Participants in Clinical Research

Regulators

Patient/Society

Institute
Investigator Sponsor
Ethics Committee Monitor
Administrator
 BMJ, 1998 317:1209-12
Edwards and Lilford

Why did patients participate in clinical trials?

61 studies reviewed

60% said they participated out of “altruism”

 Right of the research subject to
understand

ü the nature of research,

ü risks & benefits involved

ü to agree or not agree to participate.

Ethics in Clinical
Research

Dr. Urmila Thatte

TNMC & BYL Nair Hospital
 What is Clinical Research?

A systematic investigation in human

beings designed to produce

generalisable knowledge
 Practice vs. Research
Practice:
Interventions that are designed solely to
enhance the well-being of an individual patient
that has a reasonable expectation of success

Research:
Activity designed to test an hypothesis, permit
conclusions to be drawn; and thereby develop
or contribute to generalizable knowledge
 Down lanes of history ….

Ethics in Medical Practice

ä 1600BC: Charaka Samhita
ä 600 AD: Hippocratic Oath
 Research in 18th Century

ä Edward Jenner (1749-1823) tested smallpox

vaccines on his son and neighborhood
children
ä Johann Jorg (1779-1856) swallowed 17 drugs
in various doses to record their properties

No codes, Guidelines, rules or laws

Implicit faith in treating physicians
????? exploitation
 Down lanes of history ….

Ethics in Research
“It is not cruel to inflict on a few,
criminals sufferings which may
benefit multitudes of innocent
people through all centuries”
…….. Celsius
Research in 20th Century
…………
"Medical experiments"
End point of experiments - DEATH
War Crimes
Tribunal at
Nuremberg
 Nuremberg Code
1949: 10 points

voluntary (informed) consent must be

obtained: investigator’s responsibility
Clinical Trial Ethics: Nuremberg Code

The code specifies that:

• volunteers have the right to withdraw

at any time

• experiments must provide benefits

for society

• avoid unnecessary injury

no full disclosure, coercion/ undue pressure, vulnerable subjects
 Jewish Chronic Diseases Study, 1963

Cancer cells injected into senile patient

to study immunity to cancer

lack of informed consent, use of vulnerable group

 The Declaration of Helsinki
1964

Adopted by the 18th World Medical Assembly

Revised 5 times
Latest version 2000, Edinburgh, Scotland
2 Notes of clarification (Washington, 2002 – placebo
and Tokyo 2004 – post-trial access to therapy
32 principles

Para 13: protocols must be submitted to an

Ethics Committee for review, which must be
independent of the investigator, the sponsor
or any other kind of undue influence.
 Beecher Article, 1966

“Ethics and clinical research”

Henry K. Beecher

22 published medical studies presenting risk

to subjects without their knowledge or approval

 Beecher HK. Ethics and Clinical Research
NEJM 1966; 274(24):1354-60

Problems noted:
ä Dangerous research
ä No or little benefit to subjects
ä No informed consent
ä Use of coercion or undue pressure
ä Use of or exploitation of vulnerable
population
ä Withholding information about risks
ä Withholding available treatment
ä Deception
ä Risks to subjects outweighing benefits
 What Beecher had to say……

ä If suitably approached
patients themselves will
accede on the basis of trust,
to about any request their
physician may make

ä A far more dependable

safeguard than consent is the
presence of a truly
responsible investigator
 San Antonio Contraception study, 1971

Mexican-American women who came for

contraception enrolled to study the side effects of
oral contraceptives
Cross-over design: Unknown to them, only half
received contraceptive pills, others received
placebo
10 out of 76 became pregnant when on placebo

Lack of informed consent, deception, exploitation of

vulnerable population, risks to subjects outweighed
benefits
 Tuskegee Syphilis Study

American medical research

project conducted by the
U.S. Public Health Service
from 1932 to 1972,
examined the natural course
of untreated syphilis in black
American men.
 Tuskegee Syphilis Study
Results:
28 deaths,
100 cases of disability,
19 cases of congenital
syphilis

Lack of informed consent, putting subjects and their families

to risk, exploitation of vulnerable population, deception,
withholding information, no benefit to subjects
 The Belmont Report
Ethical Principles and Guidelines for the Protection of
Human Subjects of Research

The National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research
April 18, 1979
 The Belmont Report: 3 principles

ä Respect for Persons-

• autonomy of individuals
• Special protection for those with diminished autonomy
ä Beneficence
• maximize the possible benefits
• minimize possible harm

ä Justice
• subjects should be selected fairly to ensure that the benefits
and burdens of medical research are evenly distributed
 ICMR
• 1980: “Policy Statement on Ethical
Considerations involved in research on
Human Subjects”
ICMR: Ethical guidelines for biomedical
research 2000

ä Chairperson Justice
M.N. Venkatachaliah

ä Statement on general
principles

ä Statement on specific
principles
 Expectation

All institutions in the country which carry out

any form of biomedical research involving
human beings should follow these guidelines
in letter and spirit to protect safety and well
being of all individuals.
Guidelines available at-
http://www.icmr.nic.in
 General principles:
ICMR Code
1. Essentiality of research
2. Voluntariness of participation:
Informed consent
3. Non-exploitation: vulnerable
populations
4. Privacy and Confidentiality: HIV
5. Risk minimisation
6. Professional Competence of researcher
 General principles:
ICMR Code

7. Accountability and Transparency

8. Maximisation of public interest and

distributive justice

9. Institutional arrangements

10. Public domain

11. Totality of responsibility

12. Compliance to guidelines

Council for International Organization of
Medical Services (CIOMS)

How to apply Declaration of Helsinki

effectively in developing countries,
given their socioeconomic
circumstances, laws and regulations,
and executive and administrative
arrangements
 1990’s

The Decade of
Harmonization
 ICH - International Conference on
Harmonization, 1996

Joint initiative by regulators and industry

from three regions - US, EU & Japan

Three observers:
ä WHO
ä Canada
ä IFPMA (International Federation of
Pharmaceutical Manufacturers Association)
 India

§ 2001 Indian GCP

§ 2005 Schedule Y of Drugs and Cosmetics
Act Amendment: pertinent to clinical
trials
Some ethical issues
 Respect for Persons

ä Treat individuals as autonomous human beings

ä Do not use them as a means to an end

ä Allow them to choose for themselves and provide

extra protection to those with limited autonomy

 Respect for Persons

ä Elements of Autonomy (self determination):

Mental capacity
Voluntariness
ä Application
§ Requirement to obtain informed
consent
§ Requirement to respect privacy of
research subjects
§ Protection of vulnerable subjects
 Respect for Persons

ä Vulnerable population
§ Very poor
§ Illiterate
§ Prisoners
§ Tribals
§ Students
§ Women
§ Children, elderly
§ Psychiatrically ill
 Beneficence

ä Minimize harms and maximize benefits

ä Over-riding responsibility of
investigator

ä Applies to physical, mental and social

well being
 Beneficence

ä Applications
§ Use best possible research design to
minimize harms and maximize benefits

§ Make sure the researchers are able to

perform procedures and handle the risks

§ Prohibition of research without a favorable

risk-benefit ratio
 Justice

ä Treat people fairly

ä Design research so that its burdens and benefits are shared
equitably

ä Applications
§ Requirement to select subjects equitably (distribute risks and
benefits: research in developing countries without potential
benefits)

§ Requirement to avoid exploitation of vulnerable populations

 Confidentiality

§ Whether to inform family of diagnosis - HIV

§ Indiscriminate disclosure of identity may
lead to
§ Psychosocial harm
§ Stigmatisation
§ Discrimination
 Avoiding Exploitation

ä Voluntary, written, informed consent

ä IRB Review
 Informed consent

ü Consent given by a competent individual who

ü Has received the necessary information

ü Has understood the information

ü And having understood the information has arrived
at a decision without having been under any
coercion, undue influence or inducement or
intimidation
 Informed consent

ü Written informed consent

ü Voluntary

ü from every subject

ü before any study related procedure

ü and documented on EC approved form

ü adhere to GCP, based on Helsinki Declaration

 Informed consent: Why?

ü Based on the principle that competent

individuals are entitled to choose freely
whether to participate in research or not.
ü Protects the individual’s freedom of
choice and respect for individual’s
autonomy.
ü Protects the subjects rights
 Who gives the consent?

ä Subject
if subject unable to give consent ( minor ,
dementia etc.) then -

ä Subject’s legally acceptable

representative
subject should be informed to the extent
compatible with his/her understanding and
consent sought and documented.
What transpires during the informed
consent process?

ü Investigator or his delegate should discuss all

pertinent aspects of study including the informed
consent form
ü Answer any queries / doubts
ü Consent requested
ü Consent documented if given
ü Copy given to participant

Ultimate responsibility is investigator’s

 How should the consent be
documented?

Signed and dated by

§ Subject / subject’s legally acceptable

representative

§ Person conducting the informed consent

discussion
§ If subject / subject’s legally acceptable representative is
illiterate, an impartial witness
 Important issues

ü no coercion / undue influence

ü ample time for decision

ü opportunity to discuss
 Informed Consent: Non-English
speaking/Illiterate subject

ü Summary and consent in the vernacular

ü Written translation
ü Thumb impressions allowed

DOCUMENT METHOD OF OBTAINIING

CONSENT
Witness/Video tape
 Informed Consent: Children

ü Approval of older children: understand

the concepts: assent

ü Consent from parents/legally acceptable

representative
 Informed Consent Form

ü Approved by EC

ü Contents should not imply any waiving of legal

rights of subject

ü Signed and dated copy provided to subject /

subject’s legally acceptable representative

 Informed Consent: Any
alternatives?

NO
§ When research involves less than minimal risk e.g.
analysis of patient records or stored human tissues
§ During emergency : Patient or the legal guardian is
informed after he/she regains consciousness or is able
to understand the study.
§ Particular care in “vulnerable” population: illiterate,
prisoners, students, unconscious patients
 Therefore, Informed Consent . . .

. . . is not a piece of paper.

. . . is not a signature.

It is a PROCESS by which we . . .
. . . ENSURE that our subject’s right to be
informed, and right to consent to research, is
protected.

. . . DOCUMENT our efforts to protect the

subject’s rights to the satisfaction of independent
observers.
 Avoiding Exploitation

ü Voluntary, written, informed consent

ä IRB Review
 Ethics Committee

Any board, committee or other group

formally designated by an institution to
üreview,
üapprove the initiation of and
üconduct periodic review of
biomedical research involving
human subjects.
 All proposals on

biomedical research involving human

subjects

must be cleared

by an

Ethics Committee
Ethics Committees: Why?

An objective review of research

activities involving human
subjects by a group of diverse
individuals is most likely to
protect human subjects and
promote ethically sound research
 Ethics Committees: Why?

ü To protect the study subjects’

well-being, rights & confidentiality
ü To meet the mandate of Declaration of
Helsinki
ü To make clinical research
- acceptable to regulatory authorities
- journal editors
What to submit to Ethics Committee?

ü Pharmaceuticals
ü Medical Devices
ü Medical Radiation and Imaging
ü Surgical Procedures
ü Medical Records All Clinical Research!
ü Biological Samples
ü Epidemiological, Social and
Psychological Investigations
What to submit to Ethics Committee?

No one / no study is above ethics

ü prospective /retrospective

ü patients/volunteers

ü modern/alternative

ü drugs/procedures

ü new drugs/marketed
 Composition of the EC

A reasonable number of members

who collectively have the
qualifications and experience to
review and evaluate the science,
medical aspects and ethics of the
proposed trial
 Composition of the EC

ä Multidisciplinary

ä Independent

ä Competent
 Composition of the EC

Heterogeneous group of at least 7 members

ü Qualified
ü Experienced in their professional field
ü Proficient to review and evaluate both
scientific & ethical aspects (familiar with GCP )

Maximum of 15 members recommended

 Composition of the EC

Chairperson : Outsider

Member – Secretary

At least 1 member
ü basic medical scientist
ü clinician
ü legal expert
ü social scientist/philosopher/priest
ü lay person
 Composition of the EC

ü External scientific expert

ü Adequate representation : age, gender etc.
ü Experts may be invited

ü Patient groups may be represented

List of members and their CV’s :

readily available for audit or
inspection.
 What does an EC do for
Clinical Research?

ä Before the study begins:

§ Submission of research proposal

§ Review of proposal

§ Decision making process

§ Issuing an approval

§ Record keeping
 What does an EC do for
Clinical Research?

ä During the study:

§ Review of amendments ( Protocol, ICD)

§ Review of Serious Adverse Events

§ Protocol deviations

§ Progress (study status)

§ Record keeping
What does an EC do for
Clinical Research?

ä After the study:

§ Study report,

§ Post trial management

§ Publishing

§ Record keeping
 Who should deal with the EC?

The chief investigator not the sponsor

 Documents to be Submitted
for Review

§ Trial protocol(s)

§ Informed Consent Documents (ICD)

§ Subject recruitment procedures

(advertisements)

§ Investigator’s brochure (IB), safety

information.

§ Amendment(s).

§ Regulatory approvals
 Review

§ Scientific vs. ethical review: cannot be separated.

§ Scientifically unsound research is unethical: it

may expose human subjects to risk or
inconvenience for no purpose.

§ Even if no risk of injury, wasting of participants

time is loss of valuable resource.
 Criteria for EC Approval of
Research Proposal

ä Suitability of Investigator
§ Qualifications, Experience
§ Supporting Staff, Available Facilities
§ Time available
 Criteria for EC Approval of
Research Proposal
ä Suitability of Protocol
§ Objectives of the study
§ Scientific efficiency
§ Justification: risks/ inconveniences vs.
benefits
§ Risks & benefits to the trial subject
§ Subject safety measures
§ Confidentiality of subjects and data
§ Regulatory aspects
 Criteria For Approval

§ Equitable Selection Of Subjects

§ Time Provision - Monitoring the Data

§ Confidentiality of subjects and data

§ Informed consent process

 Communication with EC
during the study

§ Updated documentation
§ Written summaries of the trial status annually
or more frequently if requested
§ Serious Adverse Events (+ provide additional
information as requested)
§ Summary of the trial’s outcome upon
completion
§ Amendments to protocol, ICD
 EC : Approval

Written approval

§ Date of the meeting

§ Documents reviewed (versions & dates)

§ List of members present and quorum

§ Signed by Member – Secretary of EC

 EC : Approval

ü No study can be started without EC

approval

ü No changes made without prior written EC

approval

ü EC may revoke any prior approval

depending on ongoing review
Special Concerns and
Issues faced in our
Ethics Committee
 Special Concern:
Herbal Remedies

Association of competent person trained in

that discipline as co-investigator is

desirable for designing and evaluating the

study.
 Issues we face in the Ethics
Committee

Regulatory authority clearance

ü DCGI permission for Phase 1-3 studies

ü “new drug” – new indication/new route of

administration/new dosage form

ü Sending samples abroad

 Challenges

If studies are NOT submitted for

review, then the safeguard of ECs is

meaningless!
 Challenges

Why are you looking at the scientific aspects of

the study?
§ Protocols are often incomplete: only CRF
submitted

§ Safety emphasis is low: interim analysis, lab tests

§ No controls: level of evidence very low
§ Efficacy and failure end points not specified

§ “Me-too” studies
§ Rescue medications (placebo arm)
 Challenges

Subjects in the study

• How will the patient be looked after the

end of study?
• Methods for retention of patients
• Multiple studies: conflict of interest and
bias in allocation
 Challenges
Consent Forms

• Is it always mandatory?? (retrospective,

perception of graduate studies, “we are doing
this anyway as a routine!!!”)

• Generic ones used

• Patient information sheet often missing

• HIV studies: confidentiality, informing

partners
 Challenges

Consent Forms

§ Children/psychiatric patients

§ Far too technical

§ Reams of material

§ International studies: FDA approval, cultural

overtones
 Challenges

Experimental work

§ Requires Animal Ethics Committee approval

§ CPCSEA nominee has to attend meetings

§ Animal House has to be registered with CPCSEA

§ Protocol has to be as per CPCSEA norms: minimal

pain and risk to animals, justification of

experimentation including number of animals used
 Ethics
Ethics is not definable, is not implementable, because
it is not conscious; it involves not only our thinking,
but also our feeling.

… Valdemar W. Setzer

ü Methodology of clinical studies

ü Way of thinking and behaviour
ü Research culture needs to be built up