1.Clinical trial standards, basic principles of “Good clinical practice”

(GCP)
 Good Clinical Practice (GCP) is an international ethical and scientific quality
standard for the design, conduct, performance, monitoring, auditing,
recording, analyses and reporting of clinical trials.
 There are 13 core principles of ICH-GCP and they are as follows:

1. Clinical trials should be conducted in accordance with ethical principles that

have their origin in the Declaration of Helsinki, and that are consistent with
GCP and the applicable regulatory requirement(s).
2. Before a trial is initiated, foreseeable risks and inconveniences should be
weighed against anticipated benefit for the individual trial subject and
society. A trial should be initiated and continued only if the anticipated
benefits justify the risks.
3. The rights, safety and well-being of the trial subjects are the most important
considerations and should prevail over interest of science and society.
4. The available non-clinical and clinical information on an investigational
product should be adequate to support the proposed clinical trial.
5. Clinical trials should be scientifically sound, and described in clear, detailed
protocol.
6. 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.
7. 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.
8. Each individual involved in conducting a trial should be qualified by
education, training, and experience to perform his or her respective task(s).
9. Freely given informed consent should be obtained from every subject prior to
clinical trial participation.
10.All clinical trial information should be recorded, handled, and stored in a way
that allows its accurate reporting, interpretation and verification.
11.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).
 12.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.
13.Systems with procedures that assure the quality of every aspect of the trial
should be implemented.

2.Ethical principles for conducting medical research involving

people as subjects

 All research involving human subjects should be conducted in accordance

with three basic ethical principles, namely (1)respect for persons,(2)
beneficence non-malificence (3) justice.
 Respect for persons incorporates at least two fundamental ethical
considerations, namely: Respect for autonomy which requires that those who
are capable of deliberation about their personal choices should be treated
with respect for their capacity for self-determination. Protection of persons
with impaired or diminished autonomy, which requires that those who are
dependent or vulnerable be afforded full security against harm or abuse.
 Beneficence and non-malificence refers to the ethical obligation to maximize
benefits and to minimize harms. This gives rise to norms requiring that the
risks of research to be reasonable in the light of the expected benefits, that
the research design to be sound, and that the investigators to be competent
to conduct the research and to safeguard the welfare of the research
subjects.
 Justice refers to the ethical obligation to treat each person in accordance with
what is morally right and proper; to give each person what is due to him or
her. In the ethics of research involving human subjects the principle refers
primarily to distributive justice, which requires equitable distribution of both
the burdens and the benefits of participation in research.
Other principles
 Accepted Scientifically
 Accepted qualified researchers
 Ethics committee review
 Accuracy of published results……etc

3.Planning a clinical trial

1. Planning a clinical trial requires overcoming a series of steps for each
deliverable that is rather standardized. Some steps are milestones in the
process, for instance, the clearance of the Ethical Review Board, without
which the trial will not be conducted.

Steps of the planning phase

 0 - Idea - Observation and identification of a problem and a potential

solution , Treatment or class of treatment.

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  1 - Literature overview and available evidence - Therapeutic model Target
population, Choice of control treatment ,Rate of outcome in control Expected
size of the effect Control treatment, Concomitant treatments

 2 - Problem formulation - Rationale Hypothesis Objectives

 3 – Synopsis - Definition of the study target population ,Rough sample

size ,Rough budget estimate

 4 - Call for investigators

 5 - Draft protocol - Definition of end-points ,Duration of follow-up Sample size

Eligibility criteria ,Treatment(s): dosage, presentation List of critical events
Follow-up schedule

 6 - Fund seeking Industry - Charities Public funds

 7 - Patient consent form - Selection of key data to be shared with the

patients , National and international rules

 8 - Ethical board - National, regional, and/or institutional boards

 9 - Study organization - Steering committee Co-ordination centre Other

committees

 10 - Operating manual and procedures - Data collection, Data circulation,

Data control

 11 - Quality assurance - Central laboratories ,End-point validation

procedure ,Overall quality assurance

 12 - Selection of investigators - Investigators eligibility criteria ,Study

committees

 13 - Finalized protocol - Clearance of all participants

 14 - Operating manual and procedures - Quality control Monitoring

procedures ,Management procedures Forms Other study procedures, Other
study documentation

 15 – Programming - Definition of the database, Data-editing programs ,Test of

programs

 16 - Investigator training - On-site pretrial visits

 17 - Site supply Documentation - Treatments

 18 - First patient recruitment - End of the planning phase

4. Design of study, phases of study

 Case Control Studies - Studies which start with the identification of persons
with a disease of interest and a control (comparison, referent) group without
the disease. The relationship of an attribute to the disease is examined by

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 comparing diseased and non-diseased persons with regard to the frequency
or levels of the attribute in each group.
 Control Groups - Groups that serve as a standard for comparison in
experimental studies. They are similar in relevant characteristics to the
experimental group but do not receive the experimental intervention.
 Controlled Clinical Trials - Clinical trials involving one or more test
treatments, at least one control treatment, specified outcome measures for
evaluating the studied intervention, and a bias-free method for assigning
patients to the test treatment. The treatment may be drugs, devices, or
procedures studied for diagnostic, therapeutic, or prophylactic effectiveness.
Control measures include placebos, active medicines, no-treatment, dosage
forms and regimens, historical comparisons, etc. When randomization using
mathematical techniques, such as the use of a rando7m numbers table, is
employed to assign patients to test or control treatments, the trials are
characterized as Randomized Controlled Trials.
 Cross-Over Studies - Studies comparing two or more treatments or
interventions in which the subjects or patients, upon completion of the course
of one treatment, are switched to another. In the case of two treatments, A
and B, half the subjects are randomly allocated to receive these in the order
A, B and half to receive them in the order B, A. A criticism of this design is
that effects of the first treatment may carry over into the period when the
second is given.
 Cross-Sectional Studies - Studies in which the presence or absence of disease
or other health-related variables are determined in each member of the study
population or in a representative sample at one particular time. This
contrasts with LONGITUDINAL STUDIES which are followed over a period of
time.
 Double-Blind Method - A method of studying a drug or procedure in which
both the subjects and investigators are kept unaware of who is actually
getting which specific treatment.
 Empirical Research - The study, based on direct observation, use of statistical
records, interviews, or experimental methods, of actual practices or the
actual impact of practices or policies.
 Longitudinal Studies - Studies in which variables relating to an individual or
group of individuals are assessed over a period of time.
 Meta-Analysis - Works consisting of studies using a quantitative method of
combining the results of independent studies (usually drawn from the
published literature) and synthesizing summaries and conclusions which may
be used to evaluate therapeutic effectiveness, plan new studies, etc. It is
often an overview of clinical trials. It is usually called a meta-analysis by the
author or sponsoring body and should be differentiated from reviews of
literature.
 Prospective Studies - Observation of a population for a sufficient number of
persons over a sufficient number of years to generate incidence or mortality
rates subsequent to the selection of the study group.

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  Qualitative Studies - Research that derives data from observation, interviews,
or verbal interactions and focuses on the meanings and interpretations of the
participants.
 Quantitative Studies - Quantitative research is research that uses numerical
analysis.
 Random Allocation - A process involving chance used in therapeutic trials or
other research endeavor for allocating experimental subjects, human or
animal, between treatment and control groups, or among treatment groups.
It may also apply to experiments on inanimate objects.
 Randomized Controlled Trial - Clinical trials that involve at least one test
treatment and one control treatment, concurrent enrollment and follow-up of
the test- and control-treated groups, and in which the treatments to be
administered are selected by a random process, such as the use of a random-
numbers table.
 Retrospective Studies - Studies used to test etiologic hypotheses in which
inferences about an exposure to putative causal factors are derived from
data relating to characteristics of persons under study or to events or
experiences in their past. The essential feature is that some of the persons
under study have the disease or outcome of interest and their characteristics
are compared with those of unaffected persons.
 Single-Blind Method - A method in which either the observer(s) or the
subject(s) is kept ignorant of the group to which the subjects are assigned.
Phases of clinical trials
 Clinical trials have five phases
 Phase 0 - Phase 0 trials are the first clinical trials done among people. They
aim to learn how a drug is processed in the body and how it affects the body.
In these trials, a very small dose of a drug is given to about 10 to 15 people.
 Phase I - Phase I trials aim to find the best dose of a new drug with the
fewest side effects. The drug will be tested in a small group of 15 to 30
patients. Doctors start by giving very low doses of the drug to a few patients.
Higher doses are given to other patients until side effects become too severe
or the desired effect is seen. The drug may help patients, but Phase I trials
are to test a drug’s safety. If a drug is found to be safe enough, it can be
tested in a phase II clinical trial.

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  Phase II - Phase II trials further assess safety as well as if a drug works. The
drug is often tested among patients with a specific type of cancer. Phase II
trials are done in larger groups of patients compared to Phase I trials. Often,
new combinations of drugs are tested. Patients are closely watched to see if
the drug works. However, the new drug is rarely compared to the current
(standard-of-care) drug that is used. If a drug is found to work, it can be
tested in a phase III clinical trial.
 Phase III - Phase III trials compare a new drug to the standard-of-care drug.
These trials assess the side effects of each drug and which drug works better.
Phase III trials enroll 100 or more patients. Often, these trials are randomized.
This means that patients are put into a treatment group, called trial arms, by
chance. Randomization is needed to make sure that the people in all trial
arms are alike. This lets scientists know that the results of the clinical trial are
due to the treatment and not differences between the groups. A computer
program is often used to randomly assign people to the trial arms.
 There can be more than two treatment groups in phase III trials. The control
group gets the standard-of-care treatment. The other groups get a new
treatment. Neither you nor your doctor can choose your group. You will also
not know which group you’re in until the trial is over.
 Every patient in a phase III study is watched closely. The study will be
stopped early if the side effects of the new drug are too severe or if one
group has much better results. Phase III clinical trials are often needed before
the FDA will approve the use of a new drug for the general public.
 Phase IV - Phase IV trials test new drugs approved by the FDA. The drug is
tested in several hundreds or thousands of patients. This allows for better
research on short-lived and long-lasting side effects and safety. For instance,
some rare side effects may only be found in large groups of people. Doctors
can also learn more about how well the drug works and if it’s helpful when
used with other treatments.

REFERENCES

1. Biomed Imaging Interv J. 2008 Jan-Mar; 4(1): e5.

Published online 2008 Jan 1. doi: 10.2349/biij.4.1.e5

PMCID: PMC3097692
PMID: 21614316
A Vijayananthan, MBBS, MRad*,1 and O Nawawi, MBBS, MRad, FRCR.

2. References:
http://www.nhmrc.gov.au/issues/humanlpreamble.htm. Produced by
NHMRC
1- Council for International Organizations of Medical Sciences
(CIOMS): Ethical Guidelines for Biomedical Research Involving
Human Subjects, World Health Organization, Geneva, Switzerland
2002.

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3.J-P Boissel 1 J Intern Med. 2004 Apr;255(4):427-38. Clinical Pharmacology Department, RTH
Laennec School of Medicine, Lyon Cedex, France. [email protected] , PMID: 1504987 ,
DOI: 10.1111/j.1365-2796.2004.01311.x
4. Green B, Johnson C, Adams A. Journal Of Chiropractic Medicine. September 2006;5(3):101-117.Last
Updated: Mar 10, 2020 2:19 PM,URL: https://research.library.gsu.edu/litrev
 https://www.nccn.org/patients/resources/clinical_trials/phases.aspx