ETHICAL GUIDELINES for BIOMEDICAL RESEARCH on HUMAN SUBJECTS
Item
- Title
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ETHICAL GUIDELINES
for
BIOMEDICAL RESEARCH
on
HUMAN SUBJECTS - extracted text
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ETHICAL GUIDELINES
for
BIOMEDICAL RESEARCH
on
HUMAN SUBJECTS
u
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INDIAN COUNCIL OF MEDICAL RESEARCH
NEW DELHI
2000
STA TEMENT OF GENERAL PRINCIPLES IN
BI0MEDICAL RESEAR CH IN VOL VING
HUMAN SUBJECTS
r
This statement of Ethical Guidelines for Biomedical
Research on Human Subjects shall be kno\Vn as the ICMR Code
and shall consist of the following : (a)
Statement of General Principles on Research using Human
Subjects in Biomedical Research
(b)
Statement ol Specific Principles on Research using Human
Subjects in speci fic areas of Biomedical Research
These Statements of General and Specific Principles may be varied,
amended, substituted and added from lime to time.
BACKGROUND
The Second World War (1939-45) in its aflcnnalh, 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 their consent and exposing them to grave risk of
death or permanent impairment of their faculties. Thus, (he first
International Statement on the ethics of medical research using human
subjects namcl). the Nuremberg C’ode was formulated in 1947, w Inch
emphasised consent and voluntariness. In 1948, Universal
Declaration of Human Rights (adopted by the General Assembly
of the United Nations) expressed concern about human beings beinu
subjected to involuntary maltreatment. In 1966, the International
Covenant on Civil and Political Rights specifically stated, 'Ko 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.'
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 an\- other, and that such research
is for the bettennent of all, especially the least advantaged.
Based on the preliminary efforts of the Council for International
Organisations of Medical Sciences (C1OMS) in 1964 at Helsinki, the
World Medical Association formulated general principles on use of
human subjects in medical research in addition to specific guidelines
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 Fluman 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 bodies
in national jurisdictions 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 principles
underlying them) outline ‘guidelines’ to be followed in their respective
jurisdictions.
GENERAL STATEMENT
Medical and related research using human beings as subjects
must necessarily ensure that (>)
The PURPOSE, of such research is that it should be directed
towards the increase of knowledge about the human condition
(ii)
Such research is CONDUCTED under conditions that no
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person or persons become a mere means for the bettennent of
others and that human beings who arc subject to anv 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
transparency; and after ensuring that the subject is placed al
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)
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Such research must be subjected to a regime of
EVALUATION at all stages of the proposal i.c..'rcscareli
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 « hich they
arc sought to be achieved, the anticipated benents and dangers
the potential uses and abuses of (he 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
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in itself.
STATEMENT OF GENERAL PRINCIPLES
II
Any research using the human beings as subjects of medical
or scientific research or experimentation shall bear in mind the
following principles -
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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
considered by an appropriate and responsible body of persons
who arc 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 subjects arc 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 human
subjects or someone on their behalf, subject to only minimal
reslilulive obligations of any advance consideration received
and outstanding. Where any such research entails treating
anv community or group of persons as a research subject,
these principles of voluntariness and informed consent shall
apply, mutatis mutdiidis. 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 considered 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 behalf of such
research subjects by someone who is empowered and under a
duty to act on their behalf. The principles ofinformed consent
and voluntariness are cardinal principles to be observed
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throughout the research and experiment, including its
aftermath 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 person 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 arc 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 subjects kept fully apprised of ail the
dangers arising in and out of the research so that they can
appreciate all the physical and psychological risks as w ell 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 arc distributed without arbitrariness,
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 recompense and rehabilitative measures arc
taken in respect of all affected, if and when necessary.
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IV.
V.
VI.
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, arc
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 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.
Principles of precaution and risk minimisation w hereby
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 arc put to the
‘ minimum risk, suffer from no irreversible adx erse 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 arc 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.
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.
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VII.
Mil.
IX.
X.
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 w'hereby, 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 arc 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.
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Principles of the maximisation of the public interest and
of distributive justice whereby, the research or experiment
and its subsequent applicative use arc conducted and used
to benefit all human kind and not just those w ho arc socially
better off but also the least advantaged; and in particular,
the research subject themselves.
Principles of Institutional arningcmvnts whereby, there shall
be a duly on all pcrsons.conncctcd 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 arc 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.
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
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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.
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 biomedical 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 safeguard the welfare and the rights of the
participants. The Ethics Committees are entrusted not only with the
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
programmes till the same are completed. Such an ongoing review is
in accordance with the Declaration ofHelsinki and all the international
effect of the research or experiment is duly monitored and
guidelines for biomedical research.
constantly subject to review and remedial action at all stages
of the research and experiment and its future use.
XII.
ETHICAL REVIEW PROCEDURES
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 arc applicable for that area of research or
experimentation, arc scrupulously observed and duly complied
with.
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 approved
BASIC RESPONSIBILITIES
I he basic responsibility of an IRC is Io unsure a compclcnl
review of all ethical aspects of the project proposals received and
execute the same free from any bias and influence that could affect
their objectivity. lECs should provide advice to the researchers on all
aspects of the welfare and safely of the research participants after
ensuring the scientific soundness of the proposed research through
appropriate Scientific Review Committees. In smaller institutions the
Ethics Committee may take up the dual responsibility of Scientific
and Ethical Review. It is advisable to have separate Committees for
These 12 principles laid down under Statement on General
Principles are common to all areas of biomedical research. The specific
each taking care that the scicnti fic review precccds the ethical scrutiny.
The scientific evaluation should ensure technical excellence of the
proposed study.
issues are mentioned under relevant topics.
The lECs should specify in writing the authority under which
the Committee is established, membership requirements, the terms of
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reference, the conditions of appointment, the offices and the quorum
requirements. The responsibilities of an IEC can be defined as
follows
1. To protect the dignity, rights and well being of the potential
research participants.
2. To ensure that universal ethical values and international scientific
standards are expressed in terms of local community values and
customs
3. To assist in the development and the education of a research
community responsive to local health care requirements
COMPOSITION
1.
2.
3.
4.
5.
Chairperson
1 -2 basic medical scientists.
1 -2 clinicians from various Institutes
One legal expert or retired judge
One social scientist / representative of non-governmental
6.
7.
8.
voluntary agency’
One philosopher / elhicist / theologian
One lay person from the community
Member Secretary
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The ethical committee at any institution can have as its
members individuals from other institutions or communities if
required. There should be adequate representation of age gender
lECs should be multidisciplinary and multiscctorial in
composition. Independence and competence arc the two hallmarks
of an I EC.
The number of persons in an ethical committee be kept fairly
small (5-7 members). It is generally accepted that a minimum of
five persons is required to compose a quorum. There is no specific
recommendation for a widely acceptable maximum number of persons
but it should be kept in mind that too large a Committee will make it
difficult in reaching consensus opinion. 12 to 15 is the maximum
recommended number.
The Chairperson of the Committee should preferably be from
outside the Institution and not head ofthe same Institution to maintain
the independence of the Committee. The Member Secretary who
generally belongs to the same Institution should conduct the business
of the Committee. Other members should be a mix of medical / non
medical, scientific and non-scientific persons including lay public to
reflect the differed viewpoints. The composition may be as
follows:-
community; etc. m the Committee to safeguard the interests and welfare
o a sections ofthe community / society. Members should be aware
of local, social and cultural norms, as this is the most important social
contro mechamsm. If required subject experts could be invited to
offer lhetr vtews, for example for drug trials a pharmacologist,
Committee.
TERMS OF REFERENCE
The IEC members should be made aware of their role and
responstb.httes as committee members. Any change in the regulatory
requirements should be brought to their attention and they should be
kept abreast of all national and international developments in this
regai .
e erms of References should also include a statement on
Terms of Appointment with reference to the duration ofthe term of
membership, the policy for removal, replacement and resignation
procedure etc. Each Committee should have its own operating
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preferably a clinical pharmacologist, should be included. Similarly,
based on the requirement of research urea, for example 11IV, ucnelic
disorders etc., spccinc patient groups may also be represented in the
procedures available with each member.
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tested, including results of relevant laboratory and animal
research.
10. For research carrying more than minimal risk, an account of
plans to provide medical therapy for such risk or injury or toxicity
due to overdosage should be included.
11. Proposed compensation and reimbursement of incidental
expenses.
12.
Storage and maintenance of all data collected during the trial.
13.
Plans for publication of results - positive or negative — while
maintaining the privacy and confidentiality of the study
' participants.
14.
A statement on probable ethical issues and steps taken to tackle
REVIEW PROCEDURES
The Ethics Committee should review every research proposal
on human subjects. It should ensure that a scientific evaluation has
been completed before ethical review is taken up. The Committee
should evaluate the possible risks to the subjects with proper
justification, the expected benefits and adequacy of documentation
for ensuring privacy, confidentiality and justice issues. The ethical
review should be done through formal meetings and should not
resort to decisions through circulation of proposals.
SUBMISSION or APPLieA TION
15.
The researcher should submit an appropriate application in a
prescribed format along with the study protocol at least three weeks
in advance. The protocol should include the following : -
1.
2.
Clear research objectives and rationale for undertaking the
investigation in human subjects in the light of existing
knowledge.
Recent curriculum vitae of the Investigators indicating
qualification and experience.
3.
4.
Subject recruitment procedures.
Inclusion and exclusion criteria for entry of subjects in the study.
5.
Precise description of methodology of the proposed research,
including intended dosages of drugs, planned duration of
6.
treatment and details of invasive procedures if any.
A description of plans to withdraw or withhold standard
therapies in the course of research.
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7.
The plans for statistical analysis of the study.
8.
Procedure for seeking and obtaining informed consent with
sample of patient information sheet and informed consent
forms in English and vernacular languages.
Safety of proposed intervention and any drug or vaccine to be
9.
the same.
All other relevant documents related to the study protocol
including regulatory clearances.
16.
Agreement to comply with national and international GCP
17.
protocols for clinical trials.
Details of Funding agency / Sponsors and fund allocation for
the proposed work.
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DECISION MAKING PROCESS
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The I EC should be able to provide complete and adequate
review of the research proposals submitted to them. It should meet
periodically at Irequcnt intervals to review new proposals, evaluate
annual progress of ongoing ones and assess final reports of all rcsearcl
activities involving human beings through a previously scheduler
agenda, amended wherever appropriate.
I.
The decision must be taken by a broad consensus after the quorun
requirements are fulfilled to recommend / reject / sugges
modification for a repeat review or advice appropriate steps. Th'
Member Secretary should communicate the decision in writing
2.
A member must voluntarily withdraw from the IEC while making
a decision on an application which evokes a conflict of interest
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3.
4.
5.
6.
7.
8.
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which should be indicated in writing to the chairperson prior to
the review and should be recorded so in the minutes.
If one of the members has her/his own proposal for review, then
the member should not participate when the project is discussed.
A negative decision should always be supported by clearly defined
reasons.
An IEC may decide to reverse its positive decision on a study in
the event of receiving infonnation that may adversely affect the
benefit / risk ratio.
The discontinuation of a trial should be ordered if the IEC finds
that the goals of the trial have already been achieved midw ay or
unequivocal results arc obtained.
In case of premature termination of study, notification should
include the reasons for termination along with the summary of
results conducted till date.
The following circumstances require the matter to be brought to
the attention of IEC :
a.
b.
c.
r.--
any amendment to the protocol from the originally
approved protocol with proper justification;
serious and unexpected adverse events and remedial
steps taken to tackle them;
any new information that may influence the conduct
of the study.
9.
1 f ntvcbbdiy,
necessary, iiic
(he appncanuinvestigator
applicant/investigator may be invited to present
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the protocol or offer clarifications in the meeting. Representative
of the patient groups or interest groups can be invited during
deliberations to offer their viewpoint.
10. Subject experts may be invited to offer their views, but should
not take part in the decision making process. However, her/his
opinion must be recorded.
11. Meetings are to be minuted which should be approved and signed
by the Chairperson.
interim review
meeha
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the Special circumstances and the
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s ould be brought to the notice of the main committee. This can be
done for the following;reasons :
i)
ii)
re-examination of a proposal already examined by the IEC'
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SUCh 35 exami™'on of case
JvLUlUb CIC.,
iii)
an urgent proposal of national interest.
record keeping
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n < j ^ll <1ocunlcn,alion and communication of an IEC arc to be
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prescrvcd accord.ng 1O wr.|c|i proc^r’r'”b
confidentiality is to be maintained during access and reirirv-1
procedures. Records should be maintained for the following :
i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
x.
xi.
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lhe Constitution and composition of the IEC;
the curriculum vitae of all IEC members;
standing operating procedures of the IEC;
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national and International guidelines;
copies of protocols submitted for review;
all correspondence with IEC members’ and investigators
regarding application, decision and follow upagenda of all IEC meetings;
minutes ofall IEC meetings with signature ofthc Chairperson;
copies of decisions communicated to the applicants;
aTudtwid' n°tifiCati0n issucd for P^ature termination of
a study with a summary of the reasons;
final report ofthe study including microfilms, CDs and Videorecoramgs.
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It is recommended that all records must be safely maintained
after the completion / termination of the study for at least a period of
15 years if it is not possible to maintain the same permanently.
SPECIAL CONSIDERA TIONS
While all the above requirements are applicable to biomedical
research as a whole irrespective of the specialty of research, there are
certain specific concerns pertaining to specialised areas of research
which require additional safe guards / protection and specific
considerations for the IEC to take note of. Examples of such instances
are research involving children, pregnant and lactating women,
vulnerable subjects and those with diminished autonomy besides issues
pertaining to commercialisation of research and international
collaboration. The observations and suggestions of IEC should be
given in writing in unambiguous terms in such instances.
GENERAL ETHICAL ISSUES
All the research involving human subjects should be conducted
in accordance with the four basic ethical principles, namely autonomy
(respect for person / subject) beneficence, non-maleficence (do no
harm) and justice. The guidelines laid down are directed at application
of these basic principles to research involving human subjects. The
Principal Investigator is the person responsible for not only undertaking
research but also for observance of the rights, health and welfare of
the subjects recruited for the study. She/he should have qualification
and competence in biomedical research methods for proper conduct
of the study and should be aware of and comply with the scientific,
legal and ethical requirements of the study protocol.
I.
1.
INFORMED CONSENT PROCESS
Informed Consent of Subject : For all biomedical research
involving human subjects, the investigator must obtain the
informed consent of the prospective subject or in the case of an
individual who is not capable of giving informed consent, the
consent of a legal guardian. Informed consent is based on the
principle that competent
individuals
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------- s arc entitled to choose freely
whether to participate in research or not. Informed
consent protects the individual’s freedom of choice and respect
for individual's autonomy.
When research design involves not more than minimal risk
(for example, where the research involves only collecting data from
subject s records) the Institutional Ethics Committee may waive off
some of the elements of informed consent.
Waiver of informed consent could also be considered during
conditions of emergency. However, this would be permissible only if
Ethical Committee has already approved the study or use of drug.
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However, the patient or the legal guardian should be informed after
she/he regains consciousness or is able to understand the study.
3.
the investigator must provide thn ’
j p®rtICIPate m research,
inro™ti.„ in the
nd™the following
should not only be scientific^
6le 10 undcrsland which
2. Obligations of investigators regarding informed consent: The
investigator has the duty to i.
ii.
iii.
iv.
"““,d
Communicate to prospective subjects all the information
necessary for informed consent. There should not beany
restriction on subject’s right to ask any questions related to
the study us any restriction on this undennines the validity of
informed consent.
Exclude the possibility of unjustified deception, undue infiuence
and intimidation. Deception of the subject is not permissible.’
However, sometimes information can be withheld till the
completion of study, if such information would jeopardize the
validity of research.
Seek consent only after the prospective subject is adequately
ii.
iii.
iv.
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assurances to prospective subject, which may influence the
subject's decision to participate in the study.
vii.
vi.
material changes in the conditions or procedures of the
research or new infonnation becomes available during the
ongoing trial.
Not use intimidation in any form which invalidates informed
consent. The investigator must assure prospective subjects that
their decision to participate or not will not affect the patient clinician relationship or any other benefits to which they are
entitled.
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^ightleas'advantageolsto the
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maintained ic the limits tn
As a general rule obtain from each prospective subject a signed
form as an evidence of informed consent (written informed
v.
the aims and methods of the research'
he expected duration of the subject participation'
treatment to which she / he is being subjected’0
v.
informed. Investigator should not give any unjustifiable
consent) preferably witnessed by a person not related to (he
trial, and in case of incompetence to do so, a legal guardian or
other duly authorised representative.
Renew the informed consent of each subject, if there are
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consequences of breach ofconfidcndality;
viii.
ix.
x.
he
an"C"1a,cd
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responsibility of investigators1
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f°rrCl”‘l "W h>' 'he in.os.lg.,or,
»hh“?,'°r“bj"'!r”di“hiiiiyo.fe,hresui,i„gta^
xi.
or loss of benefits
xii.
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address and phone numbers’
xiii.
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P'rec"“
XT^a,™^
rmm .he research and irthem".^
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xiv.
xv.
board/ committee detennincs that a conflict of interest may damage
the scientific integrity of a project or cause harm to research
participants, the board should advise accordingly. Institutions need
self-regulatory processes to monitor, prevent and resolve such
conflicts of interest. Prospective participants in research should also
be informed of the sponsorship of research, so that they can be aware
of the potential for conflicts of interest and commercial aspects of
the research. Undue inducement through compensation for individual
participants, families and populations should be prohibited. This
prohibition however, does not include agreements with individuals,
families, groups, communities or populations that foresee technology
transfer, local training, joint ventures, provision of health care
reimbursement, costs of travel and loss of wages and the possible use
of a percentage of any royalties for humanitarian purposes.
secondary purposes or would be shared with others, clear
mention of the same;
risk of discovery of biologically sensitive information;
publication, if any, including photographs and pedigree charts.
The quality of the consent of certain social groups requires
careful consideration as their agreement to volunteer may be unduly
influenced by the Investigator.
II.
COMPENSATION FOR PARTICIPATION
Subjects may be paid for the inconvenience and time spent,
and should be reimbursed for expenses incurred, in connection with
their participation in research. They may also receive free medical
services. However, payments should not be so large or the medical
services so extensive as to induce prospective subjects to consent
to participate in research against their better judgement (inducement).
All payments, reimbursement and medical services to be provided to
research subjects should be approved by the IEC. Care should be
taken :
i.
ii.
iii.
when a guardian is asked to give consent on behalf of an
incompetent person, no remuneration should be offered except
a refund of out of pocket expenses;
when a subject is withdrawn from research for medical
reasons related to the study the subject should get the benefit
for full participation;
when a subject withdraws for any other reasons he/she should
be paid in proportion to the amount of participation
Academic institutions conducting research in alliance with
industries / commercial companies require a strong review to probe
possible conflicts of interest between scientific responsibilities of
researchers and business interests (e.g. ownership or part-ownership
of a company developing a new product). In cases where the review
20
HI.
T
SELECTION OF SPECIAL GROUPS AS
RESEA R CH SUBJECTS
Pregnant or nursing women : Pregnant or nursing women
should in no circumstances be the subject of any research
unless the research carries no more than minimal risk to the
fetus or nursing infant and the object of the research is to
obtain new knowledge about the foetus, pregnancy and
lactation. As a general rule, pregnant or nursing women should
not be subjects of any clinical trial except such trials as arc
designed to protect or advance the health of pregnant or
nursing women or foetuses or nursing infants, and for which
women who are not pregnant or nursing would not be suitable
subjects.
a. The justification of participation of these women in clinical
trials would be that they should not be deprived arbitrarily
of the opportunity to benefit from investigations, drugs,
vaccines or other agents that promise therapeutic or
21
preventive benefits. Example of such trials are, to test the
efficacy and safety of a drug for reducing perinatal
c.
transmission of HIV infection from mother to child, trials
for detecting fetal abnormalities and for conditions
d.
associated with or aggravated by pregnancy etc. Women
should not be encouraged to discontinue nursing for the
sake of participation in research and in case she decides
to do so, harm of cessation of breast feeding to the nursing
child should be properly assessed except in those studies
e. research should be conducted in settings in which the
child and parent can obtain adequate medical and
psychological support;
f. interventions intended to provide direct diagnostic,
therapeutic or preventive benefit for the individual child
subject must be justified in relation to anticipated risks
involved in the study and anticipated benefits to society;
g. the child’s refusal to participate in research must always
be respected unless there is no medicallx acceptable
alternative to the therapy provided/ tested, provided the
where breast feeding is harmful to the infant.
b.
Research related to termination of pregnancy :
Pregnant women who desire to undergo Medical
Termination of Pregnancy (MTP) could be made subjects
for such research as per The Medical Termination of
Pregnancy Act, GOI, 1971.
:r*
c.
i- _
/ ii.
h.
Research related to pre-natal diagnostic tech-niques : In
must ensure that a.
b.
children will not be involved in research that could be
carried out equally well with adults;
the purpose of the research is to obtain knowledge relevant
to health needs of children. For clinical evaluation of a
new drug the study in children should always be carried
out after the phase III clinical trials in adults. It can be
studied earlier only if the drug has a therapeutic value in a
primary disease of the children;
consent has been obtained from parents / guardian;
interventions that are intended to provide therapeutic
benefit are likely to be at least as advantageous to the
individual child subject as any available alternative
interventions;
i. - the risk presented by interventions not intended to benefit
the individual child subject is low when compared to the
importance of the knowledge that is to be gained.
pregnant women such research should be limited to detect
the foetal abnormalities or genetic disorders as per the
Prenatal Diagnostic Techniques (Regulation and
Prevention of Misuse) Act, GOI, 1994 and not for sex
determination of the foetus.
Children : Before undertaking trial in children the investigator
a parent or legal guardian of each child has given proxy
consent;
the assent of the child should be obtained to the extent of
the child’s capabilities such as in the case of mature minors,
adolescents etc.;
iii.
Vulnerable groups : Effort may be made to ensure that
individuals or communities invited for research be selected in
such a way that the burdens and benefits of the research arc
equally distributed.
a. research on genetics should not lead to racial inequalities;
b. persons who are economically or socially disadvantaged
c.
should not be used to benefit those who are better off than
them;
rights and welfare of mentally challenged and mentally
differently able persons who are incapable of giving
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informed consent or those with behavioral disorders must
be protected;
d. adequate justification is required for the involvement of
subjects such as prisoners, students, subordinates,
employees, service personnel etc. who have reduced
autonomy as research subjects.
IV.
ESSENTIAL INEO RMA TION ON CONFIDENT
IALITY FOR PROSPECTIVE RESEARCH
SUBJECTS
Safeguarding confidentiality - The investigator must safeguard
the confidentiality of research data, which might lead to the
identification of the individual subjects. Data of individual subjects
can be disclosed only in a court of law under the orders of the
presiding judge or in some cases may be required to communicate
to drug registration authority or to health authority. Therefore,
the limitations in maintaining the confidentiality of data should
be anticipated and assessed.
V.
VI.
INTERNA TIONAL COLLABORA TION/
ASSISTANCE IN BIO-MEDICAL /HEAL TH
RESEARCH
Research in biomedical and health areas have been subjects of
international interaction over the centuries. However, it was only in
the second half of the 20"’ Century, especially since 1960s, that the
scope of co-operation and collaboration assumed such proportions
as to have exploitative connotations with commercial and human
dimensions. On the one hand, collaboration in medical research
suggests an interest in humane and civil society, while on the other it
could give the impression of experimentation on the population of
one country by another. Different levels of development in terms of
infrastructure, expertise, social and cultural perceptions, laws relating
to intellectual property rights etc., necessitate an ethical framework
to guide such collaboration. The same concerns are applicable even if
and when there is no formal collaboration between countries, but the
research is undertaken with assistance from sponsors in the form of
international organisations (Governmental, non-Govcrnmcntal or
others for example, Wl IO, IJNICIH-, UNAIDS etc,).
COM PENSA T/ON FOR ACCIDENTAL INJUR 1
SPECIAL CONCERNS
Research subjects’who suffer physical injury as a result of
their participation arc entitled to financial or other assistance to
compensate them equitably for any temporary or permanent
impairment or disability. In case of death, their dependents are entitled
to material compensation.
Obligation of the sponsor to pay The sponsor whether a
pharmaceutical company, a government, or an institution, should
agree, before the research begins, to pro\ ide compensation for
any physical or mental injury for which subjects are entitled to
compensation or agree to provide insurance coverage for an
unforeseen injury whenever possible.
24
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Given the magnitude and severity of the health problems in
different countries, capacity building to address ethical issues
that arise out of collaborative research must be promoted on
a priority basis.
2.
Strategies should be implemented to build capacity in various
countries and communities so that they can practise meaningful
self-determination in health development, can ensure the
scientific and ethical conduct of research, and can function as
equal partners with sponsors and others in a collaborative
process. Community representatives should be involved in an
25
should be decided at the outset. No individual centre should publish
•
any data till appropriate authorities accept the combined report.
The code of the administered drug could be broken in the event of
human population for determination of its safety and biological effects
including immunogenicity. This phase includes study of dose and
a severe adverse reaction occurring during the conduct of a double
blind trial necessitating such a step.
route of administration and should involve low risk subjects. For
example, immunogenicity to hepatitis B vaccine should not be
determined in high risk subjects.
2.
•
•
•
Contraceptives
All procedures for clinical trials arc applicable. Subjects should
be clearly informed about the alternatives available.
In women where implant has been used as a contraceptive for
trial, a proper follow up for removal of the implant should be
done, whether the trial is over or the subject has withdrawn from
the trial.
Children bom due to failure of contraceptives under study should
Phase II:- This refers to the initial trials examining effectiveness
(immunogenicity) in a limited number of volunteers. Vaccines can be
prophylactic and therapeutic in nature. While prophylactic vaccines
are given to normal subjects, therapeutic or curative vaccines may be
given to patients suffering from particular disease.
Phase IIIThis focuses on rassessment of safety and, effectiveness
in the prevention of disease, involving controlled study
' on a larger
number of volunteers (in thousands) in multicentres.
be followed up for any abnormalities if the woman does not opt
for medical termination of pregnancy.
MONITORING AND REPORTING ADVERSE REACTIONS
ORE\ENTS
I’
Any serious adverse events occurring during (he course of
the trial should be immediately brought to the attention of ethics
committee, sponsors and Drug Controller General of India. At the
end of the trial, all adverse events whether related to trial or not are to
be listed, evaluated and discussed in detail in the final report.
II.
VACCINE TRIALS
The guidelines to conduct the clinical trial on
investigational vaccines are similar to those governing a drug trial.
The phases of these trials differ from drug trials as given below :
Phase I
This refers (o the first introduction of a vaccine into a
SPECIAL CONCERNS
•
Some vaccines that contain active or live - attenuated micro-
‘ organisms can possibly possess a small risk of producing that
particular infection. The subject to be vaccinated should be
informed of the same.
• The subjects in conTol groups or when subjected to ineffective
vaccines run a risk of contracting the disease.
The risks associated with vaccines produced by recombinant DN A
techniques are not completely known. However, for all the
recombinant vaccines / products the Guidelines issued by (he
Department of Biotechnology should be strictly followed.
III.
CLINICAL TRIALS WITH SURGICAL
PROCEDURES/MEDICAL DEVICES
Of late, biomedical technology has made considerable progress
m the conceptualisation and designing of bio-equipments. Several
34
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medical devices and critical care equipments have been developed
and many more are in various stages of development. However, only
through good manufacturing practices (GMP) can the end products
reach the stage of utilisation by society. Most of these products are
only evaluated by Central Excise testing for taxation purposes which
discourages entrepreneurs to venture in this area with quality products
especially when they do not come under the strict purview of the
existing regulatory bodies like ISI, BSI and Drugs Controller General.
Ibis is evidenced by the very low number of patents or propriety
medical equipments manufactured and produced in the country. As
the capacity of the country in this area is improving day by day the
need for a regulatory mechanism / authority is increasingly obvious.
The concept of regulations governing investigations involving
biomedical devices is therefore relatively new in India. At present,
except for needles and syringes these are not covered by the Drugs
and Cosmetics Act, 1940. The Chief Executive of the Society of
Biomedical Technology (SBMT) set up under the Defence Research
Development Organisation (DRDO) has drafted a proposal for the
setting up of a regulatory authority, tentatively named as the Indian
Medical Devices Regulatory Authority (IMDRA). Until (he guidelines
arc formulated and implemented by this Regulatory Authority clinical
trieds with biomedical devices should be approved on case to case
basis by committees constituted for the specific purpose.
DEHMTIONS
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Depending upon risks involved the devices could be classified
as follows:-
36
Non critical devices - An investigational device that does not
present significant risk to the patients eg. Thermometer, BP
apparatus.
b)
Critical devices - An investigational medical device that
presents a potential serious risk to the health, safety or welfare
of the subject - for example, pace markers, implants, internal
catheters.
All the general principles of clinical trials described for drug
trials should also be considered for trials of medical devices. As for
the drugs, safety evaluation and pre-market efficacy of devices for 1 3 years with data on adverse reactions should be obtained before pre
market certification. The duration of the trial and extent of use may
be decided in case to case basis by the appropriate authorities.
However, the following imponant factors that are unique to medical
devices should be taken into consideration while evaluating the related
research projects :
•
•
•
Medical devices : A medical device is defined as an inert diagnostic
or therapeutic article that does not achieve any of its principal intended
purposes through chemical action, within or on the body unlike the
medicated devices which contain pharmacologically active substances
which are treated as drugs. Such devices include diagnostic test kits,
crutches, electrodes, pacemakers, arterial grails, intra-ocular lenses’
oithopaedic pins and other orthopaedic accessories.
a)
•
•
•
Safety data of the medical device in animals should be obtained
and likely risks posed by the device should be considered.
Clinical trial of medical devices is different from drug trials, as
fomicr cannot be done in healthy volunteers. Hence Phase 1 of
drug trials is not necessary for trial on devices.
Medical devices used within the body may have greater risk
potential than those used on or outside the body, for example,
orthopaedic pins vs crutches.
Medical devices not used regularly have less risk potential than
those used regularly, forexamplc, contact lens vs intraocular lenses.
Safety procedures to introduce a medical device in the patient
should also be followed as the procedure itself may cause harm to
the patient.
Informed consent procedures should be followed as in drug trials.
The patient information sheet should contain information on
following procedures to be adopted if the patient decides to
withdraw from the trial.
37
rv.
DIAGNOSTIC AGENTS - USE OF RADIO
ACTIVE MA TERIALS AND X-RA YS
later be used in allopathic hospitals, the procedures laid down by the
office of the Drugs Controller General of India for allopathic drugs
should be followed. This does not pertain to guidelines issued for
In human beings, for investigation and treatment, different
radiations - X-ray, gamma rays and beta rays, radiopaque contrast
agents and radioactive materials are used. The relative risks and
benefits of research proposal utilising radioactive materials or X-rays
should be evaluated. Radiation limits for the use of such materials
and X-rays should be in accordance with the limits set forth by the
regulatory authority (BARC) for such materials. ( BARC - Bhabha
Atomic Research Centre, Mumbai).
clinical evaluation of Ayurveda, Siddha or Unani drugs by experts in
those systems of medicine which may be used later in their own
lospitals and clinics. All the general principles of clinical trials
described earlier pertain also to herbal remedies. However, when
chmeal tnals of herbal drugs used in recognised Indian Systems of
Medicine and Homeopathy are to be undertaken in Allopathic
ospitals, assocmtion ofphysicians from the concerned system as co
in vest.gators / collaborators / members of the expert group is desirable
lor designing and evaluating the study.
SPECIAL CONCERNS
•
.
•
•
•
•
•
V.
Informed consent should be obtained before any diagnostic
procedures.
Information to be gained should be gathered using methods that
do not expose subjects to more radiation than exposed normally.
Research should be performed on patients undergoing the
procedures for diagnostic or therapeutic purposes.
Safety measures should be taken to protect research subjects and
others who may be exposed to radiation.
The protocol should make adequate provisions for detecting
pregnancies to avoid risks of exposure to the embryo.
information to subject about possible genetic damage to offspring
should be given.
Non-radioactive diagnostic agents arc considered as drugs and
the same guidelines should be followed when using them.
SPECIAL CONCERNS
given bdow>erba' Pr°dl,C,SCan bC,Ong ,0 cilhcro^l*lc three categories
I■
Ayui veda, Siddha or Unanl literature or the plant may actually be
regularly used by physicians of the traditional systems of medicine
for a number of years. The substance is being clinically evaluated
for same md.cation for which it is being used or as has been
described in the texts.
Ultrasound to be substituted wherever feasible.
CLINICAL EVALUATION OF HERBAL
REMEDIES AND MEDICINAL PLANTS
A lot is known about the use ofl, plant or its extract in the ancient
I
icn an extract of a plant or a compound isolated from the plant
las to be clinically evaluated for a therapeutic effect not originally
described m the texts of traditional systems or, the method of
preparation is different, it has to be treated as a new substance or
new chemical entity (NCE) and the same type of acute, subacute
and chrome toxic.ty data will have to be generated as required by
For the herbal remedies and medicinal plants that are to be
clinically evaluated for use in the Allopathic System and which may
'
the regulatory authority before it is cleared for clinical evaluation.
38
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3. An extract or a compound isolated from a plant which has never
been in use before and has not ever been mentioned in ancient
literature, should be treated as a new drug, and therefore, should
undergo all regulatory requirements before being evaluated
clinically.
literature of above-mentioned traditional systems ofMedicine, carries
out clinical evaluation of the plant without any concept or training in
these systems of medicine. Hence, it is necessary to associate a
specialist from these systems and the clinical evaluation should bz.
carried out jointly.
It is important that plants and herbal remedies currently in use
or mentioned in literature of recognised Traditional System of Medicine
is prepared strictly in the same way as described in the literature while
incorporating GMP norms for standardisation. It may not be necessary
to undertake phase I studies. However, it needs to be emphasised
that since the substance to be tested is already in use in Indian
Systems of Medicine or has been described in their texts, the need for
testing its toxicity in animals has been considerably reduced. Neither
would any toxicity study be needed for phase II trial unless there are
reports suggesting toxicity or when the herbal preparation is to be
used for more than 3 months. It should be necessary to undertake
4 - 6 weeks toxicity study in 2 species of animals in the circumstances
pointed out in the preceding sentence or when a larger multiccntric
phase III trial is subsequently planned based on results of phase II
study.
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Clinical trials with herbal preparations should be carried out
only after these have been standardised and markers identified to
ensure that the substances being evaluated arc always the same. The
recommendations made earlier regarding informed consent,
inducements for participation, information to be provided to the
subject, withdrawal from study and research involving children or
persons with diminished autonomy, all apply to trials on plant drugs
also. These trials have also got to be approved by the appropriate
scientific and ethical committees of the concerned Institutes. However,
it is essential that such clinical trials be carried out only when a
competent Ayurvedic, Siddha or Unani physician is a co-invcsligator
in such a clinical trial. It would neither ethically acceptable nor morally
justifiable, if an allopathic physician, based on references in ancient
When a Folklore medicine/Ethnomedicine is ready for
commercialization after it has been scientifically found to be effective,
then the legitimate rights/share of the Tribe or Community from whom
the knowledge was gathered should be taken care of appropriately
while applying for the Intellectual Property Rights and / Patents for
the product.
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41
STATEMENT OF SPECIFIC PRINCIPLES
FOR EPIDEMIOLOGICAL STUDIES
questions would pertain to interactions with individual subjects,
sources of funding or employer, fellow epidemiologist and the
society at large. Need for a code of ethics for epidemiologists is being
recognised globally and the issues for such a code in the context of
epidemiological research in India deserve attention.
INTRODUCTION
Epidemiology is defined as the study of the distribution and
determinants of health related states or events in specified populations
and the application of this study to control health problems.
Epidemiological studies are of primary importance in a large
developing country like ours where the natural historx. incidence,
prevalence and impact on morbidity and mortality of a variety of
diseases are not known. It has usually been considered that
epidemiology of infectious diseases is of prime importance in our
country. However, the evolving pattern of change in the society
with upward economic mobility and increasing number of middle
Epidemiological research differs from clinical research in the
context of the large number of study subjects and generally a long
time frame. If some mistakes or aberrations get delected during the
course of conduct of such studies, repealing the whole exercise will
be expensive, time consuming and may not even be feasible. Hence
utmost care needs to be taken for various aspects - technical, practical
and ethical.
DEFINITIONS
classes would mean that a significant number of life style related
diseases such as Ischaemic Heart Disease arc increasing. There is
Observational Epidemiology : This includes the following types
very little information about this and it would be uscfulto undertake
long term cohort studies in different population groups.
Epidemiological studies arc generally considered in two
categories - observational and experimental. Designs of these studies
are based on cross-sectional, case-control or cohort approaches.
Epidemiological studies cover research, programme evaluation and
surveillance. Scope of ethical guidelines for epidemiological studies
are concerned with epidemiological research. Ethics in epidemiological
studies is multidimensional covering clinical medicine, public health
and the social milieu.
Perhaps the code of ethics is much better understood for
. clinical research, where the interaction between a patient and a clinical
researcher is of supreme importance. In epidemiological research the
a.
Cross Sectional Studies (Surveys) : This is primarily
population based and involves selecting random samples of
the population to be rcprcscnlativc bitNcd on ccnwin data and
then applying questionnaires to understand the prevalence of
various diseases. Its aim is to assess aspects of the health
of a population or to test hypotheses about possible cause
of disease or suspected risk factors.
b.
Case Control Studies: This usually compares the past
history of exposure to risks among patients who have a
specified condition/discase (cases) with the past history of
exposure to this among persons who resemble the cases in
such respects as age, sex socioeconomic status, geographic
location, but who do not have the disease, (controls) Case
researcher is dealing with a group of individuals and the questions
faced by an epidemiologist are more of a professional nature. These
control studies can be done by following up available records,
usually records in a hospital, but in the context of a country
like ours it may require direct contact between research
42
43
1.
c.
workers and study subjects and informed consent to
participation in the study is necessary. However, if it entails
only a review of medical records, informed consent may not
be required and indeed may not be feasible.
that all individuals in an epidemiological research are treated alike
keeping in mind the rules of distributive justice. The welfl.
the individual has to be balanced against the welfare of the
community and society at large.
Cohort Studies: These are longitudinal or prospective
studies of a group of individuals with differing exposure levels
The C.I.O.M.S / W.H.O Guidelines for Epidemiological
Research assumes that the individuals or population being studied
to suspected risk factors. They arc observed over a long
period usually several years. The rate of occurrence of the
condition of interest is measured and compared in relation to
identified risk factors. It requires a study of large number of
subjects for a long time and involves asking questions, usually
routine medical examination and sometimes laboratory
investigations. Individuals are being followed up as the
arc capable ofgiving informed consent understanding the implications
of the study. With large segments of our population, given their level
of education, the full understanding in the sense of industrialised
countries may not be achievable. How the principle of “do no harm”
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is ensured under such circumstances without being paternalistic is a
major issue that has to be taken into consideration in ethical
guidelines.
cohort and it is essential to identify precisely every individual
to he studied.
Experimental Epidemiology:
In experimental epidemiology the investigators alter one or
more parameters under controlled conditions to study the effects
ol the intervention. These are usually randomised controlled trials
done to test a preventive or therapeutic regimen or the efficacy of a
diagnostic procedure. Although these are strictly speaking
epidemiological studies they conic under the purview of clinical
evaluation of drugs. devices / products / vaccines etc. The possibility
of use of placebo as one of the ami of the trial should be explained
and informed consent taken in such studies.
In cohon or survey techniques for incidence and prevalence
of various diseases, a major issue that has to be considered is
how much ofintenention is justified and whether one is justified in
withholding interventions. For example, if you are looking at
longitudinal morbidity in a population group, should you give them
health education that is well established with regard to preventive
aspects, or should you leave (hem alone so that the natural evolution
of the disease can be studied? I Icallh education or other interventions
including non-hcahh interventions can be quite expensive. An alternate
strategy that may be followed is to make curative therapy available to
the population at their own request. This usually involves running a
chmc, which is readily accessible to the population without any other
intervention. How ex er, it is generally considered unethical to withhold
intervention or sen ices.
GENERAL PRINCIPLES
General ethical principles of respect for persons, duty to
maximise possible benefits and minimise possible harm are important
considerations in ethical guidelines. At the same time it is essential
44
SPECIFIC PRINCIPLES
1.
Informed Consent: When individuals are to be the subject
of any epidemiological studies, the purpose and general
objectives ot the study has to be explained to them keeping in
45
mind their level of understanding. It needs to be ensured that
to consent. Such inducements are not permissible.
privacy will be maintained.
However, it is necessary to provide for adequate compensation
for loss of wages and travel / other expenses incurred for
participating in the study.
In the context of developing countries, obtaining
informed consent has been considered many times as difficult/
impractical / not meeting the purpose on various grounds such
as incompetence to comprehend the meaning or relevance of
the consent and culturally being dependent on the decision of
the head of the family or village /community head. I low ever,
there Is no alternative to obtaining individual's informed
consent but what should be the content of the informed consent
5.
All risks involved including the risk of loss of privacy must
be explained to the participants in an epidemiological study.
6.
The design of the study should ensure that the benefits of
the study are maximised for the individuals and communities
taking part in the study.This means that at the onset itself the
investigators should design the way in which the results of
the study are going to be communicated and also decide
whether individuals identified at particular risk during the
course of the studies would be informed. Il may also be
is also a crucial issue.
In spite of obtaining informed individual consent, it is
quite likely that the subjects / patients may not be fully aware
of their rights. In this context, the role of investigator is crucial
necessary in some instances to inform the concerned family
and he / she should remain vigilant'and conscious of his / her
members about the results. For example, as in AIDS. STD
obligations towards the subjects / patients, all through the
etc. It may not always be possible to communicate study results
to individuals but research findings and advise should be
publicized by appropriate available means. It is also important
that the beneficial results of epidemiological studies arc fed
into the health system and nccessary4raining modules should
be developed as part of the epidemiological project.
course of the studies.
2.,
In most epidemiological research it would be necessary to
have the consent of the community which can be done
through the Village Leaders, the Panchayat head, the tribal
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leaders etc.
7.
3.
In obtaining the consent of individuals or communities it is
important to keep in mind that working through peer groups
or through Panchayat etc. may mean that the individuals or
community would feel reluctant to disagree and refuse to give
consent because of societal pressures. This is something that
has to be carefully avoided.
4.
Particularly in a country like India, with the level of poverty
that is prevalent it is easy to use inducements, especially
financial inducements, to get individuals and communities
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8.
All attempts should be made to minimise harm to the
individuals and society at large. Special consideration for the
cultural characteristics of the communities that arc being
studied is essential to prevent any disturbance to cultural
sensitivities because of the investigation.
Maintaining confidentiality of epidemiological data is
absolutely essential. A particular concern is the fact that some
population based data may also have implications to issues
like national security and these need to be carefully evaluated
at the beginning.
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9.
In all situations where there is likely to be conflicts of interest
it must be ensured that the interest of the individuals involved
STA TEMENT OF SPECIFIC PRINCIPLES
FOR HUMAN GENETICS RESEARCH
in the study are protected at all cost.
10.
11.
Scientific objectivity should be maintained with honesty and
impartiality, both in the design and conduct of the study and
in presenting and interpreting findings. Selective withholding
INTRODUCTION
of data and similar practices are unethical.
In no other area of biomedical research there has been a greater
concern for ethical issues than in the field of human genetics. It has
largely stemmed from the movements of eugenics and nazism in
nineteen twenties and thirties. In recent years this concern has grown
even further because of the possibility of commercial eugenics. While
the advent of recombinant DNA technology has provided one of the
most powerful tools in the hands of mankind to unravel the mysteries
Ethical Review Procedures: In all Ethical Committees at
least one or two individuals with an understanding of the
principles of epidemiological ethics have to be included. These
Committees should be independent and comprise of
epidemiologists, clinicians, statisticians, social scientists,
philosophers, legal experts and representatives from
community / voluntary groups who should be aware of local,
social and cultural norms, as this is the most important social
II
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control mechanism.
12.
Distinction between re'search and programme evaluation:
It is difficult to make a distincti’on between epidemiological
research and programme evaluation. Whenever a programme
evaluation and surveillance is launched, the monitoring and
evaluating mechanisms should clearly be planned and ethically
cleared before initiation as is done in all epidemiological studies.
!
of the human genome, it has also led to a great deal of concern about
our ability to handle the information so derived. With the successful
completion of Human Genome sequencing in June 2000 there is an
urgent need for clear-cut guidelines and dissemination of information
to all stakeholders through media and public debates as there is a
great need for improving awareness and understanding of human
genetic disorders amongst public, the majority of whom have little
knowledge of genetics.
The knowledge about human genes and genetic diseases prior
to fifties was so poor that there was hardly any human genetic,
experimentation. Since then, and especially in the past two decades,
there has been a veritable explosion in knowledge in the field of human
genetics which has culminated in gene therapy (the ultimate in therapy
for genetic diseases) and various other therapies based on genetic
engineering including the glib talk of ‘ Designer babies’. Serious issues
related to participation of human subjects in genetic research arc raised
particularly when the intervention involves rights of human embryo
and subjects who are not competent to give informed consent. Besides
the Human Rights issues of dignity, autonomy, and justice, the Human
Genome Project (HGP) has also precipitated an unprecedented concern
for Intellectual Property Rights. Recent experiments on cloning sheep
and mice have brought human cloning into the realm of possibility,
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raising additional set of Ethical, Legal and Social Issues (ELSI). This
caljs for laying down of special guidelines to contain the potential^
harm without clamping a moratorium on research and service in this
field. Also, there should be no restrictions in availing the gains of
latest technology, which arc beneficial to the mankind. In fact ensuring
access to genetic services to all irrespective of their ability to pay,
particularly to those who need it the most, is an equally important
understandable to layman about presentation and natural
course of the disease, interventions available and their outcome,
as also implication of the information for progeny and family,
has special place in clinical research in this field.
(iii)
Genetic counscUing deals with discussion on personal matters
such as reproductive options, and the couple may have to make
a choice with far reaching social implications. Therefore, it
calls for special care that should be documented in research
moral concern.
proposals and carefully considered by the Institutional Ethics
Committee.
In this rapidly evolving field there is a need for a watchdog
body to continuously monitor such developments and respond to
emerging ethical issues promptly and judiciously.
(iv)
Genetic manipulations have consequences for the future, some
of which are unknown. Hence, greater care towards potential
GENERAL GUIDELINES
Clinical research in fields of human genetics and human
genome, including gene therapy, besides being subject to general ethical
considerations of protection from harm and voluntariness of
participation has following additional considerations : -
(i)
The harm may not only be physical, but also psychosocial.
Psychologically, the genetic information may produce anxiety
and depression or damage familial relationship, which should
be safeguarded. Appropriate communication skills arc
necessary' for genetic counselling. There is a likelihood of social
stigmatisation and discrimination in schooling, employment,
health and general insurance, which requires much greater care
in recruiting subjects in research study, obtaining infonned
consent and maintaining confidentiality of research findings,
than in any other area of research.
dangers is necessary.
(V)
There is greater likelihood of situations cropping up where
there is conflict of interest between an individual, and.that of
family and society at large. Careful guidelines need to be
evolved by peers in the profession to tackle such situations.
The professional societies should actively participate in these
activities.
(vi)
1 he science of Medical Genetics is progressing very rapidly.
Therefore, there is a need for frequent updating of any
guidelines for research in this field. To meet this challenge
not only the guidelines should be flexible, but there should
also be a built-fn mechanism to review the guidelines from
time to time.
,
(vii) . The Institutional Ethical Committees reviewing research
proposals related to research on human genetics should have
(ii)
There is great importance of spoken word in medical genetics,
since genetic counselling is akin to therapy in other fields. In
that sense in medical genetics, the ‘word’ is equivalent to drug/
intervention in other fields ofniedicine. Written explanation
50
necessary expertise, which includes knowledge of latest
developments in the field of human genetics. In areas of doubt,
open discussion should be encouraged. This has to be the
51
Subject recruitment
responsibility of National agencies e.g. Central Ethical
Committee (ICMR) and / or National Bioethics Committee
(DBT) to organize national debates on such issues to evolve
consensus on them.
(viii)
I
Concerned with the misuse of genetic tests, particularly for
the pre-selection of sex, the Government of India has enacted
a law known as “The Prenatal Diagnostic Techniques
(Regulation & Prevention of Misuse) Act 1994”. All
researchers in this area shall follow the provisions of this act
(and such other acts which may be passed in future).
The familial nature of research cohorts involved in pedigree
studies can pose a challenge for ensuring that recruitment procedures
are free erf elements that unduly influence decision to participate. The
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PEDIGREE STUDIES
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These involve obtaining history of other members of the family
of the proband under investigation. It may reveal information about
the likelihood of individual members of the family being either carriers
of genetic defects or being affected by the disease.
Special privacy and confidentiality concerns arise in genetic
family studies because of relationship between the participants. It
should be kept in mind that within families each person is an individual
who has the right to keep the information about himself or herself
confidential. Family members arc not entitled to know each other’s
(ii)
Revealing who else in the family has agreed to participate may
lead to breach ofconfidentiality.
If a proband is used for revealing his personal interest he/she
(iii)
may put undue pressure on relatives to enroll in the study.
Direct recruitment by telephone calls etc. may be seen as an
invasion of privacy by family members.
(iv)
Contact through personal physicians may imply that their health
care may get compromised if they do not agree to participate.
i
There is no satisfactory alternative, which can be
recommended. The likely problems arc listed, so that appropriate
caution may be exercised.
Informed consent
diagnosis. Before revealing medical or personal information about
individuals to other family members, investigator must obtain consent
of the individual to do so. In view of the cultural background of our
For biogenetic research involving human subjects certain
special considerations have to be kept in mind while obtaining informed
country where woman is still a vulnerable and exploited subject,
consent of the prospective subjects enrolled in the study. These are in
revealing information to the husband that his wife is the carrier of
balanced chromosomal translocation (leading to recurrent abortions
addition to general principles that are applicable to all medical research.
or a genetic syndrome in her child) or that she is a carrier of a single
gene causing ‘X’ linked or recessive disease, may lead to grounds for
a divorce despite the fact that the husband himself is a carrier of the
autosomal recessix e disorder. While general principles of counseling
require presence of both the spouses, necessary care must be taken
not to end up in breaking the families.
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(i)
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very nature of research exerts pressure on family members to take
part, because more complete the pedigree, the more reliable the
resulting information. Problems of the following kind could arise:
Confidentiality of data
This includes codification of the biological samples, where
necessary. The investigator must establish secure safeguards for the
confidentiality of the research data. Subjects should be told of the
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Adequate counseling should be given to subjects on the
limits of the investigator’s ability to safeguard confidentiality and
of the anticipated consequences of breach of confidentiality. When
commercial companies, are involved in research, it is necessary to
protect researchers and subjects from possible coercion/inducement
meaning of genetic information they receive. Only those persons
who are quaiified and experienced in communicating the meaning
of genetic information should undertake genetic counseling.
to participate in the study.
IL
Academic institutions conducting research in alliance with
industries / commercial companies require a strong review to probe
possible conflicts of interest between scientific responsibilities of
researchers and business interests (c.g. ownership or part-ownership
Genetic screening implies search in population of individuals
who have, or arc susceptible to have a serious genetic disease; or
who, though not at risk themselves, are carriers and thus at risk of
having children with the particular genetic disease.
of the investigator in the company developing a new product). In
cases where the Ethics Committee determines that a conflict of interest •
may damage the scientific integrity of a project or cause harm to
research participants, it should advise accordingly. Institutions need
self-regulatory processes to monitor, prevent and resolve such conflicts
of interest.
Prospective participants in research should also be
J informed of the sponsorship of research, so that they can be aware
of the potential for conflicts of interest and commercial aspects of the
research.
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Undue inducement through compensation for individual
participants, families and populations should be prohibited. This
prohibition, how ever, docs not include agreements with individuals,
families, groups, communities or populations that foresee technology
transfer, local training, joint ventures, provision of health care or
of information infrastructure, reimbursement costs of travel and loss
of wages and the possible use of a percentage of any royalties for
It is essential that screening must be purposive. Also, besides
validation of screening tests, it shall also be ensured that a suitable
intervention is possible. Rarely, screening may be permissible to
allay anxiety, but it should not be forgotten that response of different
individuals may vary. It should not entirely be a matter of individual’s
choice, but should be determined after careful evaluation by the health
care provider. Depending on nature of the genetic defect that is
identified and‘its pattern of inheritance, siblings and other blood
rclutions ns well ns existing and future offsprings may be affected.
This raises ethical questions that diffcr significantly, from the normal
lules and standards applied to handling of personal medical records.
•
humanitarian puq?oscs.
Defining risks and benefits
Potential risks and benefits should be discussed thoroughly
with prospective subjects. In genetic research, the primary the risks
GENE TIC'SCREENING
•
A well informed consent is, therefore, essential. Those being
screened are entitled to receive sufficient information in a way
that
i.
they can understand what is proposed to be done.
ii.
they must be made aware of any substantial risk.
iii.
they must be given time to decide whether or not they
would like to participate or withdraw from screening.
Details about the disorder to be screened and its inheritance pattern,
reliability of the screening test and what will be done with the
are psychosocial rather than physical.
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samples should be explained. Information about the implications
of a positive screening test (abnormal) should also be explained.
•
Confidentiality should be maintained in handling of results with
emphasis on responsibility of individuals with a positive (abnormal)
result to inform partners and family members. It needs to be
emphasized that co/hsent for screening or a subsequent
confirmatory test does not imply consent to any specific treatment
or termination of the pregnancy.
•
General guidelines have to be followed for a vulnerable individual
i.e. minors, mentally ill, prisoners, students, subordinates and
people who do not speak the language of the investigator etc.
•
Genetic counseling should be readily available for those who are
being screened. Law protects confidentiality of medical
information, but this is not absolute. Information may be disclosed
where it is in the public interest to do so, or if required by the
court of law. However, great care is needed in this regard as well.
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Anonymous testing: Researchers may conduct anonymous testing
on general population in order to establish prevalence of genetic traits
diseases. Blood spots collected for screening newborns for treatable
disorders could also be used for this purpose. In case information
derived from stored specimens might be useful to an individual, the
code ofanonymity may be broken with the approval of the Institutional
Ethics Committee (IEC).
III.
Recombinant protein products
Genetic disorders, which require replacement therapy like
ADA deficiency, do not pose any ethical problem. Replacement with
animal products should follow the rules as stipulated for other diseases.
Screening new borns : Screening of new boms is permissible to
detect those genetic diseases like phenylketonuria where serious effects
of the disease could be prevented by a suitable intervention such as
special diet or treatment. It should not be done when there is no
immediate cure / intervention for diseases manifesting later in life.
The same applies to investigations to detect genetic, chromosomal,
metabolic abnormalities, etc. The diseases can be screened as and
when intervention/therapy becomes available in future.
Gene Tlicrnpy .
The goal of human genetic research is to alleviate human
suffering. Gene therapy is a proper and logical part of this effort.
Gene therapy should be subject to all the ethical codes that apply to
research invoh ing patients.
i)
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Prenatal testing: It is aimed at detecting presence of abnormalities
in the foetus. The foetal sample for examination may be obtained
through amniocentesis, chorionic \ illi sampling, placentocentesis,
cordoccntesis (blood sampling from the umbilical cord) and skin or
other biopsies. Foetal cells in maternal circulation can also be used
for prenatal testing. Non-invasive methods should be preferred
whenever available.
THERAPEUTIC TRIALS INCLUDING GENE
THERAPY
Somatic cell gene therapy is the only method that may be
permissible for the purpose of preventing or treating a serious
disease when it is the only therapeutic option. Il should be
restricted to alleviation of life threatening or seriously disabling
genetic disease in individual patients and should not be
permitted to change normal human traits. However, rapid
advance in science necessitates periodic review of guidelines
in this area. This includes evaluation of safety and efficacy of
DNA vaccines and transgenic foods as well.
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Gene Therapy trial consists of two parts. The first
part is preparation of the ‘gene construct’ to be administered,
and the second part is evaluation of the efficacy and safety of
the administered ‘gene (construct)’. As far as the first part is
concerned, the guidelines and clearance for it is to be regulated
by the National Bioethics Committee under Department of
Biotechnology (DBT) and for the second part clearance from
the local IEC and Central Ethical Committee (CEC) of the
ICMR. shall he obtained.
Safety should be ensured especially because of the
possibility of unpredicted consequences of gene insertion. All
gene therapy trials should have the provision for long term
surveillance. Informed consent must be taken especially
regarding uncertainties about outcome. Children could be
candidates for therapy, if the therapy is meant for a childhood
disorder.
ii)
Germ Line Therapy is prohibited under the present state of
knowledge in these areas.
Hi)
A-'
Gene Therapy for enhancement of genetic characteristics
(so called designer babies) should not be attempted, as wc
possess insufficient information at present to understand the
effects of attempts to altcr/cnhancc the genetic machinery' of
humans. Also, the influence of environmental interaction on
the expression of genetic characters is poorly understood.
It is not safe or ethical for parents to give, for example,
growth hormone to their normal offspring in order to produce
very large football or basketball players. Similarly it would be
unethical to use genetic engineering for improvement of
intelligence, memory etc. even if specific gene/genes are
identified in future.
iv)
intelligence and physical, mental and emotional characteristics
is prohibited.
IV.
HUMAN. GENOME PROJECT (HOP)
The human genome project (HGP) is an international research
effort, the goal of which was to determine the location of estimated
40 - 1,00,000 genes and to sequence the entire human DNA. Another
component of the programme is to analyze the DNA of a set of non
human model organisms, which may contribute to understanding of
the human genome. The project began formally in 1990 and has been
completed by June 2000. This project has resulted in exploring the
potential for profoundly altering our approach to medical care from
treatment of advanced disease to prevention, based on the identification
of individuals at risk, and designing it specific to targets / individuals.
Implications of using this genetic knowledge pose a number
of questions for:
i.
individuals and families - whether to participate in testing, with
whom to share the results, and how to act on them;
ii. health professionals - when to offer testing, how to ensure its
quality, how to interpret the results and to whom to disclose
infonnation;
iii. employers, insurers, the courts and other social institutions - the
relative value of genetic information to the decision they must
make about individuals;
iv. governments - about how to regulate the production, and use of
genetic tests and the information they provide and how to provide
Eugenic Genetic Engineering for selection against
personality, character, formation of body organs, fertility,
58
access to testing and counselling services for society; and
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the society-how to improve public understanding of science and
its social implications and increase participation of the public in
v
science policy making.
The above questions should be addressed to by the scientific
community before application of this knowledge cou|d be considered
as ethically valid.
Primary use:
Primarv use is the use for original intent for which consent
and approval of Local IEC has been obtained. It is recommended
that normally the use of the samples shall be reserved for this purpose
Pre-morbid diagnosis in adults: It may be carried out with informed
consent. However, appropriate genetic counseling must be provided
and documented before offering such services,
dna banking
only.
DNA diagnosis in forensics : The laboratories carrying out DNA
diagnosis in forensics should follow the guidelines evolved by National
Accreditation Board for Laborntorica functioning under the
Department of Science and Technology.
Secondary Use:
Every request for secondary use shall be examined by the
Institutional Ethical Committee:
i.
ii.
iii.
to ensure that the proposed use does not transgress the original
consen’ given for the earlier study;
the validity of the objectives of the new study; and
provisions for ensuring anonymity of the samples for secondary
use.
VI.
DNA DIAGNOSIS
The general principles of informed consent, confidentiality and
other criteria used for any investigation in genetics should be followed.
This includes any fertilization involving manipulation of
gametes outside the human body and the transfer of gametes or
embryos into the body.
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The consequences of DNA testing for conditions for which
no treatment is available or for conditions manifesting late in life e.g.
breast cancer, Alzheimer’s disease etc. should be seriously considered
before embarking on such studies. Information so derived should not
disclose the’identity of the individuals.
VII. ASSISTED REPRODUCTIVE TECHNIQUES
I;
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Pre-implantation DNA diagnosis : It is a type of prenatal diagnosis.
Same precautions and safeguards should be adopted for this purpose
also.
Pre-morbid diagnosis in children : Parents are advised not to get
the diagnosis done especially in cases like Huntington’s disease etc.
for which there is no available intervention till the child reaches the
age of proper “consent”
V.
I
Since the knowledge in this field is new, and relatively complicated, a
DNA test must be preceeded and followed by appropriate genetic
counselling.
•
Informed consent should include information regarding use of spare
Cloning (through nuclear transplantation or embryo splitting) :
.
The possibility of human cloning cannot be rejected since sheep and
mice have already been cloned. However, since its safety, success,
utility and ethical acceptability is not yet established, research on
cloning with intent to produce an identical human being, as of today,
embryos. It should be made clear whether embryos that are not
used for transfer could or could not be used for research purposes
or implanted in another woman’s womb, or “preserved “ for use
at a later date or destroyed. Investigators should ensure that
participants are informed and consent is taken in writing on the
•
•
is prohibited.
above issues.
Investigators should clarify the ownership of the embryos that
they belong to the biological mother or the laboratory. Abortions
. 17//. PRENATAL DIAGNOSIS
This should be performed only for reasons relevant to the health
of the foetus or the mother. Prenatal diagnosis should not be performed
solely to select the sex of the child (in the absence of an X-linked
disorder). Sex selection, whether for male or female, denigrates the
fundamental personhood of those yet to be bom. and has the power
to harm societies by unbalancing sex ratios. The potential harm to
large groups of people outweighs any immediate benefits to individuals
or families. The Government of India has already passed legislation
banning diagnosis of sex for non-medieal reasons.
should never be encouraged for research purposes.
There is no ethical objection at the moment for IVF or any other
related procedure for research or for clinical application.
Respect for embryo can be shown by (1) accepting limits on
what can be done in embryo research, (2) committing to an inter
disciplinary process of peer group review of planned research, and
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(3) carrying out an informed consent process for gamete and embryo
donors. Further, respect for the embryo’s moral status can be shown
by careful regulation of conditions of research, safeguards against
commercial exploitation of embryo research, and limiting the time
within which research can be done to 14 days i.c. when the primitive
streak appears. This restriction is in keeping with the policy in several
nations that permit research with embryos. At this time, the
development of nervous system begins and the embryo begins to
Prenatal diagnosis can be used to prepare parents for the birth
of a child with a disability. Therefore, prenatal diagnosis should be
available to.such parents who request it but oppose aboil ion, provided
that they understand and arc willing to accept the risks to the foetus.
become a distinct individual.
In some eases, prenatal diagnosis may be performed to protect
the health of the mother. These include clinically confirmed eases of
morbid anxiety or situations where prenatal paternity testing would
benefit the mother's mental health (c.g. i f rape occurred while a couple
was trying to conceive).
Women have a special position as care givers for children with
disabilities. Since the bulk of care falls upon the women, she should
make the final decision among reproductive options, without coercion
from her partner, her doctor, or the law. Choice is more than the
absence of legal prohibition or coercion. Choice should include the
economic and social ability to act upon a decision, including disability.
There should be a positive right to affordable genetic services, safe
abortion and medically indicated care for children with disabilities.
Professionals should recognize the human and economic costs
involved in prenatal diagnosis and should limit its use to situations
where there is a clear benefit.
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impact of the information desired shall be explained to the
participants.
iv)
The analysis of DNA samples shall be carried out by Indian
scientists / laboratories. No sample shall be sent out without
following the guidelines of the Government of India (GOI) in
this regard. In the event of failure of agreement the guidelines
of the country (India) shall prevail. International collaboration,
if any, shall be carried out with well-documented MOU, which
is approved by the Institutional Ethical Committee. This should
include the scope of utilization of exchanged material and
related 1PR issues, as well as concerns for human rights.
Scientists involved in these studies shall ensure that rights and
sensitivities of the participating individuals and populations are
protected. Relevant issues like (a) consent for collection of samples,
(b) access to these samples and for what purposes, (c) Property rights
of the DNA; and (d) quality control of the laboratories shall be
appropriately documented in the research proposal for scrutiny by
the Institutional Ethical Committees.
A major concern regarding these studies is the possibility that
generated information may produce ethnic disharmony. Therefore,
great care is necessary for handling of this data, particularly, in reference
to release of news to media and publication of research results.
STA TEMENT OF SPECIFIC PRINCIPLES
FOR RESEARCH IN TRANSPLANTATION
INCLUDING FETAL TISSUE
TRANSPLANTA TION
INTRODUCTION'
The practice of transplantation is in its infancy in India. The
exceedingly high cost restricts its application, and also reduces the
interest in research into this field. The same reason makes it imperative
that Indian scientists should devise means of reducing the cost and
improving the success rate, to make it feasible to increase the number
of Indians who can benefit by this treatment.
At present the protocols dc\ ised in the West are followed which
are not necessarily ideal. The ethical principles of research in human
subjects have been well enunciated in the Declaration of Helsinki
adopted by the World Medical Association in 1964, and amended in
1975, 1983, 1989 and 1996. Transplantation, however, raises some
peculiar aspects, and these will have to be weighed in that light. The
problem has been considered with special reference to the following
points:I.
II.
in.
IV.
Transplants from live or cadaver donors
Embryonic and foetal tissue and organ transplantation
Xeno-transplantation
Transplantation for cosmetic purposes.
I. TRANSPLANTS FROM LIVE OR CADAVER
DONORS
DEFINITIONS
Cadaver: A dead body. For purposes of this document, the term
refers to a dead human body.
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annexure
up approximately 10% of the DNA. The total informational content
Mutation : A process by which the DNA of an organism changes or
mutates. In humans this can lead to disease such as thalassemia in
which the mutatiqh results in decreased production of beta or alpha
globin. The. mutant gene is passed on from parent to the offspring, so
the condition is inherited. In viruses and other infectious organisms,
mutations can lead to emergence of organisms with new characteristics.
It can make them more virulent or resistant to antibiotics thus
of an individual is known as ‘genome’.
increasing their infectivity.
definitions
Genetic material / genome : Genetic material refers to DNA or any
other material carrying hereditary information in each cell of an
organism. It consists of unique, single copies of genes, vt/hich make
Chromosome: The thread-like DNA in a cell is divided into several
Recombination : A cross-over between two members of a
homologous pair of chromosomes results in the formation of a
recombined chromosome wherein a new set of gene (allele)
arrangement is created.
separate lengths. Each length forms a structure called a chromosome.
There arc two copies of each chromosome in every cell. Human cells
contain 23 pairs of chromosomes.
Gene: A gene is a length of DNA that contains the information needed
to make one polypeptide. For example, the beta globin gene contains
the information needed to make the beta globin polypeptide found in
Transgencsis : This refers to the introduction of a foreign gene into
an animal or other organism. The transferred gene is called a
transgene.
hemoglobin of red blood cells. More than one gene may be involved
in making one protein, and more than one polypeptide may be formed
HUMAN GENOME DIVERSITY
from one gene as a result of alternate splicing. -
Department of Biotechnology, Government of India has
brought out a document on genomic diversity which envisages the
following:-
Genetic Engineering : It is the process of creating new DNA such
as by cutting and patching (recombinant DNA technology). Several
other technologies such as site directed mutagenesis, vector mediated
integration or deletion of DNA etc. have evolved and arc continuing
i)
There is worldwide interest in the study of genomic diversity
of anthropologically well-defined populations for
understanding the origin of people which has evolutionary
implications.
ii)
This may require establishment of national repository of
biological samples (DNA, cell lines etc.) but it should be done
with appropriate safeguards and regulations to ensure
to evolve.
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Ilctcrozygote : Each cell of an organism contains two copies of each
ucne. In a heterozygote, the two genes of a pair are different from
each other (allelic).
anonymity of the sample ( the identity of the sample should
not be no traceable) and protection of the rights of the people.
llomozygote : Each cell of an organism contains two copies of each
gene. In a homozygote, both copies of the gene are identical to each
iii)
other.
(■
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It shall be ensured that participation in these studies is entirely
voluntary, and no coercion or inducement is employed for the
purpose. The intent for collection of these samples and possible
i!*
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Death: This was originally defined as entire and continuous
cessation of respiration andcirculation.lt has since been recognise
that the heart could continue beating for a time, even for days, though
the brain lacked the ability to maintain respiration and sustain life.
Death of the brain stem, also called brain death, has since been
recognised internationally, and in the ‘Indian Transplantation of
Human Organs Act’, 1994.
Brain death: This is as specified in ‘Transplantation of Human
Organs Act, 1994’ with ‘ Transplantation of Human Organs Rules,
1995’. Salient features arc described below:• Entire, permanent, and irreversible cessation of functions of the
brainstem-this is synonymous with brain-stem death, since the
centres for the control of essential body functions such as
consciousness, respiration, and blood pressure are situated within
the brain stem. In many countries strict criteria for diagnosis of
brain death have been established. These include the presence of
deep coma, the absence of any brain-stem functions such as
spontaneous respiration, pupillary reactions, eye movements,
gag and cough reflexes, and the exclusion of low body
temperature and drugs as relevant to the comatose state. The
EEG is a useful (but not essential) confirmatory test. Brain death is
when ‘Damage is judged irremediable’ based on its context, the
passage of time, and the failure of all attempts to remedy it.
Secondly, all possible causes of reversible brain-stem dysfunction,
such as hypothermia, drug intoxication, or severe metabolic
upset, must be excluded. Finally, the absence of all brain-stem
rcHexcs must be demonstrated, and the fact that the patient cannot
breathe, however strong the stimulus, must be confirmed.
When testing the brain-stem reflexes, the following normal
responses must be looked for: (1) constriction of the pupils in
response to light. (2) blinking in response to stimulation of the
cornea, (3) grimacing in response to firm pressure applied just
above the eye socket, (4) movements of the eyes in response to
the ears being flushed with ice water, and (5) coughing or
gagging in response to a suction catheter being passed down the
airway. All responses have to be absent on at least two occasions
with an inten al of six hours between them. Apnoea, which also
must be confirmed twice, is assessed by disconnecting the patient
from the’ventilator, (prior to this test, the patient is fully
oxygenated by administering 100% oxygen for several minutes to
ensure that the patient will not suffer serious oxygen deprivation
while being disconnected from the ventilator). The purpose of
this test is to establish the total absence of any inspiratory effort
as the carbon dioxide concentration in the blood (the normal
stimulus to breathing) reaches more than sufficient levels to
stimulate any respiratory centre cells that may still be alive.
GUIDELINES ON LIVE DONOR TRANSPLANTS
1. Donation from a live donor should be restricted to renewable
tissues like bone marrow, or to a paired organ whose removal will
not greatly alter physiological functions, like the kidney. Since
the removal of an eye will compromise binocular vision and
produce disfigurement, it should not be permitted in a live donor.
2. Surgery on the donor inflicts bodily harm on him or her, the
extenuating circumstances being the saving of another human
life. It is imperative that no risk be imposed on the donor beyond
that inherent in surgery and the loss of a vital organ. Any manner
of experimentation, though it may be intended to improve the
survival of the grail, should be prohibited if there is the slightest
extra risk to the donor. Examples arc pre-treatment of the
donor with immuno-suppressives or anticoagulants.
3. Every such research project should be preceded by careful
assessment of predictable risks and compared to foreseeable
benefits and improvement in the success rate of transplantation.
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4. The interests of the donor should always take priority over those
of the recipient of the transplant.
should be taken and adequate facilities should be available to
protect the donor from the most remote possibility of harm.
5. In view of the risk involved, the voluntary consent of the donor is
absolutely essential. Further, the donor should be informed of all
possible risks in a manner easily understood by the subject before
the consent is taken.
11. The donor should be at liberty to withdraw from the
experiment and to abrogate the consent given earlier, with no
requirement to offer any explanation of the reasons for his or her
doing so.
6. ftIl follows that the donor should have the legal capacity to give
consent and be in a position to exercise free power of choice
without the slightest element of force, duress, or coercion, and
should have sufficient knowledge and comprehension of the subject
to be able to make a decision with full understanding of the
consequences. Children and mentally incompetent adults as also
individuals with restricted autonomy should not be used as organ
donors or as subjects for such experiments.
12, If at any lime during the course of the experiment the investigator
comes to know that there is risk to the donor or to the recipient
as a result of the procedure, it is his or her responsibility to
terminate the experiment forthwith.
7. Since the experiment would have consequences for the recipient
too, the donor must be fully infonned of the nature of the
procedures and the possible effects on the recipient before consent
is taken.
8. The responsibility of providing the above infonnation to the donor,
and of making sure that he / she understands fully the implications
of what is to be done and what he or she consents to, rests
entirely on the individual who directs the research project.
9. The experiment should be such as to yield fruitful results for the
overall good of the donee without any risk to the life of the donor.
The experiment should be undertaken only if there is no other
method available of finding the answer to the question raised.
10. The experiment should be so planned and conducted as to avoid
all unnecessary risks to the donor, to the organ to be
transplanted, and to the recipient of the organ. Proper precautions
70
13. This does not preclude any treatment or procedure done on the
organ or tissue after removal from the donor's body, aimed at
reducing its antigenicity and improving graft survival.
Creation of human beings for transplantation purposes should
he banned.
GUIDELINES ON CADA VER DONOR TRANSPLANTS
1. Every one should give a thought to the need for organ donation
aflcr death. In such an event one should make a decision and
inform the next of kin, and register oneself with an appropriately
constituted authority. Where one is opposed to donating his or
her organs, this too, should be made known to the next of kin, so
that this wish ofthedeceasedmayberespectedaflerdeath. Such
a “Living Will” is in vogue in a number of countries in the world.
2. In the absence of such prior directions from the deceased, the
person in lawful possession of the body will make the decision to
use the organs or not, as he may think fit, after consultation with
the family.
71
<
3. It is important that the medical team uses the body only for the
purpose for which consent has been given.
<
4. Remaining tissue and organs should be treated with the respect
due to a human body, and will not be used for any purpose to
which explicit consent had not been given.
3.
The transplant research team should have high technical
expertise.
5. Under no circumstances should financial gain be made from any
such procedure.
4.
Adequate data management, tissue storage facilities, and
surveillance procedures should be available in a centre before
it is authorised to conduct research into transplantation.
5.
If, at any time, a patient should refuse to take part as a subject
for a research project, it should in no way interfere with
his or her right to receive treatment of the best quality, which
the team is capable of providing.
6.
Under no circumstances should there be a conflict between
scicnti fie content of a study and the best interests of the patient.
Should there be need to choose, the experiment should be
abandoned and the patient should receive the best treatment
possible.
II.
EMBRYONIC AND FOETAL TISSUE AND
ORGAN TRANSPLANTATION
4
4
4
(
I
protocol for transplantation should be carefully reviewed by
an appropriate committee of suitably qualified scientists,
jurists and other eminent members of society, so that its
scientific and ethical basis may be impartially evaluated.
6. There shall be no coercion and no monetary inducements offered
to the family of the prospective cadaver donor.
7. Confidentiality of the donation must be maintained on both sides:
the recipient and his or her family will not be informed of the
identity of the donor, and the family of the donor will equally be
kept unaware of who receives the donated organ. This is
essential to avoid any form of exploitation by the donor s family.
GUIDELINES ON RECIPIENTS OF TRANSPLANTS
1.
2.
The patient with failure of a vital organ is at a particular
disadvantage in developing countries due to the enormous
cost involved for the available interventions. If the organs
involved arc the kidneys, most Indians cannot afford
to maintain themselves oh dialysis. Similarly ventilators arc
available at very few centres. There are no artificial supports
for other organs like the heart, the lungs and the liver, so
death is imminent and no means is available to keep
the individual alive short of replacing the organ concerned.
Thus a measure of urgency is introduced into the search for a
donor organ.
A desperate patient may consent to procedures which put him
or her at risk. It is all the more important that every research
INTRODUCTION
Human foetal tissue has been used in research for a wide
range of purposes over decades. The thought of using foetal cells as
transplants was first occasioned when scientists attempted to find
ways of treating patients with loss of nene cells in the brain and
spinal cord. Since damaged nerve cells do not regenerate, repair
to damage in the brain and spinal cord is severely limited. Attempts to
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WWon^ieuroriesinto repair and re-growth have yet to bear fruit.
That was when the attempts to transplant healthy neural tissue into
damaged areas of the brain were started in an effort to allow the re
establishment of damaged neural circuits. The immunological
complications that result, whenever any foreign tissue is transplanted
into a human, proved a barrier.
The use of foetal tissue is one of the means to minimise the
chances of rejection. In the early vVecks after conception, foetal cells
multiply rapidly and show very little antigenicity because many surface
antigens would not yet have developed. These cells are not fully
differentiated and adapt easily to the signals received from surrounding
tissue in a host. They grow and differentiate in such a manner that
they are integrated to form part of the host organ. Foetal cells can
also be successfully presented by cooling and be reanimated. As the
technology for developing immortal foetal cell lines for study of gene
regulation, pattern formation in embryogenesis, as models of cell
interaction and function, for vaccine development and study on cell
growth and regulation, cancer and immune response was perfected,
hopes for the use of these cells as transplants strengthened.
Non-ncural foetal tissue transplantation has included
injection of immune cells from the thymus and liver of aborted
foetuses into the umbilicus of a 30 week old foetus with bare
lymphocyte syndrome, a rare and always fatal immuno-dcficiency
disorder. Success has also been reported on the use of foetal thymus
in the reconstitution of a severe combined immuno-deficient (SCID)
child in Italy who survived 17 years exhibiting normal immune
responses even though his T cells were of foetal donor origin. Other
potential uses of foetal tissue include treatment of diabetes, genetic
retinal abnormalities, optic nerve and spinal cord injury, Alzheimer’s
disease, aplastic anaemia, acute leukaemia / lymphoma and liver
failure.
74
DEFINITIONS
Embryonic state: Between 15 days and 8 weeks posbconception of
a pregnancy. In the absence of more precise infonnation (i.e.
menstrual cycle length), conception is presumed to have taken place
two weeks after thebeginning of the woman’s last menstrual
period. The distinction of the 15-day stage as the beginning of the
embryonic stage is not arbitrary: the pre-embryo is not isomorphic
with the later developmental stages, since cells cannot yet be defined
as contributing to the embryo or to the extra-embryonic tissue, and
complete implantation has not yet been accomplished. Al 8 weeks,
the rudiments of nearly all the main structures have been laid dow n
giving a general appearance of a mammal-lo-bc with four limbs and
a head.
Foetal stage: Subsequent period between 8 weeks and the lime the
baby is bom, at approximately 38 weeks post-conception (40 weeks
post-last menstrual period).
(a)
(b)
Live aborted foetus : If an aborted foetus is alive, it is a person,
no matter how short the period of gestation, and using it for an
experiment would, in law, be considered un assault upon it,
Dead foetus : An expelled or delivered foetus that exhibits
no heart beat or spontaneous breathing. Some organs, tissue
and cells remain alive for varying periods after the moment of
death of the foetus.
Neonate stage : Newly bom live individual of any gestation period.
GUIDELINES FOR RESEARCH ON FOETAL TISSUE
OR ORGANS FOR TRANSPLANTATION
1.
Every transplantation or research project involving the use
of embryonic or foetal tissue must be approved by the local
75
scientific and ethics committees and referred to National or
Central Ethical Committee for final approval.
2.
3.
i
4.
The researcher shall not be a party to deliberate conception
and / or subsequent abortion for the sake of obtaining tissue
or organ for research or saving the life of a family member or
for the purpose of commercialisation.
No research is permitted on the live aborted foetus.
5.
Tissue for transplantation or research may be obtained from
dead embryos or foetuses, their death resulting from legally
induced or spontaneous abortion. Death of an intact embryo
or foetus is defined as absence of respiration and heart beat.
6.
Voluntary, infonned, written consent will bc’oblaincd from
the mother in two stages-first for the abortion, next for (he
donation of tissue from the foetus. The mother’s decision
to donate foetal tissue is sufficient for the use of the tissue
unless the father objects in writing. In cases of incest or rape,
the lather's objection carries no significance.
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All members of the hospital or research staff - medical and
paramedical -directly involved in any of the procedureswill
be fully informed of the purpose and implications of the
research project.
7.
The mother will not dictate who shall receive the foetal tissue
taken for transplantation.
8.
Anonymity of donor and recipient will be maintained so that
neither party is aware of the identity of the other.
9.
The procedure of abortion, or its timing, will not be
iniluenced by the requirements of the transplantation
activity. These should solely be based on concern
safety of the mother.
the
10.
Those participating in termination of pregnancy will not, in
any way, be party to the subsequent usage of embryonic or
foetal tissue for commercial purposes.
11.
The procurement of embryos, foetuses or their tissue for
commercial purposes will not involve profit or remuneration.
12.
Intact embryos or foetuses will not be kept alive
artificially for the purpose of removing usable material.
13.
Tissues from aborted foetus can be cultured and banked
for use in research on transplantation. If such stored tissue is
to be subsequently used for any purpose other than the original
objective, a fresh sanction will be obtained from the scientific
and ethical committees.
14.
Cells obtained from foetuses will not be patented for
commercial considerations for (heir subsequent usage.
15.
Use of umbilical cord blood from a live foetus or neonate
for transplantation: The fundamental principle in any
operation on a live foetus or neonate will be to ensure that no
harm will occur to the foetus or neonate. Since the exact
timing ofthe clamping of the umbilical corcl has a significant
impact on the neonate and early clamping may cause an
abrupt surge in arterial pressure resulting in cerebral intra
ventricular haemorrhage, particularly in premature neonates,
normal clamping protocol will be followed when collecting
foetal blood for transplantation. There is a risk that the neonate
donor may need his or her own cord blood later in life. If the
blood has been used for another, he or she might be without
blood when it is needed. Parents will be fully informed of the
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risks of the donation and written consent obtained from them
on behalf of the foetus.
16.
Use of tissue or organs from dead anencephalic foetus or
neonate (foetus or neonate lacking brain development above
the level of the brainstem) is permitted. Physicians may
provide anencephalic neonates with ventilator assistance and
other medical therapies that arc necessary to sustain organs
till such limo as the diagnosis of death is made on the basis
of cessation of cardiac function. Retrieval and
transplantation of organs of anencephalic foetus arc ethically
permissible only after such diagnosis of death is made.
17.
No transplantation of foetal tissue into man will be
permitted unless the following criteria have been met:
i.
there will be a detailed scientific basis for such
transplantation;
animal experiments must show successful results - eradication
of disease, elimination or amelioration of symptoms and signs
or successful substitution of deficient chemicals and restoration
of normal physiological function by the transplant. These must
be documented in one or more indexed journals with good
peer review mechanisms;
all records pertaining to animal experiments must be complete
and submitted to specialist and general scientific scrutiny.
These records must be preserved for a minimum period of
five years after the completion of the study preferably on a
permanent basis as far as possible;
Success in animal experimentation must be shown on a long
term basis. The studies must include investigations on animals
receiving the transplants at periodic intervals after the
procedure specially with reference to unequivocal
demonstration of absence of any transmission of disease
through the transplant.
11.
in.
IV.
V.
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vi.
vi.
vii.
IX.
X.
18.
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Trials in human patients will commence only on those patients
where no other form of treatment is available and where, in
the absence of the transplant, the patient is likely to suffer
relentless deterioration in his health with fatal termination.
After obtaining her consent, the mother‘must be screened
for transmissible disease. If possible, the material to be
transplanted must also be similarly screened.
Trials in human patients will be carried out only at the
institutions having clinical and research facilities needed for
such trials, including those that may be required to treat
complications that may follow such research.
The research group and the institution(s) in which they work
will undertake to conduct free of charge the research on
their human subjects and also treat completely any
complication that may fohow their sludv even if it appears
several years after the conclusion of the sludv.
The research group will provide the human subjects a printed
document explaining in simple, non-lcchnical language, the
purpose of the study, details of the procedures the human
subject is to undergo, complications that may follow these
procedures, financial implications, interests of the researchers
in the conduct of the study, and a commitment to treat
completely and free ofcost any complication dial may ensue,
The human subject must certify in writing that he has studied
and understood the contents of this document and that he/
she is willing to participate in the study.
Any adverse effects noted will be immediately discussed with
members of the ethics committee and the project grounded if
these cannot be explained or reasonably corrected in die course
of the study.
The local ethics committee must ensure report-back measures
at every stage of research and confinn that a detailed report
on the procedures, findings and conclusions is submitted to
an indexed journal for publication even when the results are
79
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19.
III.
of a negative nature. The National/Central Ethics Committee
should be kept informed.
Tissue: A collection of similar cells, all of which perfonn the same
function. An example is neural tissue within the brain.
As with therapeutic transplantation, constantly updated local
(metropolitan), regional or national lists of available tissues
and organs should be maintained to ensure that optimal use is
made ofall available donations. These lists should be made
freely available to all authorised research workers.
Transgenesis: The introduction of a foreign gene into an animal or
organism. The transferred gene is called transgene.
XENOTRANSPLANTATION
INTRODUCTION
1
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Paucity of organs from humans for transplantation into other
humans has led to the search for other sources such as animals. Initially
. the focus was on the great apes, as they appear to be nearest to man
in the evolutionary scale. It was soon realised that unbridled use of
simians would lead to possible extinction of their species. Attention
has thus turned to other animals.
DEFINITIONS
Primates: The most highly evolved of animals. Includes simians and
homo-sapicns.
i
Simians:
The monkey species, including the great apes.
Species:.: Group of individuals sharing similar biological
characteristics and who can breed within the group to produce fertile
offspring.
■
Source animal: Animal from whom tissues or organs are removed
for transplantation in humans. The term ‘donor animal has been
discarded as the animals cannot give consent.
80
Xeno-transplant: Transplant o f cel Is, tissueor organ from one species
to another. This principally concerns transplant from animal to man.
Zoonoses: Diseases peculiar to animals in the normal course of events
that can, under special circumstances - as after xeno-transplant - be
transferred to man.
ETHICAL CONSIDERATIONS
Transmission of disease from animal to man:
There has been considerable apprehension that tissues or organs
transplanted from animal to man may convey infection or unwanted
genetic abnormalities. This anxiety has prompted most countries, to
ban all research on transplanting animal organs to human beings till
this issue has been satisfactorily addressed. Measures proposed
include the breeding ofsucccssive generations of animals and studying
them for all known and possible unknown organisms that can cause
disease. Only those animals certified free from disease could be
considered for transplantation.
Our immune responses arc likely to reject all foreign tissue
and organs transplanted into us. The chances of rejection arc
minimised if the source animal is genetically similar to man. This is
the reason for considering the great apes as likely source animal.
Once the apes were ruled out in order to preserve their species,
attention turned to cattle, sheep and pigs. In each of these species,
transplant of unaltered tissue or organ will certainly lead to rejection.
81
with slow viruses, that produce manifestation of the disease years often decades - after they gain entry into our systems. Equally
disquieting is the fact that once an infective organism makes a jump
across species, it may spread like wildfire in the new species - in this
case, man.
Pigs are currently the animals of choice as the size of their
organs and the anatomical and physiological loads they must carry
are similar to those in man. Besides, pigs breed easily and are
maintained without much difficulty. Experimental studies have been
carried out on kidneys, liver, heart, heart valves and bone marrow,
islet cells of the pancreas and nerve ceils obtained from pigs with
encouraging results.
It is also proposed that extensive research, with long-term
follow-up studies be carried out on animal-animal transplants so that
we may learn of possible pitfalls and develop measures to avoid them
before undertaking the first experiment involving man.
Attempts are on so that pigs be engineered to possess
genetic material similar to that in man. This can be achieved by
replacing porcine genes by human genes into the cell that will form
the pig embryo. Tissues and organs from such transgenic pigs will, it
is hoped, stand the scrutiny by the immune systems of the patients
into whom they are transplanted and will be left unmolested. However,
there are possible problems in using porcine tissue or organs in
human transplantation. The average pig survives for only twenty
years. Will transplanted tissues function efficiently in man with a life
span of three score years and ten, or will they fail after two decades,
necessitating further transplants?
GUIDELINES ONXENO-TRANSPLANTA TION
1.
Experimental xeno-transplantalion must only be permitted
between different aiiimal species. Animal - to - man
transplants must not be permitted al the present level of
knowledge which may be referred to the Central/National
Ethical Committee on Human Research.
Institutional scientific and ethics committees must appro\'e of
such research studies, with special attention being paid lo
their relevance, availability of facilities for extensive,
sophisticated and long-term studies for transmission of
disease through transplantation.
Equally worrying is the possibility of transferring germs and
viruses peculiar lo pigs into man through transplanted tissues. We
arc aware of species-specific infective diseases that limit themselves
to that species. Under special circumstances - as after transplantation
- such organisms may make the leap from one species lo another and
cause untold havoc in the new species, which has no immunity against
them. Some of the most deadly viruses currently devastating
individualsand groups in some African countries - that causing Lassa
Fever, the Marburg virus and the Ebola virus are such examples.
They appear to have spread from bats or other animals to man. The
human immunodeficiency virus (HIV) also appears to fall into this
category. These questions are still unresolved.
ApartI from the known bacteria, fungi and viruses, there is
hitherto unknown and undetected, especially so
concern for
L. those
.
3.
An advisory committee consisting of reputed scientists in
the field, medical professionals, veterinary experts and
microbiologists must oversee all such transplants.
4.
Records on all research studies must be detailed,
scrupulously maintained and kept available for a long period
of lime, perhaps decades.
5.
Safeguarding the interest of the pioneer human recipients
when such transplants are permitted in future, it is proposed
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that each and every animal - to - man transplant be
very carefully vetted and sanctioned on a case-by-case basis.
In each instance, extensive studies on the animals to ensure
freedom from infection must be made mandatory. The human
recipients of tissues or organs must be carefully followed up
over a long term.
i
IV.
1.
2.
4
to be able to make a decision with full understanding of the
consequences Children and mentally incompetent adults so also
surges. W
‘mited aUt°nOmy shouId not be subjected to such
TRANSPLANTATION FOR COSMETIC
PURPOSES
• .-7 •
Research on transplantation for cosmetic purposes (such as the
creation ofa new ear after transferring tissue from the patient on
to a mould which is later implanted into the subcutaneous tissue
ofa transgenic mouse) will be governed by the same principles as
those in using donation of tissue or organ from a live donor.
Donation of tissue should be restricted to renewable tissues like
skin to an extent where such removal will not greatly alter the
normal functions of such tissue.
3. It is imperative that no risk be imposed whilst removing tissue
beyond that inherent in surgery. Any manner of experimentation,
though it may be intended to improve the survival of the graft,
should be prohibited if there is the slightest extra risk to the donor.
Examples are pro-treatment of the donor with immuno
suppressives or anticoagulants.
7. The experiment
should be such as to yield fruitful results for the
.
good of patients who need transplantation without having the
donor. The experiment should be undertaken only ifthere is no
other method available offindmg the answer to the question raised.
i
8. The experiment should be so planned and conducted as to avoid
all unnecessary risks to the donor, to the tissue to be transplanted
and to the recipient site.
9.
Where tissue is to be temporarily transferred to an animal all
necessary precautions should be taken, and adequate facilities
should be avadablc, to protect the patient from the most remote
possibility ofharm.
10. The subjects
should be at liberty to withdraw from the
.
experiment and to abrogate the consent given earlier, with no
requirement to offer any explanation of the reasons for his or
her doing so.
4. Every such research project should be preceded by careful
assessment of predictable risks in comparison with foreseeable
beiKfits and improvement in the success rate of transplantation.
5. The patient must be informed of all possible risks, including
those of failure of the transplant in a manner easily understood
by him, before his consent is taken.
84
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STA TEMENT OF SPECIFIC PRINCIPLES
FOR ASSISTED REPRODUCTIVE
TECHNOLOGIES
INTRODUCTION
The special programme by WHO on human reproduction
has estimated that there arc 60 to 80 million infertile couples
worldwide. It has also been variously estimated that between
6-10% of the couple are infertile. The advent of Assisted
Reproductive Technologies (ART) have not only enhanced the
possibility of pregnancy but have also made women conceive in
situations which would not have been possible decade ago. However
many of these technologies require enormous technical expertise
and infrastructure, carry a success rale below 30% even in the best of
hands, arc expensive, and tax the couple's endurance physically,
emotionally and economically. There is an urgent need to draw up
necessary guidelines, so that optimum benefit of these newer
technologies arc made available to appropriate persons by skilled team
of experts, al affordable health and economic cost, al identified facilities
for Assisted Reproductive Technology in our country. In order to
ensure quality of care it is imperative that a proper accreditation
procedure is followed in establishment of ART Centres, which should
follow standardised protocols and guidelines. A national registry
pertaining to all centres that arc accredited by the licensing authority
should be maintained and should contain records of treatment cycles
and outcome.
All protocols used in the laboratory for Assisted Reproduction
(AR) procedures must be documented and available as manuals. These
manuals should be revised periodically. Log books for the maintenance
and periodic overhauling of all equipments should be maintained.
The entire procedure from the ovarian stimulation protocol to the
oocyte retrieval and oocyte and sperm preparation including
evaluation of the morphology of the gametes, their number, timing of
insemination, date of embryo transfer, number of embiyos or gametes
transferred and the fate of the gametes must be documented. Abnormal
pre-embryos such as polyploid embryos should not be transferred.
Cryopreserved material must be labeled indexed and stored properly.
The laboratory personnel should be well versed with the techniques
of cryopreservation. Batches of culture media must be identified. All
agents used in the Laboratory must be entered in a Register and the
dale of their receipt entered on the box containing them. Asepsis
should be maintained at all cost. Each couple undergoing treatment
should undergo a minimal screening for HIV and Hepatitis. The
laboratory personnel should be adequately protected which include
screening and vaccinations.
It is essential that all documentation regarding every patient
treated in the centre is maintained meticulously and all precautions
arc taken lo ensure that confidentiality is maintained.
GENERAL PRINCIPLES
There is a certain clement of risk associated with all AR
procedures. Il is, therefore, necessary to ascertain the therapeutic and
research value of the AR procedure in each case.
DEFIMTJON
Assisted Reproduction is defined as ‘manipulating the gametes
outside the body and the transfer of gametes or embryos into the
body’.
Informed Consent .-After duly counseling the couple/oocyte/semen
donor, an infonned and written consent should be taken from both
the spouses as well as the donor, as the case may be. They should be
explained the various risk factors associated with the procedures in
simple language and the words that they can understand. These
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include risks associated with ovarian hyperstimulation, anaesthestic
procedures, and invasive procedures like laparoscopy, aspiration of
ovum etc. They should also be explained the possibility of multiple
pregnancies, ectopic gestation, increased rate of spontaneous abortion,
premature births, higher perinatal and infant mortality as well as
growth and developmental problems. They should also be explained
that there is no guarantee on the success / failure of the procedure.
I
Selection of Donor : The physician assumes the responsibility in
selection of the suitable donor on following terms :
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A
•
The donor should be healthy with reasonable expectation of
good quality eggs or sperms and preferably with proven fertility
record.
•
inheritance rights.
•
The physical characteristic and mental make-up of the donor should
match as closely as possible to that of the spouse of
the recipient, specially with reference to colour of the skin, eyes
and hair, height and build, religious and ethnic background, the
educational level and ABO blood type.
Written consent of the donor should be taken towards unrestricted
use of sperms or oocytes for AR, as well as
an undertaking from him/her that hc/she will not attempt to
seek the identity of the recipient. In case the donor is married,
the written consent of the spouse should be taken, if possible. '
•
Il is also desirable to restrict the use of semen from the same
donor to a maximum of 10 pregnancies to avoid the possibility
of an incestuous relationship occurring among the offsprings al a
later dale.
Blood group of the proposed donor and donee should be tested
with respect to Rh compatibility.
•
In case of the oocyte donor, incurring any health problems related
to the process ot donation, the costs of the subsequent health
care should be borne by the potential recipient couple
irrespective ot whether (hey receive oocyte donation as planned
or not.
•
In case of unused surplus / spare embryos, consent of the
concerned couple should be obtained to cryopreserve such
embryos for donation to other needy couples. Such embryo
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Identity of the donor as well as the recipient should be protected
from each other. However, all the records of the donor must be
preserved in order to trace him / her in case of any eventuality
and should be confidential.
Confidentiality of the entire procedure and its outcome is
advisable and therefore, no relative should be accepted as a donor
in order to avoid identification and claims of parenthood and
Complete physical examination of the donor should be done to
ascertain the good health of the donors of semen, oocyte or
embryo.
•
•
It is essential that donated semen is cryo-preserved and used
only after 6 months as this would enable the centre to retest the
donor after 6 months for HIV and eliminate the potential risk of
HIV transmission in the ‘window’ period of HIV infection.
No person suffering from any sexually transmitted disease (c.g.
syphilis, gonorrhea, chlamydia, herpes, HIV etc.), infectious
disease (c.g. hepatitis B, HIV) or genetically transmissible disease
should be used as donor. Sexually transmitted diseases should be
‘ruled out within a week of obtaining the seminal fluid.
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solution to infertility or any other medical bar on pregnancy, by
the intending mother.
donations should be kept anonymous. The ownership rights of
such embryos rest with the couple concerned.
5. A qualified consultant should supervise to enforce adequate genetic
screening.
SPECIFIC PRINCIPLES
6. The contract for surrogacy despite reasonable payment of
compensation on completion of adoption would be valid siibjccl
to surrogate's right to retain the baby if she so desires.
I cgitimacy of the Child born through ART : A child born through
AR is presumed to be the legitimate child of the couple having been
bom within the wedlock and with consent of both the spouses with
all the attendant rights of parentage, support and inheritance. Sperm/
oocyte donor should have no parental right or duties in relation to
the child and their anonymity should be protected.
* '
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•
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;
8. Abortion under the Abortion Law on the medical ground
should be inviolate right of the surrogate and the adopting
parents have no claim over the amounts already paid.
9. All expenses related to medical management during pregnancy,
delivery, and immediate postpartum period till adoption should
be home by the intending couple.
Preservation, utilisation and destruction of embryos :
motherhood :
•
1. It should be resorted to only when it is
i coupled with authorized
adoption wherever applicable.
2. It should be rebuttably presumed that a woman who carries the
i
Research is prohibited on embryos of more than 14 days after
fertilisation excluding the period during which the embryo was
frozen with maximum storage period of 10 years and a 5 yearly
review of semen and embryo deposits as practised in other
countries eg. U. K.
Spare embryos :
3. The intending parents should have a preferential right to adopt
3. The
the child subject to six week’s postpartum delay for necessary
•
maternal consent.
4.
.
7. The only remedy for the genetic parent would be to claim for
custody on the grounds of the best interest of the child.
1VF-ET (in-vitro fertilisation and embryo-transfer) and Surrogate
Motherhood : There arc no medico-legal problems posed by
1VF-ET with egg and sperm of married couple. Donation of either
egg or sperm is governed on the same lines as those for Artificial
Insemination Donor with the married partner as the natural or
biological mother. IVF-ET with donated egg or sperm or womb leasing
will create two to three sets of parents, genetic, biological and natural.
Following consensus has emerged universally with respect to surrogate
child and gives birth to it is its mother.
'■ ;-. h- h' •
It should be resorted to only if medically certified as the only
Embryo-splitting may be resorted to in selected cases for
overcoming the paucity of suitable embryos during ART in a
couple. Child bom of cryo-preserved embryos after divorce is
deemed to be illegitimate.
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Right of children / parents
Children bom from use of donor gametes and their social/adopted
parents have the right to know whatever medical or genetic information
about the genetic parents that may be relevant to the child’s health.
*
■;
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Pre-conceptional or pro-implantation sex selection is prohibited
except for detecting specific sex- linked genetic disorders.
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BIBLIOGRAPHY
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