Ethical Issues in Clinical Trials

Dr. Devesh D. Gosavi

Professor, Department Of Pharmacology
MGIMS, Sevagram, Wardha
& Associate Editor, Journal Of MGIMS
 Ethics

Definition:
Research ethics involves the application of fundamental ethical
principles to research activities which include the design and
implementation of research, respect towards society and others,
the use of resources and research outputs, scientific misconduct
and the regulation of research.
 Why we need ethics

We need ethics to
 Reduce the possibility of
exploitation of participants in
Clinical research.
 To ensure that their rights and
welfare are respected.
 History of Ethical Guidelines
1. The Nuremberg Code 1947

2. The Declaration of Helsinki 1964

3. U.S. Code of Federal Regulations 1974

4. The National Research Act & The IRB System 1974

5. The Belmont Report 1979

6. ICMR Guidelines 2000, 2006, 2017

7. New Drugs and Clinical Trials Rules 2019, 2023

 The Nuremberg Trial (1945-1947)
• Children in concentration camps were used for clinical trials,
exposed to low barometric pressure for altitude studies,
immersed in water to induce hypothermia, were starved, induced
burns, wounds, gangrene etc.
 The Nuremberg Trial (1945-1947)

Participants were never asked for consent;

were caused unnecessary pain, suffering, even
death; there were no benefits to the
participants whatsoever; absence of adequate
scientific rationale for conducting the
experiments.
Thalidomide phocomelia
 The Nuremberg Code 1947
• The principles established by this code for medical practice now
have been extended into general codes of medical ethics.
• This document enunciates the requirement of voluntary informed
consent of the human subject.
• This code also recognizes that the risk must be weighed against
the expected benefit.
• This code recognizes that doctors should avoid actions that injure
human patients.
 The Declaration of Helsinki 1964
• 1964 - Adopted by the 18th World Medical Assembly (latest version 2008)
• A notable change from the Nuremberg Code was a relaxation of the
conditions of consent; ‘Obtain consent, if at all possible.’
• Introduced the concept of oversight by an ‘independent committee’ Or
ethics committees.
• “All 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"
 Tuskegee Syphilis Study (1932-1972)
• Conducted by U.S. Public Health Service
to determine if syphilis causes
cardiovascular damage more often than
neurological damage & to see if the
natural course is significantly different in
black population than in whites. 399
infected persons and 201 control
population (poor sharecroppers).
Tuskegee Syphilis Study (1932-1972)
• Participants were not informed
that they had syphilis or that it
spreads through sexual contact.
• They were not given proper
treatment and were also denied
Penicillin even after it was
available for public.
Tuskegee Syphilis Study (1932-1972) continued..
• The trial was supposed to end in 1936,
but when expected results were not
seen, it was decided to just follow the
natural course of disease.
• Eventually more than 100 participants
died of tertiary syphilis.
• In 1974, a settlement of $10 million
was given to the sufferers and a
formal apology was issued by
President Bill Clinton in 1997.
 U.S. Code of Federal Regulations 1974

Common federal policy was made for the protection of human

subjects that was accepted by all agencies listed in the document.
The code is divided into four subparts:
• Basic protection applicable to all human research subjects
• Additional protections for women, human fetuses, and neonates
• Additional protections for prisoners
• Additional protections for children
 The National Research Act & The IRB System 1974

• The Commission's report set forth the basic ethical principles that
should underlie the conduct of biomedical and behavioral research
involving human subjects is titled ’The Belmont Report’.
 The Belmont Report 1979
• Gave us the general rule
that if there is any element
of research in an activity,
that activity should undergo
review for the protection of
human subjects.
• It also gave us the 3 basic
principles of Ethics:
1. Respect for Persons
2. Beneficence
3. Justice
The national ethical guidelines for biomedical and health research involving
human participant and children(2017) has 12 sections as follows:
Principles of Ethics in Clinical Trials
 Principle of Essentiality 7. Principle of professional
1.
competence

2. 8. Principle of maximisation of
Principle of Voluntariness
benefit

Principle of Non- Principle of institutional

3. 9.
exploitation arrangements

Principle of social Principle of transparency

4. 10.
responsibility and accountability

Principle of ensuring privacy Principle of totality of

5. 11.
and confidentiality responsibility

Principle of precautions and Principle of environmental

6. 12.
risks minimisation protection
1. Principle of Essentiality:

Test on human beings only if absolutely essential:

• After considering all alternatives, the use of human participants is
considered to be essential for the proposed research.
• This should be duly vetted by an ethics committee (EC)
independent of the proposed research.
2. Principle of Voluntariness:

• It is essential to respect the right

of the participant to agree or not
to agree to participate in
research, or to withdraw from
research at any time.
• The informed consent process
ensures that participants’ rights
are safeguarded.
 3. Principle of Non-exploitation:

• Inform subjects about all possible side effects

and risks.
• Ensure ample compensation for accidental
injury.
• Insurance, Rehabilitation, Life-long support
• Research participants are equitably selected so
that the benefits and burdens of the research
are distributed fairly and without arbitrariness
or discrimination.
• Sufficient safeguards to protect vulnerable
groups should be ensured.
4. Principle of social responsibility:

• The research is planned and

conducted such that creation or
deepening of social and historic
divisions is avoided.
• Social harmony in community
relationships is not disturbed in
any way.
 5. Principle of ensuring privacy and confidentiality:
• Potential participant’s identity and records are kept confidential and
access is limited to only those authorized.
• However, under certain
circumstances (suicidal
ideation, homicidal
tendency, HIV positive
status, when required by
court of law etc.) privacy of
the information can be
breached in consultation
with the EC for valid scientific or legal reasons as the right to life of an
individual supersedes the right to privacy of the research participant
6. Principle of Precaution and Risks Minimisation:

• Due care is taken by all

stakeholders at all stages of
the research to ensure that
the risks are minimized and
appropriate care and
compensation is given if any
harm occurs.
7. Principle of Professional Competence:
• Research is planned,
conducted, evaluated and
monitored throughout only by
people who are competent
and have the appropriate and
relevant qualification,
experience and/or training.
8. Principle of maximisation of benefit:

• Research is designed and

conducted in such a way that
it directly or indirectly
maximizes the benefits to it’s
participants and/or to the
society.
 9. Principle of institutional arrangements:

• Institutions where the research is

being conducted, should have
policies for appropriate research
governance.
• They should take the
responsibility to facilitate
research by providing required
infrastructure, manpower, funds
and training opportunities.
10. Principle of transparency and accountability:

• The research plan and outcomes of the research are made

available to the public through registries, reports and scientific
and other publications while safeguarding the right to privacy of
the participants.
• Any existing conflict of interest are to be disclosed and managed
appropriately.
• The research should be conducted in a fair, honest, impartial and
transparent manner to guarantee accountability.
• Related records, data and notes should be retained for the
required period for possible external scrutiny/ audit.
11. Principle of totality of responsibility:

• The professional, social and moral

responsibilities compliant with
ethical guidelines and related
regulations are binding on all
stakeholders directly or indirectly.
12. Principle of environmental protection:
• Researchers are
accountable for
ensuring protection
of the environment
and resources at all
stages of the
research, in
compliance with
existing guidelines
and regulations.
General Ethical Issues
 Risk-benefit assessment Informed consent process

Distributive justice Payment for participation

Privacy and confidentiality

Compensation for research

Ancillary care Conflict of Interest
related injury

Selection of vulnerable and

Post research access and
special groups as research Community engagement
benefit sharing
participants
 Benefit risk assessment
• The social and scientific value of
research should justify the risk
(which can be physical,
psychological, social, economic
or legal discomfort or harm).
• The researcher, sponsor and EC should attempt to maximize benefits
and minimize risks to participants so they are balanced to lead to
potential benefits at individual, societal and/or community levels.
• The EC should evaluate plans for minimizing the risk and discomfort
and decide on the merit of the research before approving it. These
should be assessed again at the time of continuing review.
Benefit risk assessment continued..
Informed consent process
 Informed consent process continued..

• Informed consent of all prospective subjects should be obtained.

• The investigator should provide following information to the
participant before getting their consent, in a language the participant
understands fully:
 Aims, methods, duration, benefits of the research
 Foreseeable discomforts/ risks
 Alternative procedures/ courses of treatment
 Any medical services to be provided to the participant by the
investigator
 Participant’s right to refuse/ withdraw at any time
 Privacy and confidentiality

• It is the responsibility of the researcher to safeguard the

confidentiality of research related data of participants.
• Limitations to ensure strict confidentiality must be explained to the
participant.
• The publication should uphold the privacy of the individuals by
ensuring that photographs or other information that may reveal the
individual’s identity are not published.
 Privacy and confidentiality continued..

• Data of individual participants/community may be disclosed in

certain circumstances with the permission of the EC such as
specific orders of a court of law, threat to a person’s or
community’s life, public health risk that would supersede personal
rights to privacy, serious adverse events (SAEs) that are required
to be communicated to an appropriate regulatory authority etc.
 Distributive justice

• Burdens and benefits of research should be equitably distributed.

• Plans for direct or indirect benefit sharing in all types of research
with participants, donors of biological materials or data should be
included in the study, especially if there is a potential for
commercialization. This should be reviewed by the EC.
 Payment for participation
• Participants may be reimbursed for
expenses incurred due to participation in
research, such as travel related expenses.
• Participants may also be paid for
inconvenience incurred, time spent and
other incidental expenses in either cash
or kind or both as deemed necessary (for
example, loss of wages and food
supplies).
• Payment should not become an undue
inducement and to be reviewed carefully
by the EC.
 Compensation for research related harm

• Research subjects who suffer physical injury as a result of their

participation are entitled to financial or other assistance that would
compensate them equitably for any temporary or permanent
impairment or disability.
• In case of death, their dependants are entitled to material
compensation.
• The right to compensate will not be waived.
FORMULAE TO DETERMINE THE QUANTUM OF COMPENSATION IN
THE CASES OF CLINICAL TRIAL RELATED INJURY OR DEATH
SEVENTH SCHEDULE
(Rules 39, 40, and 42)
1.Formula in case of clinical trial related death:
Compensation = (B x F x R) / 99.37
Where,
B = Base amount (i.e. 8 lacs)
F = Factor depending on the age of the trial subject as per Annexure 1
(based on Workmen Compensation Act)
R = Risk Factor depending on the seriousness and severity of the
disease, presence of co-morbidity and duration of disease of the trial
subject at the time of enrolment in the clinical trial.
2. A permanent disability:
Compensation = (C x D x 90) / (100 x 100)
Where,
D = Percentage disability the trial subject has suffered.
C = Quantum of Compensation which would have been due for payment to
the trial subject's nominees) in case of death of the trial subject.

3. Reversible SAE in case it is resolved:

Compensation = 2 X W X N.
Where,
W = Minimum wage per day of the unskilled worker (in Delhi)
N = Number of days of hospitalization
 Ancillary care

• Participants may receive free medical services. However, these

services/ payments should not be so extensive as to induce
prospective subjects to consent to participation.
 Conflict of Interest
• The professional
judgement concerning
participants’ welfare or
validity of research should
not be unduly influenced
by a secondary interest,
financial or non-financial
(personal, academic or
political).
• ECs must evaluate each study in light of any disclosed interests and
ensure that appropriate means of mitigation are taken.
 Selection of vulnerable and special groups as research participants

• Characteristics that make individuals vulnerable are legal status

(children, elderly); clinical conditions (cognitive impairment,
unconsciousness); or situational conditions -including but not limited
to being economically or socially disadvantaged, (for example,
certain ethnic or religious groups, individuals/communities which
have hierarchical relationships, institutionalized persons,
humanitarian emergencies, language barriers and cultural
differences).
 Selection of vulnerable and special groups as
research participants continued..
• They are to be included
in research only when
the research is directly
answering the health
needs or requirements
of the group.

• On the other hand, vulnerable populations also have an equal right to

be included in research so that benefits from the research apply to
them as well. This needs careful consideration by researchers as well as
the EC.
 Community engagement

• The community should be meaningfully engaged before, during and

after the research to mitigate culturally sensitive issues and ensure
greater responsiveness to their health needs and requirements.
 Post research access and benefit sharing

• The benefits accruing from research should be made accessible to

individuals, communities and populations whenever relevant.
• If an investigational drug is to be given to a participant post-trial,
appropriate regulatory approvals should be in place.
Responsible conduct of research
Data acquisition, management, sharing &
ownership
Reviewing and reporting research
Responsible authorship and publication
Policies for handling research misconduct
Ethical review procedures
 Ethics committee

• Independent review of clinical research by Ethics Committee ensures

the public that investigator biases:
1. Have not distorted the approach.
2. Have fulfilled Ethical requirements.
3. Will not exploit subjects.
4. Have no Conflict of interest.
 Ethics committee continued..

It is responsible for
1. reviewing and approving the protocol,
2. the suitability of the investigators, facilities,
3. methods and adequacy of information to be used
for obtaining and documenting informed consent of
the study subjects and
4. adequacy of confidentiality safeguards.
 Members of Ethics Committee
Presence of at least 5 of the following members of the ethics
committee is required to review any protocol or related documents
of a clinical trial-
1. Medical scientist (preferably a pharmacologist)
2. Clinician
3. Legal expert
4. Social scientist or representative of a nongovernmental voluntary
agency or a philosopher or an ethicist or a theologian or a similar
person
5. Lay person.
Clinical trial (CT), Ethics Committee, constituted under Rule 7 and
registered under Rule 8 of The New Drugs and Clinical Rules 2019
shall have a minimum of seven members from medical, nonmedical,
scientific, and non-scientific areas with at least
1. One lay person
2. One woman member
3. One legal expert
4. One independent member from any other related field such as
social scientist or representative of nongovernmental voluntary
agency or philosopher or ethicist or theologian.
Ethical Committee: Elements
Composition of an ethical committee
Special situations: Ethics review
Role of ethics committee
Types of review
Decision making
Exemption:
Proposals with less than minimal risk where there are no linked identifiers, for example;
Research conducted on data available in the public domain for systematic reviews or meta-analysis;
Observation of public behavior, Quality control and quality assurance audits in the institution;
Comparison of instructional techniques, curricula, or classroom management methods;
Consumer acceptance studies related to taste and food quality; and
Public health programmes by Govt agencies such as programme evaluation where the sole purpose of the exercise is refinement and improvement of the programme or monitoring (where there are no
individual identifiers).
Proposals that pose no more than minimal risk may undergo expedited review, for example;
Research involving non-identifiable specimen and human tissue from sources like blood
banks, tissue banks and left-over clinical samples;
Research involving clinical documentation materials that are non-identifiable (data,
documents, records);
Modification or amendment to an approved protocol including administrative changes or
correction of typographical errors and change in researcher(s);
Revised proposals previously approved through expedited review, full review or continuing
review of approved proposals;
Minor deviations from originally approved research causing no risk or minimal risk;
Progress/annual reports where there is no additional risk, for example activity limited to data
analysis. Expedited review of SAEs/unexpected AEs will be conducted by SAE subcommittee;
and
For multicentre research where a designated main EC among the participating sites has
reviewed and approved the study, a local EC may conduct only an expedited review for site
specific requirements in addition to the full committee common review.
Research during emergencies and disasters (See Section 12 of ICMR Guidelines
Division of responsibility of review
Continuing Review
Site monitoring
Record keeping and archiving
Registration of Ethical Committee
Accreditation of Ethics committee
Informed consent procedure
Types of consent documented

Literate Illiterate In both

Thumb
Written Audio/audio-visual
Impression/oral
Assent and consent
Audio visual recording of consent
Vulnerability
 Principles of research among vulnerable populations

• Vulnerable populations have an equal right to be included in

research so that benefits accruing from the research apply to them
as well.
• If any vulnerable group is to be solely recruited then the research
should answer the health needs of the group.
• Participants must be empowered, to the maximum extent
possible, to enable them to decide by themselves whether or not
to give assent/consent for participation.
 Principles of research among vulnerable populations continued..

• In vulnerable populations, when potential participants lack the

ability to consent, a LAR should be involved in decision making.
• Special care must be taken to ensure participant’s privacy and
confidentiality, especially because breach of confidentiality may lead
to enhancement of vulnerability.
• If vulnerable populations are to be included in research, all
stakeholders must ensure that additional protections are in place to
safeguard the dignity, rights, safety and wellbeing of these individuals.