Informed consent in Clinical Trials

Dr. Kaushik Mukhopadhyay
Assistant Professor,
Department of Pharmacology
ESI-PGIMSR, KOLKATA

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Why Informed consent ?
Every individual has the right to
‘Bodily integrity’
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There is no Black and white border..
There is always grey zone

“A process by which a subject voluntarily
confirms his or her willingness to participate in a
participate in a particular trial, after having been
having been informed of all aspects of the trial
trial that are relevant to the subject’s decision to
decision to participate.
Informed consent is documented by means of a
means of a written, signed and dated informed
informed consent form.”
Informed Consent - definition
International Conference on Harmonization
E6 - Good Clinical Practice
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Goal
“The goal of the informed consent process is
to provide people with sufficient information
so they can make informed choices about
whether to begin or continue participation in
clinical research.”
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HISTORICAL BACKGROUND OF INFORMED CONSENT
1891- Prussian Minister of Interior, tuberculin
for the treatment of tuberculosis must
not be used against a person’s will.
1898- Dr. Albert Neisser was fined by the Royal
disciplinary court of Prussia for not
seeking patient’s consent for his
experimental studies of vaccination for
Syphilis.
1907- Sir William Osler endorsed the necessity
of informed consent in medical
research.
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Walter Reed & his ICF
The informed
consent contract for
Antonio Benigno,
dated
26th November, 1900
(experiments on
yellow fever in
Walter Reed
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Timeline
Nazi human
experimentation
Nuremberg Code
1964 Declaration of Helsinki
Tuskegee syphilis
experiment
1945-46
1939-45
1932-72
Belmont Report1979
National Research Act1974
GCP Guidelines, ICH1997
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Informed consent gone wrong?
recent incidents..
• Jesse Gelsinger (gene transplant)
• James Quinn (artificial heart)
• Ellen Roche (Johns Hopkins hexamethonium death)
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Nuremberg Code (1947)
The Nuremberg Code is
a group of research
ethics principles for
human experimentation
set as a result of the
Nuremberg Trials at the
end of the Second World
War.
Doctor’s Trial
Nuremberg, Germany
December 9, 1946 to August 20, 1947
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Nuremberg Code…..Highlights
• The voluntary consent of the human subject is
absolutely essential. Investigator’s responsibility
to obtain consent.
• All unnecessary physical and mental suffering
and injury has to be avoided.
• Subject should be at liberty to bring the
experiment to an end
• Adequate facilities provided to protect the
experimental subject against even remote
possibilities of injury
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Declaration of Helsinki, 1964
• A set of ethical principles regarding human
experimentation developed for the medical
community by the World Medical Association
• Originally adopted in June 1964 in Helsinki,
Finland,
• Since it has undergone six revisions (the most
recent at the General Assembly in October 2008)
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DoH…cont.
The Declaration developed the ten principles first
stated in the Nuremberg Code, and tied them to the
Declaration of Geneva (1948), a statement of
physician's ethical duties
The Declaration more specifically addressed
clinical research, reflecting changes from the term
'Human Experimentation' used in the Nuremberg
Code.
Relaxation of the conditions of consent, now
research was allowed without consent where a proxy
consent, such as a legal guardian, was available.
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Tuskegee Syphilis Study
• Tuskegee study of untreated syphilis in Negro
male began in 1932 in Tuskegee, Alabama by PHS
(Public Health Service)
• Study purpose – to observe progression of disease
in black male (To compare result with OSLO
study)
• In 1940s penicillin became a standard treatment
for Syphilis
• Still Penicillin was withheld from the
patients
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Tuskegee Syphilis Study…THE END
End of Experiment-
• 28 men died directly form syphilis
• 100 dead of related complications
• 40 wives infected
• 19 children - congenital syphilis
On May 16, 1997, President Bill
Clinton formally apologised.
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National Research Act (1974)
• Congress mandated the establishment of
Institutional Review Boards (IRBs) to review all
federally funded human research
• Created the National Commission for the
Protection of Human Subjects of Biomedical
and Behavioural Research.
• One of the Commission’s statements was “The
Belmont Report: Ethical Principles and
Guidelines for the Protection of Human Subjects
of Research’’
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The Belmont Report
• Issued on 30 September, 1978 and published in
the Federal Register on 18 April, 1979
• Objective - “to provide an analytical framework
that will guide the resolution of ethical
problems arising from research involving human
subjects.”
• The Belmont Report is presented in three
discussion topics:
 Boundaries between practice and
research,
 Basic ethical principles
 Applications
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Boundaries Between Practice and Research
• Practice - interventions intended to solely
improve the health condition of the patient.
The goal of practice is to provide a diagnosis,
preventive treatment, or therapy that will enhance
the patient’s wellness.
• Research - activities designed to develop or
contribute to the general body of knowledge
which includes theories, principles, and
relationships.
• Subjects must clearly know which study activities
are standard practice and which are research.
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Belmont Report : Basic Ethical Principles
I. Respect for Persons: Two presumptions -
o Persons should be treated as autonomous individuals,
capable of making their own decisions.
o Not every person is capable of self-determination e.g.
persons who are immature or incapacitated
II.Beneficence:
o Beneficence is the practice of doing good, making all
efforts to improve an individual’s well being.
o Potential for risks must be justified by the greater
good to the society - a primary responsibility of the
IRB
III.Justice: (benefits and burdens equally distributed)
o Justice requires that each person is treated fairly,
equitably, and given what he or she is due.
o Justice is relevant to the selection of subjects at two
levels:
i ) Individual level
ii ) Social level
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Application of Belmont Principles:
Applications of these principles to conduct
research requires careful consideration of
A. Informed consent
B. Risks benefit assessment
C. Selection of subjects of research
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Belmont Report : Informed Consent
1. Research subjects are told every thing about the
study, including risks.
2. The information must be easy to understand.
3. Research subjects who agree to participate must
do so voluntarily, they must not be pressurized
or swayed into it.
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INFORMED CONSENT PROCESS
INFORMATION
COMPREHENSION VOLUNTARINESS
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Conceptual framework – informed consent process
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Difficulties With Informed Consent
Problems Physicians
may face
a. Use of technical
language
b. Uncertainties intrinsic
to all medical
information
c. Worried about harming
or alarming the patient
d. Hurried and pressed by
multiple duties
Problems Patients
may face:
a. Limited knowledge
b. May be inattentive or
distracted
c. Overcome by fear and
anxiety
d. Selective hearing because
of denial, fear, or
preoccupation with
illness
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Informed Consent …..
Guidelines & Laws
Guidelines
• Nuremberg Code
• DOH
• ICH, E-6 Section 4.8 (GCP)
• ICMR guidelines, 2006
Laws
• 45 CFR 46.116 Common
Rule
• 21 CFR 50. 25 FDA
• Schedule Y (appendix V)
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ICMR Guidelines
• Ethical guidelines for
research involving humans
“Ethical Guidelines for
Biomedical Research on Human
Subjects”
• Published by the Indian
Council of Medical
Research in 2000
• Revised version - 2006
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Required components of ICF
(ICMR guideline, 2006)
1. Nature and purpose of study stating it as research
2. Duration of participation with number of
participants
3. Procedures to be followed
4. Investigations, if any, to be performed
5. Foreseeable risks and discomforts adequately
described and whether project involves more than
minimal risk
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Components of ICF…..cont.
6. Benefits to participant, community or medical
profession as may be applicable
7. Alternative treatments, if available
8. Steps taken for ensuring confidentiality
9. Policy on compensation
10. Availability of medical treatment for such
injuries or risk management
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Compensations in trial related injury
(a) Adverse effects of Investigational product(s)
(b) Departure from approved protocol, scientific misconduct
or negligence by the Investigator
(c) Failure of an Investigational Product to provide attended
therapeutic effect
(d) Administration of placebo providing no therapeutic
benefits.
(e) Compensation for injury to a child in utero because of the
participation of parent in Clinical Trial.
Drugs and Cosmetics Rules (3rd amendment), 2011

11. No loss of benefits on withdrawal
12. Benefit sharing in the event of commercialization
13. Contact details of PI or local PI/Co-PI in multicentric
studies for asking more information
14. Contact details of Chairman of the IEC for appeal
against violation of rights
15. Voluntary participation
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16. If test for genetics and HIV is to be done,
counselling for consent for testing must be given
as per national guidelines
17. Storage period of biological sample and related
data with choice offered to participant regarding
future use of sample, refusal for storage and
receipt of its results
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Obligations of investigators
1. Communicate to prospective participants
2. Exclude unjustified deception, undue influence
and intimidation.
3. Seek consent only after the prospective participant is
adequately informed
4. Obtain a signed form as an evidence of informed
consent (written informed consent) preferably
witnessed by a person not related to the trial.
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Obligations of investigators
5. Take surrogate consent from the authorized
relative or legal custodian
6. Fresh informed consent of participant wherever
applicable
7. If participant loses consciousness or competence
to consent during the research period ( AD /
Psychiatric conditions) surrogate consent may
be taken from LAR
8. Assurance for continuation of existing benefits
even after withdrawal of consent 32

Fresh or Re-consent
1. Availability of new information which would
necessitate deviation of protocol.
2. When a research participant regains
consciousness from unconscious state
3. When long term follow-up or study extension is
planned later.
4. When there is change in treatment modality,
procedures, site visits.
5. Before publication if there is possibility of
disclosure of identity ( data, photograph etc.)
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Waiver of consent
1. When it is impractical to conduct research since
confidentiality of personally identifiable information
has to be maintained throughout research.
e.g. study on disease burden of HIV/AIDS.
2. Emergency situations, when surrogate consent
unavailable
3. Research on anonymised biological samples from
deceased individuals, left over samples, cell lines etc.
4. Research on publicly available information,
documents, records, works, performances, reviews etc.
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Informed consent - Schedule Y
 In all trials, a freely given, informed, written consent
is required to be obtained from each study subject.
 The Subject’s consent must be obtained in writing using an
‘Informed Consent Form’.
 Both the PIS and the ICF should be approved by the ethics
committee and furnished to the Licensing Authority.
Where a subject is not able to give informed consent,
it may be obtained from a legally acceptable
representative.
An impartial witness should be present if LAR is
illiterate.
A checklist of essential elements given in Appendix
V
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Format of informed consent form for Subjects participating in a
clinical trial
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Assent
• ‘Assent’ means a child's affirmative agreement to
participate
in research.
• “All paediatric participants should be informed to the
the fullest extent possible about the study in a language
language and in terms that they are able to
understand.” – Schedule Y
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Community consent
• Community consent is generally obtained
through a process of dialogue with the
community leadership.
• Agreement from the community leadership is
obtained prior to, but does not replace, the
consent and/or assent of individual participants.
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Victims of Drug Trials @ India
288
637
668
438
0 0
22
NA
0
100
200
300
400
500
600
700
800
2008 2009 2010 2011
SAE-related deaths in
India (2008-11)
No. of Death Compensation
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Drug Trials & India
Recently, a PIL submitted to the SC suggested that big
pharmaceuticals including GlaxoSmithKline and MSD –
had tested two HPV vaccines
( gardasil and cervarix) on
almost 24,000 tribal girls in
Andhra Pradesh and Gujarat
without proper consent.
‘Poor, sick, desperate. What more could Big Pharma ask
in Indian drug trials?’
- Anjana Ahuja, 2006
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NIH Informed Consent Authoring Tool
Web-based application, Beta Version – Pilot phase
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Summary
Informed consent is a process, not just a signed
document.
Important landmarks –Nuremberg Code, DoH,
Belmont report
Three basic components –
 Information
 Comprehension
 Voluntariness
ICMR Guidelines / Schedule Y recommendations
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References
• GCP Guidelines 4.8, ICH
• Wikipedia
• ICMR Guidelines, 2006
• Schedule Y (amended version)
• The Hindu
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Informed consent in Clinical Trials

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