A Short Note on Good Clinical Practice

Manjunath.R

#16/1, 8th Main Road, Shivanagar, Rajajinagar, Bangalore560010, Karnataka, India

*Corresponding Author Email: [email protected]

*Website: http://www.myw3schools.com/

Abstract: Good clinical practice (GCP) is an international ethical and scientific quality
standard for designing, conducting, recording, and reporting trials that involve the participation
of human subjects and was developed with consideration of the current good clinical standards
of the European Union, Japan, and the United States, as well as those of Australia, Canada,
the Nordic countries, and the World Health Organization (WHO). Compliance with this standard
provides public assurance that the rights, safety, and well-being of trial subjects are protected,
and that the clinical trial data are credible. This standard should be followed when generating
clinical trial data that are intended to be submitted to regulatory body (US Food and Drug
Administration [FDA])

Key words: subject; clinical trial, ICHGCP guidelines; sponsor; FDA; investigator.

 Pharmacodynamics: What the drug does to the body.

 Pharmacokinetics: What the body does to the drugs.

What is a drug?

The drug is an exogenous non-nutritive chemical substance which when taken in the solid form
by the mouth enter the digestive tract and there it is transformed into a solution and passed on to
the liver where it is chemically altered and finally released into the blood stream. And in
the blood it exists in two forms: bound and unbound. Depending on its specific affinity
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for proteins in the blood (albumin, globulins), a proportion of the drug may become bound
to plasma proteins, with the remainder being unbound. And since the drug-protein binding is
reversible, the chemical equilibrium exists between the bound and unbound states, such
that: Protein + drug ↔ Protein-drug complex. And the bloodstream carries the drug (free plus
bound) to the site of action. Free drug reversibly bind to the target cell surface receptors. And
the Bound drug slowly dissociates from the protein and binds reversibly to the target cell surface
receptors to produce its pharmacological effect.

Drug + Receptor ↔ Drug - Receptor complex → pharmacological effect

And the equilibrium constant for the formation of Drug - Receptor complex is given by:

K = [Drug - Receptor complex] / [Drug] [Receptor]

And K is a measure of how tightly a drug binds to the receptor: The higher the K value the drug
bind well to the receptor, the action of the drug will be longer. In general, drugs with higher K
values will require lower concentrations to achieve sufficient receptor occupancy to exert an
effect. And after its pharmacological effect drug slowly detaches from the receptor. And then it
is sent to the liver. And there it is transformed into a more water soluble compound
called metabolite and released from the body through urine, sweat, saliva, and excretory
products.

Agonists and Antagonists

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Agonists: Drugs that have the ability to produce a desired therapeutic effect when bound to the
to the target cell surface receptors.

Antagonists: Drugs that bind well to the receptor but produce no therapeutic effect.
They prevent other drugs from binding to the target cell surface receptors, thus they act
as blockers.

Potency and Efficacy

Potency: The amount of a drug that is needed to produce a given effect.

Efficacy: The maximum effect that a drug can produce after binding to the receptor.

Adverse Event and Adverse Drug Reaction

Adverse Event: an injury, symptom, or disease temporally associated with the use of a
medicinal drug, which may or may not be related to the drug.

Adverse Drug Reaction: an injury, symptom, or disease temporally associated with the use of
a medicinal drug, which is related to the drug.

Serious Adverse Event

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The adverse event is considered to be serious if it results in any of the following outcomes:

 Death.
 Prolonged or Long term hospitalization.
 Loss of consciousness, loss of speech, loss of memory and paralysis.
 Birth defect: Exposure to a medical product during pregnancy resulting in babies born
with deformed arms and legs.
 Substantial risk of dying, permanent change, impairment, damage or disruption in
function/structure, physical activities and/or quality of life.
 Internal bleeding with rapid drop in blood pressure, fatigue, a serious problem with
breathing, prolonged diarrhea lasting more than 48 hours.

Expected and Unexpected Adverse Event

Expected Adverse Event: An adverse event is considered "expected" if it is listed in the

investigator brochure or is listed in the Package Insert of a marketed drug.

Unexpected Adverse Event: An adverse event is considered "unexpected" if it is not listed in

the investigator brochure or is not listed in the Package Insert of a marketed drug.

Clinical trail

Scientific investigation of safety and efficacy of medicinal products intended for human use.

ICH GCP guidelines / E6 guidelines

ICH: International Conference on Harmonization of technical requirements for

registration of pharmaceuticals intended for human use.

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GCP: Good clinical practice

1. An individual who participates in a clinical trial as a recipient of the investigational

product is called a trail subject. And a scientifically sound clinical trial involving trail
subjects should be conducted

 in accordance with the ethical principles that have their origin in the Declaration of
Helsinki (a statement of ethical principles to promote and safeguard the rights, safety,
and well-being of the trial subjects) and in accordance with the international ethical and
scientific quality standard and the applicable regulatory requirements.
 in accordance with a clear, detailed protocol (A document that describes the objective,
design and methodology to organize a trial) that has received prior institutional review
board (IRB) or independent ethics committee (IEC) approval/favorable opinion.

2. The rights, safety, and well-being of the trial subjects should be safeguarded and clinical
trial should be continued only if the anticipated benefits to the foreseeable risks ratio is
far greater than 1.

 anticipated benefits / foreseeable risks >1 (clinical trial is continued)

 anticipated benefits / foreseeable risks < 1 (clinical trial is terminated)

3. Each individual involved in conducting a trial including

 Investigator (a qualified physician or, when appropriate, a qualified dentist who is

responsible for the conduct of the clinical trial at a trial site and / or to make important
trial - related decisions) should be qualified by education, training, and experience to
perform his or her respective tasks. And it is the responsibility of an investigator at
a trail site (the location where trial-related activities are actually conducted) to give the
medical care and to make medical decisions on behalf of trail subjects and to protect the
privacy and confidentiality of personal information of trail subjects.

4. Freely given informed consent form should be signed, dated and obtained from every
subject prior to his/ her willingness to participate in a particular trial.

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  If a subject is unable to read the informed consent form, an impartial witness (a person,
who is independent of the trial, who cannot be unfairly influenced by people involved
with the trial) should be present to read the informed consent form and any other written
information supplied to the subject.

5. Investigational products should be used, handled and stored in accordance with the
approved protocol and in accordance with applicable regulatory requirements.
Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial
subjects should be made with prior written IRB/IEC approval/favorable opinion.
6. All clinical trial information including on clinical (Pharmacokinetics and investigational
product Metabolism) and clinical information on an investigational product should
be documented, handled, and stored precisely and it should be sufficient to support the
proposed clinical trial. And systems with procedures that assure the quality of every
aspect of the trial in compliance with GCP and the applicable regulatory requirements
should be implemented.

Institutional Review Board / Independent Ethics Committee

An independent body constituted of medical, scientific, and nonscientific members whose

responsibility is

1. To review a proposed trial within a reasonable time and give its

Approval/favorable opinion

Or

Disapproval/negative opinion

regarding the conduct of the trial at a trail site.

2. To conduct continuing review of each ongoing trial at intervals (at least once per
year) to ensure

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  The safeguard of the rights, safety, and well- being of trail subjects involved in a trial.
 The proper conduct of trail in compliance with GCP and the applicable regulatory
requirements.

3. To review the protocol amendment and give its

Approval/favorable opinion

Or

Disapproval/negative opinion

4. To review and ensure that information regarding payment to subjects for participating
in the trail, including the methods, amounts, and schedule of payment to trial subjects
prorated in the written informed consent form.
5. To ensure the proper payments and compensation available to subjects.
6. To obtain the following documents:

 Signed and dated informed consent forms.

 Investigator's Brochure (IB):A complete collection of the clinical and nonclinical
information regarding the clinical study of the investigational product in trail subjects.
 Investigator's current curriculum vitae and/or other documentation evidencing his/ her
qualifications.
 Information about payments and compensation available to subjects.
 Protocol and protocol amendments.
 Subject recruitment procedures and advertisements.
 Other clinical trial-related information.

And retain for a period of at least 3 years after completion of the trial and make them available
upon request from the sponsor and/ or the regulatory bodies (US Food and Drug Administration
[FDA]).

Blinding/masking

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A procedure in which one or more persons related to the trail are kept unaware of the treatment
strategies.

 Single blinding: only subject is kept unaware of the treatment strategies.

 Double blinding: subject, investigator, monitor, and, in some cases, data analyst are
kept unaware of the treatment strategies.

If the trial is blinded, the investigator should promptly document and explain to the sponsor any
premature violation of blinding due to serious adverse event or in the case of medical emergency
to find out whether a particular subject received the investigational product, or received
a comparator (marketed product or placebo).

Phases of Clinical trail

 Preclinical research: In this phase, researchers test the investigational product in the
laboratory or in animals before it can be tested in humans. Preclinical results frame the
basis for applying an investigational new drug (IND) application to the Food and Drug
Administration (FDA) to seek permission to use the investigational product in a Phase
I trial.
 Phase I: In this phase, the investigational product is tested in a 20 to 100 of healthy
volunteers who are not at risk for disease to determine the safety and a safe dosagerange

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 (maximum concentration of the investigational product above which the investigational
product can produce harmful effects in the body), and identify side effects.
 Phase II: In this phase, the investigational product is tested in a 20 to 300 of
unhealthy volunteers with the disease to determine the efficacy [how
well the investigational product works compared to a comparator (marketed product
or placebo)]. (Placebo: a substance that has no therapeutic effect but used as a control
in testing investigational product).
 Phase III: In this phase, the investigational product is tested in a 1,000 -
3,000 unhealthy volunteers with the disease (at multiple centers) to confirm the safety,
efficacy and side effects of the investigational product. This is the final phase prior to
seek marketing approval (or to apply an new drug (ND) application to the Food and
Drug Administration (FDA) to seek permission to market the product confirming that
the investigational product is safe, effective, have anticipated benefits that outweigh the
foreseeable risks, producible in a consistent quality and purity).
 Phase IV: post marketing surveillance to understand the risks, benefits, and optimal use
of the marketed product.

In order to protect the welfare and well-being of animals used in preclinical studies, the
preclinical research is guided by 3 principles:

1. Reduce the number of usage of animals to a minimum.

2. Replace animal experiments with alternative non-animal experiments wherever
possible.
3. Design the experiment in such a way that the adverse effect on the animal is
minimized and its welfare is improved.

Investigator

A qualified physician or, when appropriate, a qualified dentist whose responsibility is

 To recruit the required number of suitable subjects and inform them about the trail and
take their voluntary consent towards the participation in the trail.

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  To recruit an adequate number of qualified staff and adequately inform them about the
protocol, the investigational product, and their trial-related duties and functions.
 To conduct the trail properly and safely in compliance with GCP and the applicable
regulatory requirements and the ethical principles that have their origin in
the Declaration of Helsinki within the agreed trial period and use, handle and store
the investigational product as described in the protocol.
 To give the adequate medical care to a subject in the case of any medical emergency or
serious adverse events (or serious adverse drug reactions) and report the expected and
unexpected serious adverse events (or serious adverse drug reactions) to the regulatory
body and the IRB/IEC and the sponsor.
 To inform the subject about the correct use of the investigational product and check at
intervals that each subject is following the instructions properly.
 To provide the accurate, liable, complete clinical and non-clinical trial related
documents for review upon request from the IRB/IEC and/ or the regulatory bodies.
 To retain the entire trail related essential documents including medical documents and a
summary of the trial’s outcome for a period of at least 2 years after completion of the
trial and make them available upon request from the sponsor and/ or the regulatory
bodies.
 To complete the trail within the agreed trial period.
 To safeguard the rights, safety and well-being of the subject involved in the trail.
 Not to implement any deviation from, or changes of, the protocol without prior review
and documented approval/favorable opinion from the IRB/IEC. If the any deviation from,
or changes of, the protocol is approved from the IRB/IEC, then it should be
documented with proper explanation.
 To allow the audit (systematic and independent examination of trial-related activities and
documents to determine whether the trial-related activities are conducted, recorded and
accurately reported according to the protocol, sponsor's standard operating procedure
(SOP: Detailed written instructions to perform a specific function), good clinical practice
(GCP) and the applicable regulatory requirements).

Vulnerable subjects

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  Patients in emergency situations with incurable diseases.
 Homeless, unemployed and impoverished persons.
 Mentally challenged persons who are incapable of giving informed consent.
 Prisoners, medical, pharmacy, dental, and nursing students.
 Nomads, refugees.
 Children, pregnant women, Fetuses.
 Addicts, sexual minorities.

Investigator should give adequate justification for the use of vulnerable subjects and special
attention should be paid to trials that involve vulnerable subjects.

Sponsor

An organization, institution, or an individual whose responsibility is

 To initiate, manage and finance the trail (including the costs of treatment of trial
subjects in the case of medical emergency or serious adverse events).
 To implement systems with procedures that assures the quality of every aspect of the
trial in compliance with the protocol, GCP and the applicable regulatory
requirements.
 To designate a qualified medical expertise professional who will be readily available to
give suggestions on trial-related medical problems.
 To employ qualified biostatisticians, clinical pharmacologists, and physicians to design
the protocol and CRF (case report form) and plans to conduct, handle, manage,

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 organize the trail and document the clinical study information in compliance with GCP
and the applicable regulatory requirements.
 To employ qualified individuals and establish an Independent Data Monitoring
Committee to supervise the overall conduct of the trial, verify the data, conduct the
statistical analyses at intervals to ensure that the trail is conducted in compliance with the
protocol, SOP, GCP and the applicable regulatory requirements.
 To retain all the essential documents for a period of at least 2 years after completion of
the trial and make them available upon request from the regulatory bodies.
 To select the qualified investigators and institutions those have adequate resources to
properly conduct the trial in compliance with the approved protocol, SOP, GCP and the
applicable regulatory requirements.
 To define, establish and designate all the trail related teams (including monitoring,
pharmacovigilance, safety and data management team) to document and manage the
trail.
 To supply the investigator / trail site with the investigational product and with the
information how to use, handle and store the investigational product.
 To report all the concerned information about adverse drug reactions (ADRs) those are
both serious and unexpected to the regulatory bodies and/ or to the IRB/IEC.
 To dispose and document the unused investigational product.

If the sponsor discontinues the trail, the sponsor should maintain all specific essential documents
for at least 2 years after formal discontinuation of the trail.

Clinical research coordinator (CRC)

Person whose responsibility is

 To handle most of the administrative responsibilities of a clinical trial on behalf of an

investigator and manage the collection of data throughout the course of a clinical trial.
 To assist the principal investigator with preparation of CRF (Case Report Form: a tool
used by the sponsor of the clinical trial to collect data from each participating trail site as

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 defined by protocol), monitoring, quality assurance, audits, and data management and
analysis.
 To manage subject's information and medical care.

CRC should perform all the duties under the supervision of investigator in compliance with
good clinical practice (GCP) and the applicable regulatory requirements.

Clinical research associate (CRA)

Person employed by a sponsor whose responsibility is

 To monitor the progress of a clinical trial at a trail site.

 To ensure the safeguard of rights, safety and well-being of trail subjects.
 To supervise the overall conduct of the trial, verify the data, conduct the statistical
analyses at intervals to ensure that the trail is conducted in compliance with the
protocol, SOP, GCP and the applicable regulatory requirements and adverse events are
correctly documented and reported.

_________________________________________________________________________

Dose: The amount of drug prescribed to be taken at one time.

Dosage: The amount of drug to be taken.

Dosage form: means by which the drug reach the target cell to give its actions.

__________________________________________________________________________

Labeling / unblinding

A procedure in which both the investigator and trail subject is kept aware of the treatment
strategies.

Randomization

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The process of assigning trial subjects to treatment or control groups using an element of
chance in order to reduce bias.

Nuremberg code (1947)

During the Nuremberg War Crimes Trials, 23 German doctors were charged with crimes
against humanity for "performing medical experiments upon prisoners and other living human
subjects, without their consent, in the course of which experiments they committed the
murders, brutalities, cruelties, tortures, and other inhuman acts." As part of the verdict, the
Court enforced some rules for "Permissible Medical Experiments", now known as the
"Nuremberg Code".

These rules include:

 Voluntary consent.
 Anticipated benefits should outweigh foreseeable risks.
 Ability of the subject to terminate participation.

References:

1. Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance

by U.S. Department of Health and Human Services Food and Drug
Administration, Center for Drug Evaluation and Research (CDER), Center for
Biologics Evaluation and Research (CBER), April 1996.
2. Pharmacokinetics and Pharmacogenomics: Clinical Implications by
Elizabeth A. VandeWaa, Ph.D.
3. Guidance for Industry Information Program on Clinical Trials for Serious or
Life-Threatening Diseases and Conditions by U.S. Department of Health
and Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER), Center for Biologics Evaluation and
Research (CBER), March 2002.
4. Protecting Vulnerable Subjects in Clinical Research: Children, Pregnant
Women, Prisoners, and Employees by Karen J Schwenzer MD.

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5. Adverse Events in Clinical Trials: Definitions and Documentation by Clinical
and Translational Science Institute / CTSI at the University of California, San
Francisco.
6. History and Principles of Good Clinical Practice by Dr Christine Maure.
7. Stressors Requiring Medication Phases of Drug Action, NUR101 Fall
2008, Lecture # 11 & 12 by K. Burger, MSEd, MSN, RN, CNE PPP by
Sharon Niggemeier RN, MS (J. Garnar & R. Kolk) Rev kburger 06, 07.
8. History and Ethical Principles by Jeffrey M. Cohen, Ph.D. Director,
Division of Education Office for Human Research Protections.

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