Ethical Guidelines for Biomedical Research on Human Subjects (2000)

1Ethical Guidelines for Biomedical Research
on Human Subjects

INDIAN COUNCIL OF ME DICAL RESEARCH NEW D ELHI
2000


TABLE OF CONTENTS


FOREWORD ………………………….. ………………………….. ………………………….. …..

PREFACE ………………………….. ………………………….. ………………………….. ………..

ACKNOWLEDGEMENT ………………………….. ………………………….. …………..

STATEMENT OF GENERAL PRINCIPLES ON ETHIC AL
CONSIDERATIONS INVOL VING HUM AN SUBJECTS ………………

ETHICAL REVIEW PROCE DURES ………………………….. ……………………

GENERAL ETHICAL ISSU ES………………………….. ………………………….. ….

STATEMENT OF SPECIFI C PRINCIPLES FOR CLI NICAL
EVALUATION OF DRUGS/ DEVICES/DIAGNOSTICS/
VACCINES/HERBAL REME DIES ………………………….. ……………………….

STATEMENT OF SPECIFI C PRINCIPLES FOR
EPIDEMIOLOGICAL STUD IES………………………….. …………………………..

STATEME NT OF SPECIFIC PRINC IPLES FOR HUMAN
GENETICS RESEARCH ………………………….. ………………………….. ……………

STATEMENT OF SPECIFI C PRINCIPLES FOR RES EARCH
IN TRANSPLANTATION I NCLUDING FOETAL TISS UE
TRANSPLANTATION ………………………….. ………………………….. ………………. 2
STATEMENT OF SPECIFI C PRINCIPLES FOR ASS ISTED
REPRODUCTIVE TECHNOL OGIES ………………………………………………
BIBLIOGRAPHY …………………………………………………………………………………
LIST OF MEMBERS OF C ENTRAL ETHICAL COMMI TTEE
AND SUB -COMMITTEES ………………………………………………………………….



Justice M.N. Venkatachaliah
(Former Chief Justice of India)
Chairperson

s
NATIONAL COMMISSION TO REVIEW
THE WORKING OF THE C ONSTITUTION
VIGAN BHAWAN ANNEXE,
MAULANA AZAD ROAD,
NEW DELHI -110011

FOREWORD
The Central Ethics Committee on Human Research (CECHR) of the Indian Council
of Medical Research has now put togethe r a set of “Ethical Guidelines for Biomedical
Research on Human Subjects”.
One of the breath -taking breakthrough in science in the recent years is its
spectacular intrusion into the nature’s hitherto closely guarded secrets of life. Genome -
mapping, Genetic Recombinant Engineering, Assisted Reproductive technology, Stem -
Cell Research, Human cloning etc. have opened up hitherto unimagined vistas in the
practical application of Biomedical Technologies for the benefit of the mankind.
Biomedical Research is perc hed on the threshold of a bold and brave new world. Crucial
to its management is the ability of the scientitists and the society to handle these forces of change. 3Correspondingly, as in all frontier -line researches, our ignorance of the areas of
the yet u nknown might, paradoxically, expand with the expansion of our knowledge.
Biomedical Research has acquired dimensions which are at once exciting and awesome. It
raises some delicate and difficult issues of ethics which need to be dealt with sensitivity to
human values and with great circumspection. While research which promises to mankind
the great blessings of Science should not be stifled by too restrictive an approach,
however, great care should be taken to ensure that something does not go out of hand.
Therefore, any system of ethical guidelines on research needs to be cognizant of, and
informed by, a sensitive balance of the risks and benefits.
Indeed in this area of research the only constancy is the constancy of change. At
no stage can the last word be said. This phenomenon is amply illustrated by the vacillating
responses of the scientific community to the extremely difficult area of human asexual
replication. The issues concern Stem Cells, the unspecialised cells which have not yet
differentiated into a specific tissue. While the present ethical guidelines of the CECHR
entertain reservations on Human Cloning, there has, in the very recent past, some drastic
rethinking on the subject in Britain. The British Government is contemplating a legislation
to lift the ban on human cloning to allow scientific research on embryo cells. Britain might,
perhaps, be the first country to authorise cloning from humans. England’s Chief Medical
Officer Professor Lam Donaldson has advised the proposed changes on the basis of a
report of an expert group chaired by him. It was felt by the expert group that, in the long
term, there could be considerable potential for the use of tissues derived from stem cells
in the treatment of a wide range of disorders by replacing cells tha t have become damaged
or diseased, such as the insulin secreting cells or liver cells etc. Views on the other side of
the Atlantic seem to be sharply divided. All these indicate that the ethical issues involved
need an on -going open -minded evaluation or re -evaluation.
The CECHR Guidelines contain, apart from the Statement of General Principies on
Ethical Considerations, separate chapters on ‘Ethical Review Procedures’; ‘General
Ethical Issues’; Statements on ‘Specific Principies for Clinical Evaluation of
Drugs/Devices/Diagnostics/Vaccines/Herbal Remedies’; Statement on ‘Specific
Principles for Epidemiological Studies’; on ‘Specific Principles on Human Genetic
Research; on ‘Specific Principles for Research in Transplantation including Foetal Tissue
Transplan tation’ and on ‘Assisted Reproductive Technologies’.

As Chairman of the CECHR, I take this opportunity to express my gratitude to the
Members of the Committee and the expert -groups for their valuable contribution.
Interaction with them was, in itself, a r ewarding and exciting experience. I particularly
acknowledge the help from Dr. G.V. Satyavati and Dr. N.K. Ganguly, the former and the
present Directors -General, respectively, of the ICMR; and the great patience and courtesy
of Dr. Vasantha Muthuswamy.





New Delhi
Dated 06 September, 2000 Justice M.N. Venkatachaliah 4




PREFACE
The need for uniform ethical guidelines for research on human subjects is
universally recognised. Indeed, it has acquired a new sense of urgen cy as the critical
issues in the areas of biogenetic research involving human subjects have become
acute. Apart from the mandatory clinical trials on new drugs, a number of
diagnostic procedures, therapeutic interventions and preventive measures including
the use of vaccines are being introduced which involve human subjects. Further, the
advent of new medical devices and radio -active materials, and therapeutic benefits
of recombinant DNA products have added a new dimension to the ethical issues that
need to be considered before evaluating these for their efficacy, utility and safety.
With the ushering -in of the era of biotechnology (including genetic
engineering) medical procedures and therapeutics have undergone tremendous
changes and many techniques based on these advances are no longer in the realms
of science fiction, but have become a reality today. Recent advances in the field of
Assisted Reproductive Technologies, Organ Transplantation, Human Genome
Analysis and Gene Therapy promise unquestionable and hitherto undreamed of
benefits to mankind. At the same time, they raise many questions of law and ethics,
stimulating public interest and concern. On the one hand, there is a need to requite
legitimate public concern, and on the other, there is need to app reciate and
encourage and not unduly deter new scientific innovations for the benefits of
mankind. The new advances in Science and Medicine are a cause for celebration, at
the same time they need careful evaluation of risk -benefit. It is imperative that
specific guidelines for such research are provided from time to time, taking into
consideration all these new and ever changing dimensions. It is, however, to be
emphasized that in their very nature and in view of the innate complexity of the
subject the Gui delines can be neither exhaustive nor static. They need to be
updated, consistent with the speed of change in Science and Technology.
The Indian Council of Medical Research (ICMR) had brought out in
February 1980, a document entitled ‘ Policy statement on e thical considerations
involved in research on human subjects ’ prepared by the ethical committee under the
chairmanship of Honorable Justice Shri H.R. Khanna. This document is being
widely used by not only ICMR but also by other Government agencies, researc h
institutions and scientists. The document, however, needed to be updated in view of
the recent developments in modern biology as also in different branches of medical
science so as to add to its contemporary relevance. 5Therefore, a Central Ethics Committ ee on Human Research (CECHR) was
constituted under the chairmanship of Honourable Justice Shri M.N.
Venkatachaliah by the then Director General, Dr. G.V. Satyavati to consider
various issues related to the Ethical, Legal and Social dimensions of research
involving human subjects. The committee first met on 10th September, 1996 and
identified following major areas and set up sub -committees of experts for drawing
up a set of guidelines:
1. Clinical evaluation of Drugs/Devices/Diagnostics/Vaccines/ Herbal reme dies
2. Epidemiological research
3. Human Genetics research
4. Transplantation research, including Fetal tissue transplantation
5. Assisted Reproductive Technologies
The CECHR met on 10th August 1997 to consider the draft guidelines
prepared by all the fiv e groups and a Draft Consultative Document was prepared
for wide circulation and subsequent regional/national debates before finalisation. A
series of four regional public debates at Calcutta, Mumbai, Hyderabad and New
Delhi on the Draft Consultative Docum ent were conducted in the years 1998 -99. The
process of public debates highlighted the regional and cultureal differences in our
country. The reports and recommendations of all the four debates along with the
comments that were received from various scient ists and scientific institutions both,
medical and non -medical, voluntary groups, and media were examined by the
concerned drafting Sub -Committees before finalising the specific guidelines in the
respective areas. A separate chapter on ‘Ethical Review Proc edures is also added. It
is proposed that these guidelines will be updated periodically pari passu with the
developments in the area of Biomedical Sciences. It is expected that 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 the safety and
well being of all individuals who participate in such research for the progress of
science through acquisition of new knowledge.
The Council acknowledges with gratitude the contribution of all the
professionals, public and the media involved in bringing out these guidelines over a
period of 4 years without which this would not have been possible.

New Delhi N.K.Ganguly
September, 2000 Director Gener al

6



ACKNOWLEDGEMENTS
The Council gratefully acknowleges the valuable contribution of all the members
of the Central Ethics Committee on Human Research and the Sub -committees for
providing continued guidance in drafting and finalizing the Guidelines.
Special thanks go to the following scientists for conducting the regional public
debates on the ‘Consultative Document on Ethical Guidelines’ :
l Prof. M.G.K. Menon, former Minister of Science & Technology and former
Member of Parliament, New Delhi.
l Dr. D. Balasubramaniam, Research Director, L.V. Prasad Eye Institute, Hyderabad.
l Dr. Sunil Pandya, Consultant, Jaslok Hospital, Mumbai.
l Prof. Partha Majumdhar, Professor, Indian Statistical Institute, Calcutta.
Our deep gratitude is extended to Prof. V . Ramalingaswami, National Professor,
All India Institute of Medical Sciences and former Director General, Indian Council of
Medical Research, New Delhi for chairing the special Sub -committee to finalize the
document.
Sincere thanks are due to various indi viduals, Institutions, government and non -
governmental organizations, media personnel etc. for their constructive suggestions.
Efforts made by Dr. Nandini K. Kumar, Assistant Director General, ICMR in
assisting during the entire process of documentation an d compilation of the Guidelines is
thankfully appreciated.
Secretarial assistance provided by Shri B.K. Gulati and Ms. Poonam Dhawan is also
placed on record.
STATEMENT OF GENERAL PRINCIPLES IN BIOMEDICAL
RESEARCH INVOLVING HUMAN SUBJECTS


This stateme nt of Ethical Guidelines for Biomedical Research on Human
Subjects shall be known as the ICMR Code and shall consist of the following : –

(a) Statement of General Principles on Research using Human Subjects in
Biomedical Research 7
(b) Statement of Specif ic Principles on Research using Human Subjects 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 Second World War (1939 -45) in its aftermath, gave rise to an intense
concern about the use of human subjects for medical research as revealed by the
shocking details of the trial of German medical practitioners accused of conducting
experiments on human subjects without th eir consent and exposing them to grave risk of
death or permanent impairment of their faculties. Thus, the first International Statement
on the ethics of medical research using human subjects namely, the Nuremberg Code
was formulated in 1947, which emphas ised consent and voluntariness. In 1948,
Universal Declaration of Human Rights (adopted by the General Assembly of the
United Nations) expressed concern about human beings being subjected to involuntary
maltreatment. In 1966, the International Covena nt 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 on use of human subjects in medical research
in addition to specific gu idelines for biomedical research, known as the Helsinki
Declaration which was revised from time to time. In February 1980, the Indian
Council of Medical Research released a ‘Policy Statement on Ethical Considerations
involved in Research on Hu man 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.’

Subsequent ly 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
bodies in national jurisd ictions have also laid down general and specific principles in
specific areas of scientific research entailing the use of human beings as subjects in
medical research. These ‘national’ Codes (drawn from the international codes and the
universal princip les underlying them) outline ‘guidelines’ to be followed in their
respective jurisdictions.
8GENERAL STATEMENT

Medical and related research using human beings as subjects must necessarily
ensure that –

(i) The PURPOSE, of such research is t hat 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 bette rment of others and that human beings
who are subject to any medical research or scientific experimentation are dealt
with in a manner conducive to and consistent with their dignity and well being,
under conditions of professional fair treatment and trans parency; and after
ensuring that the subject is placed at no greater risk other than such risk
commensurate with the well being of the subject in question in the light of the
object to the achieved.

(iii) Such research must be subjected to a regime o f 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 s ought 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 its elf.


STATEMENT OF GENERAL PRINCIPLES

Any research using the human beings as subjects of medical or scientific research
or experimentation shall bear in mind the following principles –


I. Principles of essentiality whereby, the research entailing the use of human
subjects 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 considere d 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 m embers of the human species and for the ecological and environmental
well being of the planet. 9
II. Principles of voluntariness, informed consent and community agreement
whereby, research subjects are fully apprised of the research and the impact and
risk of such research on the research subject and others; and whereby the research
subjects 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 hum an subjects 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 subject, these princi ples of voluntariness and informed consent shall
apply, mutatis mutandis , to the community as a whole and to each individual
member who is the subject of the research or experiment. Where the human
subject is incapable of giving consent and it is conside red essential that research
or experimentation be conducted on such a 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 beha lf of such
research subjects 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
afterma th and applied use so that research subjects 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 subject 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 subject’s p erson and privacy, health and life generally, and, the
overall purpose and the importance of the research.

III. Principles of non -exploitation whereby as a general rule, research subjects are
remunerated for their involvement in the research or experimen t; and, irrespective
of the social and economic condition or status, or literacy or educational levels
attained by the research subjects kept fully apprised of all the dangers arising in
and out of the research so that they can appreciate all the physic al and
psychological risks as well as moral implications of the research whether to
themselves or others, including those yet to be born. Such human subjects should
be selected so that the burdens and benefits of the research are distributed without
arbitr ariness, discrimination or caprice. Each research shall include an in -built
mechanism for compensation for the human subjects either through
insurance cover or any other appropriate means to cover all foreseeable and
unforeseeable risks by providing for remedial action and comprehensive after -
care, 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 subject and to ensure that immediate recompen se and rehabilitative
measures are taken in respect of all affected, if and when necessary.
10 IV. Principles of privacy and confidentiality whereby, the identity and records of
the human subjects of the research or experiment are as far as possible kept
confidential; and that no details about identity of said human subjects, 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 in terventions, without the specific consent in writing of the
human subject concerned, or someone authorised on their behalf; and after
ensuring that the said human subject 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 subject and
those affected by it are put to the minimum risk, suffer from no irreversible
adverse effects and, genera lly, 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, 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 a re
socially better off but also the least advantaged; and in particular, the research
subject themselves.
11 IX. Principles of institutional arrangements whereby, there shall be a duty on all
persons connected with the research to ensure that all the pr ocedures 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 ens ure 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 fo rce 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 co nstantly 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 subject 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 th at 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.


ETHICAL REVIEW PROCEDURES

The need for evaluation of research proposals has been emphasized under the
Statement of General Principles at item no. 5 pertaining to precaution and risk
minimisation. It is mandatory that all proposals on biom edical research involving human
subjects should be cleared by an appropriately constituted Institutional Ethics Committee
(IEC), also referred to as Institutional Review Board (IRB) in many countries, to 12 safeguard the welfare and the rights of the particip ants. The Ethics Committees are
entrusted not only with the initial review of the proposed research protocols prior to
initiation of the projects but also have a continuing responsibility of regular monitoring
for the compliance of the ethics of the appro ved programmes till the same are completed.
Such an ongoing review is in accordance with the Declaration of Helsinki and all the
intern