Ethical Guidelines for Biomedical Research on Human Participants (2006)

ETHICAL GUIDELINESFOR
BIOMEDICAL RESEARCHON
HUMAN PARTICIPANTS
INDIAN COUNCIL OF MEDICAL RESEARCH
NEW DELHI
2006
Published by:
Director-General
Indian Council of Medical Research
New Delhi 110 029
www.icmr.nic.in.
October, 2006
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25797524TABLE OF CONTENTS
Foreword vi
Preface vii
Acknowledgement viii
Introduction 1
Chapter I. Statement of General Principles on Ethical Considerations 2
involving Human Participants
Background 2
General Statement 3
Statement of General Principles 4
Chapter II. Ethical Review Procedures 8
Basic Responsibilities 8
Composition 9
Terms of Reference 10
Training 10
Regulation 10
Review procedures 11
Submission of application 14
Decision making process 17
Review Process 18
Periodic review 18
Continuing review 18
Interim review 18
Monitoring 18
Record keeping 19
Administration and management 19
Special considerations 19
Chapter III. General Ethical Issues 21
I. Informed Consent Process 21
II. Compensation for Participation 21
III. Conflict Of Interest 26IV. Selection of Special Groups as Research Participants 27
V. Essential Information on Confidentiality for 29
Prospective Research Participants
VI. Compensation for Accidental Injury 29
VII. Post-Trial Access 30
VIII. International Collaboration/Assistance in Bio-Medical/ 30
Health Research
IX. Researcher’s Relations with the Media and Publication 32
Practices
Chapter IV. Statement of Specific Principles for Clinical Evaluation of 34
Drugs/Devices/Diagnostics/Vaccines/Herbal Remedies
General Principles 34
Specific Principles 35
I. Drug Trials 35
II. Vaccine Trials 43
III. Clinical Trials with Surgical Procedures/Medical Devices 46
IV. Diagnostic Agents – Use of Radio – Active Materials 49
and X-Rays
V. Clinical Evaluation of Traditional Ayurveda, Siddha, Unani 50
Remedies and Medicinal Plants
Chapter V. Statement of Specific Principles for Epidemiological Studies 56
Introduction 56
Definitions 57
General Principles 58
Specific Principles 59
Chapter VI. Statement of Specific Principles for Human Genetics and 62
Genomics Research
Introduction 62
General Guidelines 64
I. Pedigree Studies 65
II. Genetic Screening 67
III. Therapeutic Trials Including Gene Therapy 69
IV. Human Genome Project (HGP) 70
V. DNA and Cell-Line Banking/Repository 71VI. DNA Diagnosis 74
VII. Prenatal Diagnosis 75
Chapter VII. Statement of Specific Principles for Research in Transplantation 77
Introduction 77
I. Transplants from Live or Cadaver Donors 77
II. Embryonic and Foetal Tissue 81
III. Xeno-Transplantation 86
IV. Transplantation for Cosmetic Purposes 88
IV. Stem Cell 89
Chapter VIII. Statement of Specific Principles for Assisted Reproductive 97
Technologies
Introduction 97
General Principles 98
Specific Principles 102
Bibliography 105
List of Members of Committee (1996-2006) 108FOREWORD
The release of revised Ethical guidelines for Biomedical Research on Human subjects
by the Council in 2000 was followed by a number of developments in science and
technology. These have led to further widening of healthcare between the developed
and developing countries. Due to globalization rapid techniques of diagnosis and therapy
are now available through R & D. The advances in the area of genetics, genomics and
molecular biology have grown by leaps and bounds with the resultant need to rein in
these advances with sufficient safeguards to protect the rights and welfare of human
participants subjected to biomedical research. Globally international agencies have been
bringing out guidelines for researchers in their countries with relevance to developing
countries. WHO and UNESCO are striving to bring a universal consensus to these
guidelines in an attempt to reduce disparity across the world.
Considering the recent advances in the field of Assisted Reproductive Technologies,
separate guidelines have been brought out by the Indian Council of Medical Research
as "National Guidelines for Accreditation, Supervision and Regulation of ART Clinics
in India"(2005). Since India is being projected as a global hub for clinical trials and the
number of corporate hospitals with state-of-the-art facilities is growing, visits by foreign
specialists using newer techniques or devices is increasing. Some Indian institutions are
also involved in making indigenous devices, which have to be tried in Indian patients
for safety and efficacy. Although a separate document has been made for regulating
the medical devices under Indian Medical Devices Regulatory Authority (IMDRA)
relevant portions have been included in this document. The guidelines for the important
biotechnology areas like stem cell research and stored tissue including DNA banking
have also been added in this revision. Taking into consideration the changing dimensions
of ethical issues in the context of new technologies and evolving universal guidelines,
the existing chapters on Clinical trials, Organ Transplantation, Human Genetics,
Epidemiology and Assisted Reproductive Technologies have also been revised.
I hope the scientific community, the regulatory agencies and the public at large will be
immensely benefited by this revised guidelines.
New Delhi
October 2006 M. S. Valiathan
Chairman
Central Ethics Committee on Human Research
ICMR, New Delhi
viviiPREFACE
It was proposed in the earlier revised "Ethical Guidelines for Biomedical Research on
Human Subjects" of 2000, that the guidelines to each of the areas described would be
updated periodically pari passu with the developments in the area of Biomedical Science.
Hence revision has been undertaken in view of the recent development in the area of
Science and technology. Further the points raised in several international and national
meetings or workshops on bioethics have been taken into account for making the changes
with relevance to Indian ethos in this third version of ethical guidelines now being
released. The Bioethics Cell of the Division of Basic Medical Sciences has over the years
acquired considerable expertise in addressing ethical queries in relation to advances
made in biological sciences and biotechnology. This revision will address most of these
in this version. The Statement of General principles remains almost the same as they
continue to have relevance for future and are template for universal application for
developing ethical guidelines in any area relevant to the Indian scenario. All the seven
major Chapters, namely, Ethical Review Procedures, General Ethical issues, Clinical
evaluation of drugs/ vaccines / devices/ diagnostics/ herbal remedies, Epidemiological
studies, Human genetics and Genomics research, Transplantation research and Assisted
reproductive technologies required updating as per the prevalent ethical debates around
the globe. Care is taken to include new areas like stem cell research and therapy and
biobanking while elaborating many existing topics to make it more user friendly.
As promised during the release of the ethical guidelines of 2000 about periodic update,
the present version is being released. I hope this effort will continue to bring out future
revisions to keep pace with the global developments in the area of Bioethics.
New Delhi N. K. Ganguly
October 2006 Director General, ICMRACKNOWLEDGMENT
This is to acknowledge with gratitude the contributions made during the last five years
by the professionals, public and the media through personal interaction during the
innumerable workshops organized by the Bioethics Cell of the Council in bringing out
these guidelines. We hope that this spirit of togetherness will continue to help us in
updating these guidelines in the coming years to keep pace with further new
developments.
The Bioethics Cell of the Council gratefully acknowledges the valuable contribution of
all the members of the panel who reviewed this third version and provided continued
guidance in drafting the new guidelines and finalizing them. Special thanks are due to
Dr. U. M. Thatte and Dr. Reider Lie for their elaborate suggestions.
The patronage of Dr. N. K. Ganguly, the Director General, ICMR for his continued
support for preparation of the third version of the Council's Ethical Guidelines is
gratefully acknowledged.
The contribution of Dr. Geeta Jotwani, Dr. Roli Mathur, Dr. Hemalatha Somsekhar, Dr.
Sanjeeva Majumdar, Dr. A. C. Kar, Mr. J. N. Mathur and Ms. Neelam Chaudhary is
highly appreciated for the assistance given for updating these guidelines and bringing
out the document.
New Delhi Vasantha Muthuswamy,
October 2006 Senior Deputy Director General
Nandini K. Kumar,
Deputy Director General
viiiINDIAN COUNCIL OF MEDICAL RESEARCH 1INTRODUCTION
The Indian Council of Medical research brought out the 'Policy Statement on Ethical
Considerations involved in Research on Human Subjects' in 1980 and revised these
guidelines in 2000 as the 'Ethical guidelines for Biomedical Research on Human
Subjects'. Due to further rapid developments in science and technology in India after
the release of the second version, it became necessary to update these guidelines to
make adequate specific provision to meet ethical challenges posed by these advances.
Necessitated by the globalization leading to increasing research in the developing
world, the international guidelines released in 2002 by the developed countries
including the revised CIOMS guidelines focused on observance of ethical norms
relevant to different pluralistic cultural environment in these countries for the
protection of the research participants in these regions. In India the challenge faced is
to apply universal ethical principles to biomedical research in the multicultural Indian
society with a multiplicity of health-care systems of considerably varying standards.
The scope of this third version of the Council's guidelines takes note of these changes,
and in keeping with the national policies and the demands of Indian culture, addresses
ethical issues in specific situations to the extent possible. While on one hand, research
involving human participants must not violate any universally applicable ethical
standards, on the other hand, a researcher needs to consider local cultural values
when it comes to the application of the ethical principles to individual autonomy and
informed consent. In India, one will have to consider autonomy versus harmony of
the environment of the research participant. In research on sensitive issues, this will
have to be properly addressed in the research protocol to safeguard the human rights
of the dependent or vulnerable persons and populations.
Some of the points in the international guidelines for biomedical research on human
participants, which have relevance to international collaborative research initiatives,
have been included in this version. Detailed description of vaccine trials, herbal
products, biobanking, and stem cell research etc. has been provided to make the
document reflect current ethical requirements, which can be applied to Indian
circumstances from ethical, legal and social angle. The intention is to update this
document at frequent intervals to keep the scientific community knowledgeable
about the current concepts in bioethics, which is a dynamic process. Such an exercise
is in keeping with similar trends seen in many countries and worked out by
international agencies.2 INDIAN COUNCIL OF MEDICAL RESEARCHSTATEMENT OF GENERAL PRINCIPLES IN BIOMEDICAL
RESEARCH INVOLVING HUMAN PARTICIPANTS
This statement of Ethical Guidelines for Biomedical Research on Human
Participants shall be known as the ICMR Code and shall consist of the following:-
(a)Statement of General Principles on Research using Human Participants in
Biomedical Research
(b)Statement of Specific Principles on Research using Human Participants in specific
areas of Biomedical Research
These Statements of General and Specific Principles may be varied, amended,
substituted and added from time to time.
BACKGROUND
The shocking details of the post Second World War (1939-45) trial of German medical
practitioners accused of conducting experiments on human participants without their
consent and exposing them to grave risk of death or permanent impairment of their
faculties raised grave concern about subjecting human subjects to medical research.
Thus, the first International Statement on the ethics of medical research using human
subjects namely, the Nuremberg Code was formulated in 1947. Although informed
consent for participation in research was recorded in 1900, the Nuremberg Code
highlighted the essentiality of voluntariness of this consent. In 1948, Universal
Declaration of Human Rights (adopted by the General Assembly of the United
Nations) expressed concern about rights of human beings being subjected to
involuntary maltreatment. In 1966, the International Covenant on Civil and Political
Rights specifically stated, ‘No one shall be subjected to torture or to cruel, inhuman
or degrading treatment or punishment. In particular, no one shall be subjected without
his consent to medical or scientific treatment .’
Based on the preliminary efforts of the Council for International Organisations of
Medical Sciences (CIOMS) in 1964 at Helsinki, the World Medical Association
formulated general principles and specific guidelines on use of human subjects in
medical research, known as the Helsinki Declaration, which was revised from
time to time. In February 1980, the Indian Council of Medical Research released aINDIAN COUNCIL OF MEDICAL RESEARCH 3‘Policy Statement on Ethical Considerations involved in Research on Human
Subjects’ for the benefit of all those involved in clinical research in India. In 1982,
the World Health Organisation (WHO) and the CIOMS issued the ‘Proposed
International Guidelines for Biomedical Research involving Human Subjects.’
Subsequently the CIOMS brought out the ‘International Guidelines for Ethical
Review in Epidemiological studies’ in 1991 and ‘International Ethical Guidelines
for Biomedical Research involving Human Subjects’ in 1993. Over the years,
various bioethics advisory bodies in national jurisdictions like Nuffield Council of
Bioethics and European Commission on Ethics have also laid down general and
specific principles in specific areas of scientific research involving human beings as
subjects in medical research. These ‘national’ Codes drawn from the international
codes and the universal principles therein provide the ‘guidelines’ that should be
followed in their respective jurisdictions. Meanwhile the international studies
conducted in developing countries sponsored or funded by developed countries
highlighted the global health divide and the ethical issues related to the 10/90 gap.
National Bioethics Advisory Bodies and Funding organizations of developed nations
took note of this and to rectify the situation revised guidelines which had relevance
to developing countries as evident from Report of National Bioethics Advisory
Committee, USA, by 2000 and Guidelines by Nuffield Council of Bioethics, UK and
CIOMS, Geneva by 2002. The Helsinki Declaration underwent changes five times,
the last one being in 2004. Still the controversy about use of placebo and post-trial
access as described in it is being debated. The most recent documents on ethics are
those of UNESCO’s “The Universal Declaration on Human Genome and Human
Rights” (1997), “The International Declaration on Human Gene Data” (2003)
and “Universal Declaration on Bioethics and Human Rights” (2005).
GENERAL STATEMENT
Medical and related research using human beings as research participants must
necessarily ensure that -
(i)The PURPOSE, of such research is that it should be directed towards the increase
of knowledge about the human condition in relation to its social and natural
environment, mindful that the human species is one of the many species in a
planet in which the well being of all species is under threat, no less from the
human species as any other, and that such research is for the betterment of all,
especially the least advantaged.
(ii)Such research is CONDUCTED under conditions that no person or persons
become a mere means for the betterment of others and that human beings who
are subject to any medical research or scientific experimentation are dealt withStatement of General Principles in Biomedical Research Involving Human Participants4 INDIAN COUNCIL OF MEDICAL RESEARCHin a manner conducive to and consistent with their dignity and well being,
under conditions of professional fair treatment and transparency; and after
ensuring that the participant is placed at no greater risk other than such risk
commensurate with the well being of the participant in question in the light of
the object to the achieved.
(iii)Such research must be subjected to a regime of EVALUATION at all stages of
the proposal i.e., research design and experimentation, declaration of results
and use of the results thereof, and that each such evaluation shall bear in mind
the objects to be achieved, the means by which they are sought to be achieved,
the anticipated benefits and dangers, the potential uses and abuses of the
experiment and its results, and above all, the premium that civilised society
places on saving and ensuring the safety of each human life as an end in itself.
STATEMENT OF GENERAL PRINCIPLES
Any research using the human beings as participants shall follow the principles
given below –
I.Principles of essentiality whereby the research entailing the use of human
participants is considered to be absolutely essential after a due consideration of
all alternatives in the light of the existing knowledge in the proposed area of
research and after the proposed research has been duly vetted and considered
by an appropriate and responsible body of persons who are external to the
particular research and who, after careful consideration, come to the conclusion
that the said research is necessary for the advancement of knowledge and for
the benefit of all members of the human species and for the ecological and
environmental well being of the planet.
II.Principles of voluntariness, informed consent and community agreement
whereby research participants are fully apprised of the research and the impact
and risk of such research on the research participant and others; and whereby
the research participants retain the right to abstain from further participation
in the research irrespective of any legal or other obligation that may have been
entered into by such human participants or someone on their behalf, subject to
only minimal restitutive obligations of any advance consideration received and
outstanding. Where any such research entails treating any community or group
of persons as a research participant, these principles of voluntariness and
informed consent shall apply, mutatis mutandis , to the community as a whole
and to each individual member who is the participant of the research or
experiment. Where the human participant is incapable of giving consent and it
is considered essential that research or experimentation be conducted on suchStatement of General Principles in Biomedical Research Involving Human ParticipantsINDIAN COUNCIL OF MEDICAL RESEARCH 5a person incompetent to give consent, the principle of voluntariness and informed
consent shall continue to apply and such consent and voluntariness shall be
obtained and exercised on behalf of such research participants by someone
who is empowered and under a duty to act on their behalf. The principles of
informed consent and voluntariness are cardinal principles to be observed
throughout the research and experiment, including its aftermath and applied
use so that research participants are continually kept informed of any and all
developments in so far as they affect them and others. However, without in
any way undermining the cardinal importance of obtaining informed consent
from any human participant involved in any research, the nature and form of
the consent and the evidentiary requirements to prove that such consent was
taken, shall depend upon the degree and seriousness of the invasiveness into
the concerned human participant’s person and privacy, health and life generally,
and, the overall purpose and the importance of the research. Ethics committee
shall decide on the form of consent to be taken or its waiver based on the degree
of risk that may be involved.
III.Principles of non-exploitation whereby as a general rule, research participants
are remunerated for their involvement in the research or experiment; and,
irrespective of the social and economic condition or status, or literacy or
educational levels attained by the research participants kept fully apprised of
all the dangers arising in and out of the research so that they can appreciate all
the physical and psychological risks as well as moral implications of the research
whether to themselves or others, including those yet to be born. Such human
participants should be selected so that the burdens and benefits of the research
are distributed without arbitrariness, discrimination or caprice. Each research
shall include an in-built mechanism for compensation for the human participants
either through insurance cover or any other appropriate means to cover all
foreseeable and unforeseeable risks by providing for remedial action and
comprehensive aftercare, including treatment during and after the research or
experiment, in respect of any effect that the conduct of research or
experimentation may have on the human participant and to ensure that
immediate recompense and rehabilitative measures are taken in respect of all
affected, if and when necessary.
IV.Principles of privacy and confidentiality whereby the identity and records of
the human participants of the research or experiment are as far as possible
kept confidential; and that no details about identity of said human participants,
which would result in the disclosure of their identity, are disclosed without
valid scientific and legal reasons which may be essential for the purposes of
therapeutics or other interventions, without the specific consent in writing ofStatement of General Principles in Biomedical Research Involving Human Participants6 INDIAN COUNCIL OF MEDICAL RESEARCHthe human participant concerned, or someone authorised on their behalf; and
after ensuring that the said human participant does not suffer from any form
of hardship, discrimination or stigmatisation as a consequence of having
participated in the research or experiment.
V.Principles of precaution and risk minimisation whereby due care and caution
is taken at all stages of the research and experiment (from its inception as a
research idea, its subsequent research design, the conduct of the research or
experiment and its applicative use) to ensure that the research participant and
those affected by it including community are put to the minimum risk, suffer
from no known irreversible adverse effects, and generally, benefit from and by
the research or experiment; and that requisite steps are taken to ensure that
both professional and ethical reviews of the research are undertaken at
appropriate stages so that further and specific guidelines are laid down, and
necessary directions given, in respect of the conduct of the research or
experiment.
VI.Principles of professional competence whereby the research is conducted at
all times by competent and qualified persons who act with total integrity and
impartiality and who have been made aware of, and are mindful of, preferably
through training, the ethical considerations to be borne in mind in respect of
such research or experiment.
VII. Principles of accountability and transparency whereby the research or
experiment will be conducted in a fair, honest, impartial and transparent manner
after full disclosure is made by those associated with the research or experiment
of each aspect of their interest in the research, and any conflict of interest that
may exist; and whereby, subject to the principles of privacy and confidentiality
and the rights of the researcher, full and complete records of the research
inclusive of data and notes are retained for such reasonable period as may be
prescribed or considered necessary for the purposes of post-research monitoring,
evaluation of the research, conducting further research (whether by the initial
researcher or otherwise) and in order to make such records available for scrutiny
by the appropriate legal and administrative authority, if necessary.
VIII. Principles of the maximisation of the public interest and of distributive
justice whereby the research or experiment and its subsequent applicative use
are conducted and used to benefit all human kind and not just those who are
socially better off but also the least advantaged; and in particular, the research
participants themselves and or the community from which they are drawn.
IX.Principles of institutional arrangements whereby there shall be a duty on allStatement of General Principles in Biomedical Research Involving Human ParticipantsINDIAN COUNCIL OF MEDICAL RESEARCH 7persons connected with the research to ensure that all the procedures required
to be complied with and all institutional arrangements required to be made in
respect of the research and its subsequent use or application are duly made in
a bonafide and transparent manner; and to take all appropriate steps to ensure
that research reports, materials and data connected with the research are duly
preserved and archived.
X.Principles of public domain whereby the research and any further research,
experimentation or evaluation in response to, and emanating from such research
is brought into the public domain so that its results are generally made known
through scientific and other publications subject to such rights as are available
to the researcher and those associated with the research under the law in force
at that time.
XI.Principles of totality of responsibility whereby the professional and moral
responsibility, for the due observance of all the principles, guidelines or
prescriptions laid down generally or in respect of the research or experiment in
question, devolves on all those directly or indirectly connected with the research
or experiment including the researchers, those responsible for funding or
contributing to the funding of the research, the institution or institutions where
the research is conducted and the various persons, groups or undertakings
who sponsor, use or derive benefit from the research, market the product (if
any) or prescribe its use so that, inter alia, the effect of the research or experiment
is duly monitored and constantly subject to review and remedial action at all
stages of the research and experiment and its future use.
XII.Principles of compliance whereby, there is a general and positive duty on all
persons, conducting, associated or connected with any research entailing the
use of a human participant to ensure that both the letter and the spirit of these
guidelines, as well as any other norms, directions and guidelines which have
been specifically laid down or prescribed and which are applicable for that
area of research or experimentation, are scrupulously observed and duly
complied with.
These 12 principles laid down under Statement on General Principles are common
to all areas of biomedical research. The specific issues are mentioned under relevant
topics.Statement of General Principles in Biomedical Research Involving Human Participants8 INDIAN COUNCIL OF MEDICAL RESEARCHETHICAL REVIEW PROCEDURES
The need f