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E
Not to be Quoted
DRAFT
Consultative Document
on
Ethical Guidelines on Biomedical
Research involving Human Subjects
Indian Council of Medical Research
New Delhi
1997
TABLE OF CONTENTS
Page No.
Foreword
Preface
i-ii
Terms of Reference
iii
List of Members
iv-vii
Part A-General Principles
1-6
Statement of General Principles on Ethical
Considerations involving human subjects
in Medical Research
Part B-Specif ic ..Principles
7-94
Statement of Specific Principles on Ethical
Considerations involving human subjects
in specific areas of medical research
(a)
(b)
(c)
(d)
(e)
Human Genetics
Organ Transplantation including fetal
tissue transplantation
Clinical Evaluation of Drugs/Diagnostics/
Vaccines/Herbal Remedies
Epidemiological Research
Assisted Reproductive Technologies
Part C-Appendices:Documents of relevance
and interest
(i)
7-26
27-43
44-60
61-65
66-94
1-18
Extracts on professional and ethical
principles from the Medical Council Act 1956
-Code of Ethics of the Medical Council of India
1-11
(ii) Extracts from well-known Codes of Ethics on the use
of Human Subjects in Medical Research
(a)
(b)
c
The Nuremberg Code
Helsinki Declaration
12-13
14-18
TTr-rct
arroln
National Human Rights Commission
reel
npf.
. H0001
Sardar Ratal Bhawan. Sansad Marg, New Delhi-110 001 INDIA
(W) O'! 1-3340891.3347065 (w) 3018085
Justice M. M VenkatachaHah
: 91-011-3366537, 3340016
Phone : (O) 011-3340891, 3347065 (R) 3018085
Fax : 91 011-3366537, 3340016
Telegraphw Address : HUMANRIGHT
E-mail: nhrc.deuax400.nicgw.nic.in
Chairperson
FOREWORD
Our generation shares the excitement of watching the
profound transformation of our planet before
fools
of scientific
research
are
are
our very eyes.
emerging as great
instruments of enlightenment progressively demystifying
the processes and products of evolution. All these generate
a sense of great wonder and awe imparting, in a non-trivial
sense, legitimacy to the teleological argument.
Genetic research is poised for a break-through in
effective cancer treatment by combining
Gene Therapy
with Immunology, ft is also predicated that in the next 50
years human life span would go up to 140 years.
But biological research on human subjects also hanps
on a thin thread whose
snapping might let loose an
unstoppable hurtling to the unknown fraught with
possibilities of some thing seriously going out of hand.,
Experiments on human subjects raise serious issues of
PREFACE
The need for uniform ethical guidelines in research on human
subjects has been well recognised, and at the present time this
need is more acute because, apart from the mandatory clinical
trials on new drugs,
a number of diagnostic procedures,
therapeutic interventions and preventive measures including the
use of vaccines are being introduced which require proper testing
on human beings.Further, the advent of new medical devices and
radioactive materials as also the therapeutic benefits of
have added a new dimension to ethical
recombinant DNA products
issues that need to be considered before evaluating these
substances.
With the setting in of the era of biotechnology (including
genetic
engineering)
medical
procedures
and
therapeutics
have undergone tremendous changes and many techniques based on
these advances are no longer in the realms of science fiction,
but have become a reality today. Recent advances in the field of
assisted reproductive techniques, organ transplantation, human
genome analysis and gene therapy
offer unquestionable benefits
to mankind but at the same time raise numerous questions of law
and ethics, stimulating public interest and concern at various
levels.
On the one hand, there is a need to satisfy legitimate
public concern, while on the other, one has to appreciate the
need to encourage new scientific innovations for the benefit of
mankind.
It has therefore become imperative to provide specific
guidelines for such research, taking into consideration all these
new dimensions.
The Indian Council of Medical Research (ICMR) had brought
out in February 1980, a document entitled, Policy statement on
ethical considerations involved in research on human subjects
prepared by the ethical committee under the chairmanship of
Hon’ble Justice H.R.Khanna.
This document has been widely used
for 17 years by not only ICMR but also by
other agencies and
scientists.
The document however needs to be updated in view of
the recent developments in modern biology as also in different
branches of medical science so that it could serve as an useful
guide to all scientists and agencies involved in research on
human subj ects.
Therefore, a
Central ethical committee on human research
(CECHR) was constituted by the ICMR under the chairmanship of
Hon’ble Justice M.N.Venkatachaliah to consider various issues
related to the ethical, legal and social dimensions of research
on human beings.The committee met on 10th September 1996 and
identified following four major areas and the sub-committees for
drawing up detailed guidelines:
J
1.
Human Genetics research
2.
Transplantation
transplantation
3.
Clinical
remedies
4.
Epidemiological research
research
evaluation
of
including
Fetal
tissue
Drugs/Devices/Vaccines/Herbal
Apart rrom
from tnese
these the report of a separate committee drafting
nparu
-------- and ethico-legal issues of Assisted reproductive
the technical
technologies was also to be considered by this committee.
The CECHR met on 710th
“ ' August
’
1997 to consider the draft
reports prepared by all the five groups and following detailed
discussions the present draft has been prepared for wide
circulation and subsequent national debate
—! before finalisation.
The Terms of Reference,
Sub-Committees are appended.
list of Members of CECHR and the
(ii )
TERMS OF REFERENCE
a)
To review ethical, legal, social and other issues of
research involving/affecting human subjects.
b)
To formulate general principles for such research.
c)
To formulate
research.
d)
To examine the possibilities of setting up machinery
and mechanism to monitor, implement and review the
general and specific guidelines► so formulated, and to
• - - •
as may be necessary
further formuiate such guidelines
from time to time.
e)
f)
g)
guidelines
on
specific
To examine and review the guidelines,,
mechanisms so formulated in the light
gained from time to time.
areas
of
such
machinery find
of experience
To consider the wider implications of biomedical and
health research and suggest ways and means in which
and
dicussion
inter-disciplinary
and
inter-agency
consultations can take place on an ongoing basis.
To consider ways and means in which these guidelines
for research can be disseminated to increase awareness
amongst researchers, concerned persons, institutions
and the community.
(ih*)
LIST OF MEMBERS
CHAIRMAN
1.
Hon. Justice M.N. Venkatachaliah ,
Former Chief Justice of India &
Chairman,
National Human Rights Commission,
New Delhi-110001.
MEMBERS
2.
Dr. G. V. Satyavati,
Director General,
Indian Council of Medical Research,
New Delhi - 110029
3.
Director General of Health Services,
Nirman Bhawan,
New Delhi
4.
Dr.. L.H. Hiranandani
A-3, Amarchand Mansion
Madam Cama Road,
Bombay - 400039
5.
Dr.. M.S. Valiathan
Vice-Chancellor
Manipal Academy of Higher Education,
Manipal
6.
Dr.. Ran jit Roy Choudhury,
Emeritus Scientist
National Institute of Immunology,
New Delhi.
7.
Dr.. B.N. Dhawan,
Emeritus Scientist
Central Drug Research Institute,
Lucknow 226001
8.
Dr. J.S. Guleria,
K-ll, Green Park Extension
New Delhi.
9.
Dr. P. N. Teindon
Emeritus Professor,
Deptt. of Neurosciences,
AlIMS, New Delhi.
10.
Dr. B.N. Tandon
M-52, Greater Kailash Part II
Nev; Delhi.
(iv?
J
!!•
Dr. Indira Nath
Prof & Head,
Deptt. of Biotechnology,
AlIMS, New Delhi.
12 .
Dr. Saraswati Swain
General Secretary
National Institute of Applied Human
Research and Development
Cuttack - 753013
13.
Dr. S.N.Channabasavanna/Dr .M.Cowrie Devi,
Director,
National Institute of Mental Health
and Neurosciences,
Bangalore - 560012
14.
The Director,
AIIMS, New Delhi.
15.
Dr. Kamala Gopala Rao
1017, 25th Main
Banashankari, 2nd Stage
Bangalore-560070
16.
Suit Rami Chhabra,
B 5/19,Safdarjung Enclave,
New Delhi.- 110029
17.
Dr. Manju Sharma
Secretary
Deptt. of Biotechnology
New Delhi- 110003
18.
Smt. Shailaja Chandra
Additional Secretary [Health]
Ministry of Health and Family Welfare,
Nirman Bhawan,
New Delhi
19.
Dr. P. Das Gupta,
Drugs Controller General of India,
Nirman Bhawan, New Delhi.
20.
Dr. Y.S. Rajan,
Senior Advisor (Technology),
Confederation of Indian Industry,
India Habitat Centre,
Lodi Road, New Delhi.
21.
Dr. Badri N. Saxena
Additional Director General,
Indian Council of Medical Research
New Delhi.
CV)
k
22 .
Dr.Kalyan Banerjee,
Director,
National Institute of Virology,
Pune.
23 .
Dr.Rajeev Dhavan,
Senior Advocate,
Supreme Court of India
New Delhi.
24 .
Dr. S.K. Bhattacharya,
Director,
National Institute of Cholera
and enteric diseases,
Calcutta.
25.
Dr. N. Medappa
Sr.DDG & Chief, Division of Publication & Planning,
Indian Council of Medical Research,
New Delhi.
26.
Dr. R. Ravi
Deputy Director General (SG),
Indo Foreign Cell,
Indian Council of Medical Research,
New Delhi.
MEMBER SECRETARY
27 .
Dr.Vasantha Muthuswamy
Deputy Director General & Chief,
Division of Basic Medical Sciences,
Indian Council of Medical Research,
New Delhi.
MEMBERS OF THE SUB-COMMITTEES
FOR GENERAL PRINCIPLES
1.
2.
Dr.Rajeev Dhawan, Supreme Court of India, New Delhi
Dr.Vasantha Muthuswamy, ICMR, New Delhi
FOR SPECIFIC PRINCIPLES
1,
Human Genetics Research
1.
2.
3.
4.
Dr.P.N.Tandon, AlIMS, New Delhi
Dr.S.S.Agarwal, SGPGI, Lucknow
Dr.Manorama Thomas, St.J.MC, Bangalore
Dr.I.C.Verma, AIIMS, New Delhi
(vi)
Chairman
Member
Member
Member
2.
Transplantation Research
1.
2.
3.
4.
5.
3.
evaluation
clinical
Remedies etc.
1.
2.
3 ♦
4.
5.
6.
4.
of
Chairman
Member
Member
Member
Resource Person
Drugs/Diagnostics/Vacoinea/Herbal
Dr.Ranjit Roy Chaudhury, Nil, New Delhi Chairman
Member
Dr.B.N.Dhawan, CDRI, Lucknow
Member
Dr.S.S.Handa, RRL, Jammu
Member
Dr.C.D.Tripathi, MAMC, New Delhi
Resource Person
Dr.Usha Gupta, MAMC, New Delhi
Resource Person
Dr.S.B.Lall, AIIMS, New Delhi
Epidemiological Research
1.
2.
3.
4.
5.
Dr.M.K.Mani, Apollo Hospital, Chennai
Dr.Sunil Pandya, KEM Hospital, Mumbai
Dr.R.P.Shanmugam, CMC, Chennai
Dr.Vinod Kochupillai, AlIMS, New Delhi
Dr.J.Amalorpavanathan, CMC, Chennai
Dr.V.I.Mathan, CMC, Vellore
Dr.P.S.S.Sundar Rao, Karigiri, T.Nadu
Dr.R.Prabhakar, TRC, Chennai
Dr.M.D.Gupte, IRMS, Chennai
Chairman
Member
Member
Member
Assisted Reproductive Technologies
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12 .
13 .
14 .
Dr.R.P.Soonawalla, Mumbai
Dr.Sadhana Desai, Mumbai
Dr.Mehroo Hansotia, Mumbai
Dr.H.S.Juneja, IRR, Mumbai
Ms.Kusum Kumar, New Delhi
Dr.Pritam Phatnani, Mumbai
Dr.Firuza Parikh, Mumbai
Dr.Mahendra Parikh, Mumbai
Dr.Somnath Roy, New Delhi
Dr.S.I..Chauhan, ICMR, New Delhi
Dr.Prema Ramachandran, ICMLR, New Delhi
Dr.V.K.Behal, MOH&FW, New Delhi
Dr.K.Kehar, MOH&FW, New Delhi
Dr.B.N.Saxena, ICMR, New Delhi
(vii)
Chairman
Member
Member
Member
Member
Member
Member
Member
Member
Member
Member
Member
Member
Convener
Part A
General Principles
t
involved
in
consi derat ions
as the IOMR
shall be known
This
Biomedical
Code and shall consist of the on Research using Human
Statement of General Principles
Biomedical Research
(a)
Subjects in
Research using
‘ : principles'* on Biomedical Research
Statement of Specific
(b)
in specific areas of
Human Subjects —
2j principles may be
and Specific
These Statements of General
to time.
and added from time
t—
varied, amended, substituted u.._
BACKGROUND
- (1939-45); ,} there
Second World War
subjects
human c*
In the aftermath of the
Ll.j use. of the
— statement
about
the
on the
international
was an intensified concern
The
first
:
--was
the
Nuremberg
subjects
for medical research,
luntariness.
The
research using human
pthics of medical i-■.
and vo
of
the
trial
or
Code of 1947, Which emPhasls®d’ consent
l the aftermath
experiments
m
conducting conditions where
Nuremberg Code was evo _____
e
l
of
medical
Practitioners
accused
"their consent and j resulting in their
medical research wlthout
put to grave risks
In 1948,
the human subjects ^ere t to th
their Lfaculties.
.
deaths and permanent ^Pa“a" Rights (adopted by the General
rights concern
Universal Declaration
Motions) expressed human
in
maltreatment
.
Assembly of the United
to involuntary
about h’^an beings being co^enant on Civil and political Rights
Covenant
subjected to torture or to
1966. the Internauiwucxj, 77
sploltically BWted,6e
or punishment.
treatment Without his consent to
<!rUtlcUla?'““ <>»•
*” ’"MeCted to
particula ,
entific treatment".
medical or scientiz
council
for
the
Counciefforts
by
7rTOMS) the World
Following
preliminary
Medical Sciences (CIONS)
in
} the Declaration at "
H. down
Association
which reseaich in
time to time
time and
an
Lj in medical
which was 1---— subjects
“^research
In
i for biomedical 1r— released a
of Medical Research
in Restarch
bo
iderat ions
• nVOive.! --in
involved
•’Policy stateraent on
the
benefit
of
ag
Wor
id
Heilth
World
for India.
in
1982,
h
Internati >nal
on Human Subjects’*
in
________
research
clinical
the CIONS ^S^O^°S Human Subjects.
Organisation (WHO) and
for
Z.-. Guidelines
Biomedical Research
Guidelines for E-„
issued
^Internationa
1
ind
CIOMS
studies
Subsequently
Research
Ep
Ethical
Review of
for
tGuidelines
iox
Ethical
••international
S TS.1
•
1
involving Human subjects1* in 1993.
Over the years, various
bodies in national jurisdictions have also laid down general and
specific principles in respect.of medical research generally and
in specific areas of scientific research entailing the use of
human beings as a subject.
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 -
(i)
The PURPOSE, of such research is that it should be directed
towards the increase of knowledge about the human condition
in relation to its social and natural environment, mindful
that the human species is one of the many species in a
planet in which the well being of all species is under
threat — no less from the human species as any other; and
that such research is for the betterment of all, especially
the least advantaged.
(ii) Such research is CONDUCTED under conditions that no person
or persons become a mere means for the betterment of others
and that human beings who are subject to any medical
research or scientific experimentation are dealt with in a
manner conducive to and consistent with their dignity and
well being under conditions of professional competence,
fair treatment and transparency; and, after ensuring that
the subject is placed at no greater risk, other than such
risk commensurate with the well being of the subject in
question in the light of the object to the achieved.
(iii)Such research must be subjected to a regime of EVALUATION at
all stages of the proposal i.e., research design and
experimentation, declaration of
results and use of the
results thereof; and, that each such evaluation shall bear
in mind the objects to be achieved, the means by which they
are sought to be achieved, the
anticipated benefits and
dangers, the potential uses and
abuses of the experiment
and its results and, above all, the premium that civilised
society places on saving and ensuring the safety of each
human life as an end in itself.
STATEMENT OF GENERAL PRINCIPLES
Any research using the human beings as subjects of medical
or scientific research or experimentation shall bear in mind the
following principles -
I.
Principles of essentiality whereby, the research
entailing
the use of human subjects is considered to be absolutely
essential after a due consideration of all alternatives; in
the light of the existing knowledge in the proposed area of
2
>
research and after the proposed research has
£ y
vetted and considered by an appropriate and responsib_e bo y
of persons who are external to the research and who after
careful consideration, come to the conclusion that
ie sal
research is necessary for the advancement of knowledge and
for the benefit of all members of the human species and tor
the ecological and environmental well being of the planet.
II.
Principles of voluntariness, informed consent and community
agreement whereby, research subjects are fully apprised o^
the research and the impact and risk of such research on the
research subject and others; and, whereby the research
the
right
to
abstain
from
further
retain
subjects
------or
participation in the research irrespective of any legal
other obligation that may have been entered into by such
lialf, subject to only
human subjects or someone on their behalf
minimal restitutive obligations of any advance consideration
Where any such research entails
received and outstanding,
group
of persons as a research
treating any community or
subject, these principles of voluntariness and informed
to —
the community as; a
consent shall apply, mutatis mutandis,f —
the subject of
whole and to each individual member who is
the research or experiment.
Where the human subject is incapable of giving consent
essential that
that
research
or
and
it
is
considered essential
experimentation be conducted on such a person incompetent to
give consent, the principle of voluntariness and informed
consent shall continue to apply and
and such
such consent and
voluntariness shall be obtained and exercised on behalf of
such research subjects by someone 1who is empowered and under
a duty to act on their behalf-
The principles of informed consent and voluntariness
are cardinal principles to be observed throughout the
and
its aftermath
including
research and experiment,
continually
are
applicative use so that
research
subjects
■
--- kept informed of any and all developments in so far as they
However, without in
affect them and others.
in any
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 invasiyeness
into the concerned human subject’s person and privacy,
health and life generally, and, the overall purpose and the
importance of the research.
III. Principle of non-exploitation whereby, as a general rule,
research subjects are remunerated for their involvement in
the research or experiment; and, irrespective of the social
and economic condition or status, or literacy or educational
levels attained by the research subjects kept fully apprised
of all the dangers arising in and out of the research so
that they can appreciate all the physical risks as well as
3
• ' » research whether to themselves or
moral implications of- the
including
those
yet to be born.
others, :
Such human subjects should be selected so that the
and benefits of the research are distributed
burdens
without arbitrariness, discrimination or caprice.
Each research shall include an inbuilt ™^anVhrOuq£
compensation
for
for the human subjects erther though
insurance cover or
any other appropriate means
to cover
or
all foreseeable and
unforseeable
risks
by
pro^idi
9 .
and
after-care,
remedial action and comprehensive» after-care
treatment during and after the> research
research or
or experiment, or
the
conduct
of research
respect of any effect that
the
human
subject
and to ensure
experimentation may have on
and
rehabilitative
measures are
thcit immediate recompense
affected, if and when necessary.
:
taken TnVe^ect'of^aill
whereby, the
Principles of privacy and confidentiality
; of the research
the
human
subjects
identity and records
of as possible kept confidential; and,
are as
tar
as
or experiment are
as far
no details about identity of said
that
result in the disclosure of their ijent y,
which wouldwithout
sound scientific
scientific masons which may be
disclosed, tor the sound
purposes
of ther.p.utxcs^.or pOth^
essential
for the purposes of
interventions,without the specific consent
or someone authorised on their
human subject
concerned,
ensuring that
'
the said human subject
behalf; and, after
any form of hardship
hardship, discrimination
does not suffer from a
consequence of having
participated
1
or stigmatisation as
in the research or experiment.
' r due
Principles of precaution and risk minimisation whereby,
V.
research
and
care and caution is taken at all stages of thefl
idea, its
experiment (from its inception asia/efe^“ research or
subsequent research design, the conduct o
thgt the
experiment and its applicative use)
the
research subject and those affected by
adverse effects
minimum risk, suffer from no irreve
research or
and,
generally,
benefit from Xns are taken to ensure
experiment; and that requisite st p
f
research
that both professional and ethical rev^®
further and
are undertaken at appropriate stages so that f
ions
specific guidelines are laid down, and ^ecessa Y
given,
in respect of the conduct of the researcr
experiment.
professional compotence whereby,, the research
VI. Principles
and qualified
persons
is conducted at all times
— 1/
by competent
<- *-.
T'*' and
.....
____ a
. .V. x-,
who have
integrity
and
impartiality
who act with total :*
.
ethical
been made aware of, and are mindful of, the of such
respect
considerations to be borne in mind in
research or experiment.
IV.
4
whereby, the
VII. Principles of accounranxixvy
transparency fair, honest,
accountability
research or experiment will I
a fUn disclosure is
---- , after
a h or experiment of
impartial and transparent■ man
c
or
by those associated with the
the research
esearch^^^
any
in the research,
.
each aspect of their 3-ntcrest
.
where
by,
subject
to
y exist;
conflict of interest that may
exist, and
an whereby th rights
and confidentiality
the principles of
the research
complete records
such reasonable
inclusive of data and notes are retained for
for the
period as may be prescribed or considered necessary
monitoring evaiuavxun
evaluation
purposes of post-research
H
---b
(whether
by the initial
research
research, conduting further
and
in
order
to
make
such records
researcher or otherwise)
available for scrutiny by the appropriate legal and
administrative authority, if necessary.
VIII.Principle of the maximisation of the public interest and of
benefit all human kind and not just those who are s!?Cia^
better
off
but
also the
least
advantaged;
and,
particular, the research subject themselves.
IX.
X.
XI.
Principle of Institutional Arrangements whereby, there shall
with the research
o
be a duty on all persons connected
required
to
be
complied
with
ensure that all the procedures
in
1 to be made ir.
and all institutional arrangements required
use
or
its
subsequent
research and
the
of
respect
and
transparent
u made in a bonafide to ensure that
application are duly
take all appropriate steps to ensure
manner; and to take/
uxl-o, materials
andand
data
connected
with the
research reports
materials
data
<-research are <duly preserved and archived.
the research and any
Principle of Lpublic domain whereby, evaluation in response
*
- ““i or
further research, experimentation
is brought into the
to,and emanating from such research
--public domain so that its results; are generally made known
subject to such
scientific and other publications
l
through
to
the
researcher
and those
rights as are available
under the law in force at that
associated with the research
:----time.
the
totality of responsibility whereby,
Principle of
due
for
the
responsibility,
and
moral
professional
or
guidelines
principles,
all
the
observance
<of
the
of
prescriptions laid down generally or in respect
on
all
those
devolves
research or experiment
in question,
<
the
research
or
directly or
indirectly connected with
those
responsible
experiment — including thei researchers,
of the research,
for funding or contributing to the funding the research is
the institution or institutions f where i or undertakings
conducted and the various persons, groups
the research, market
1------ from
--who sponsor, use or derive benefit
use
— so that, inter
the product (if any) or prescribe its
experiment
is duly
alia, the effect of the research or
5
monitored and constantly subject to review and remedial
action at all stages of the research and experiment and its
future use.
XII. Principle of Compliance whereby, there is a general and
positive, duty on all persons conducting,,
conducting, associated or
research
entailing
the use of a human
connected with any
that
both
the
letter
and the spirit of
subject to ensure
as
well
as
any
other
norms,
directions and
these guidelines,
down or
laid
i
have
been
specifically
guidelines which
area of
that
which
are
applicable
for
prescribed and
scrupulously
observed
and
are
s
research or experimentation,
duly complied with.
6
PART B
SPECIFIC PRINCIPLES
(a)
Human Genetics Research
(b)
Transplantation Research i ncluding
Fetal Tissue Transplantation
(c) v/Clinical Evaluation of Drugs/Devices/
Vaccines/Herbal Remedies
(d) y Epidemiological Research
(e)
Assisted Reproductive Technologies
STATEMENT OF SPECIFIC PRINCIPLES
ON HUMAN GENETICS RESEARCH
INTRODUCTION
In no other area of biomedical research there has been a
greater concern for ethical issues than in the field of human
genetics.
While the advent of recombinant DNA technology has
provided one of the most powerful tools in the hands of mankind
to unravel the mysteries of the human genome,
genome, it has also led to
a great deal of concern about our ability to handle the
information so derived.
Human beings cannot be experimental animals in any field of
research.
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
decade, there has been a veritable explosion in knowledge which
has culminated in gene therapy (the ultimate in thereapy for
genetic
diseases)
and
various
other
aspects
of
genetic
engineering.Serious issues related to participation of human
subjects in genetic research are 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 monkeys bring human cloning into the realm of
possibility, raising
Ethical, Legal and Social Issues (ELSI)
as important aspects of HGP. This calls for laying down of rules
and regulations in a stepwise fashion with the least amount of
ambiguity.Special guidelines are required
to contain the
potential harm without clamping a moratorium on research and
service in this field.
PREAMBLE
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 which
require special guidelines:1.
The harm may not only be physical, but also psycho-social.
Psychologically, the genetic information may produce anxiety
and depression or damage familial relationship, which should
be
safeguarded.
There
is
a
likelihood
of
social
stigmatisation and discrimination ini employment, health and
general insurance, which requires much greater care in
recruiting subjects in the study, obtaining informed consent
and ma intai n ing confidentiality of research findings, than
in any other area of research.
7
2.
There is great importance of spoken word in medical
genetic counselling is akin to therapy in
genetics, since
other fields. In that sense the 'word* is equivalent to
drug/intervention in medical genetics,, Written explanation
understandable to layman about the disease/interventions,
and outcome as also the implication of the information
generated for progeny and family, has special place in
clinical research in this field.
3.
Genetic Counselling deals with the discussion on personal
matters such as reproductive options, and the couple has to
make choices which have far reaching social implications.
It, therefore, calls for special care which should be
documented in research proposals carefully considered by
Ethical review committees.
4.
Genetic manipulations have consequences for the future, some
of which are unknown. Hence, greater care towards potential
dangers is necessary.
5.
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 are
needed to be evolved by the peers in the profession to
tackle such situations. The professional societies should be
called upon to actively participate in these activities.
6.
The science of Medical Genetics is progressing very rapidly.
Therefore, there is 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-in mechanism to review the
guidelines from time to time. The Ethical Review Commitees
should have necessary expertise which include knowledge of
latest developments. In areas of doubt open discussion shall
be encouraged.
7.
Concerned with the misuse of genetic tests, particularly for
the preselection of sex, the Government has enacted
a law
known as "The Prenatal Diagnostic Techniques (Regulation &
Prevention of Misuse) Act 1994". The provisions of this act
shall be followed by all researchers in this area (and such
other acts which may be passed in future).
8.
These guidelines are not only for research on human
subjects, but are part and parcel of the clinical practice
of Medical Genetics as well.
DEFINITIONS
Genetic material/Genome
Genetic material refers to the material made of DNA in each
cell of any organism. The DNA is divided into genes.
Each gene
contains
the
information
required
to
produce
one
8
polypeptide/protein needed by the organism.
Chrcmosome
several
in a cell is divided into called a
DNA
thread-like
The
structure
Each length forms a chromosome in every
separate lengths.
of? each
There are two copies of
chromosome.
chromosomes.
Human cells contain 23 pairs
cell.
Gene
that contains the information
A gene is a length of DNA
For example, the beta globin
needed to make one• polypeptide,
beta globin
needed to make the
More
gene contains the information
the hemoglobin of red blood cells,
:
polypeptide found in
and
more
involved in making one protein,
than one gene may be
result
of
be formed from one gene as a
taan one polypeptide may
alternate splicing.
Genetic Engineering
It is the
process of
the genetic material of an
the process
— changing
--of genetically
The
main method
animal or an organism or a plant.
The main
i---modifying the organism is by transgenesis.
Hetero-zygote
> copies of each gene,
Each cell of an organism contains two
pair
are different from
of a
In a heterozygote, the two genes
each other.
Homozygote
;
of each gene,
Each cell of an organism contains two copies
identical
to each
are
In a homozygote, both copies of the gene
other.
Mutation
-- ;
or
---j-jy wJ-J j eft
wutatt .Pt°ln
eZX
S^,'eat„he1oaDrtoOais:naseOr.S1S"s thalassemia
In humans this can
in decreased -production of beta or
in which the mutation results
parent to
alpha globin.
The mutant gene is passed down
and
theH offspring anTlo^hrconJition
8
is"
inherited.
In
viruses^
— -> condition is inherited.
of
other infectious organisms, mutations can lead to
rg
more
organisms with new characteristics.
~ It can make cnem their
orw' resistant
virul ent
c
cj+'ar>+' to antibiotics thus increasing
infectivity.
Patent
■ for
~ • a limited period,
* ; a monopoly right, granted,
A patent is
the
publication
to the world
in return for y
---.-Tv
given to an inventor
1...at large of the details of an invention .
9
Recombination
A cross-over between two members of a pair of chromosomes
results in the formation of a recombined chromosome wherein a new
set of gene arrangement is created.
Transgenesis
This refers to the introduction of a foreign gene into an
a
<
animal or other organisms. The transferred gene is called
transgene.
Transplantation
Transplantation involves the removal of organs, tissue or
cells from one organism and their implantation into another
organism.
GENERAL PRINCIPIiES
The 12 principles laid down under Statement on General
Principles are common to all areas of biomedical research, The
specific issues are mentioned under relevant topics.
Review Committee in Human C-Jenetics
All institutions where research is> carried out on human
genetics; should have an Ethical Review Committee with adequate
expertise
in
the
field.
Scientific
competence
of
the
investigator and sound scientific methodology should be essential
It includes appropriate
prerequisites for genetic research.
<
and field testing of the protocols,
training, planning, pilot
containment where necessary and quality control of laboratory
techniques.
Informed Consent
For all biogenetic research
involving humani 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 proxy consent
of
a
properly
authorized representative/legal guardian should be taken.
Research involving children
Before
undertaking
research
investigator must ensure that :
children
carried
involving
will not be involved in
out equally with adults;
research
the
children,
that
might
be
the purpose of the research is to obtain knowledge relevant
to the health needs of children;
a
parent
or
legal
guardian
of
10
each
child has
given
proxy
consent;
obtained to the extent
the consent of each child has been
of the child’s capabilities;
P^t101?3^:e
61
in
^ research ^J
must oc^Wt^e
the
research
be respected unless according
,
there is no medically
child would receive therapy for which the
acceptable alternative;
interventions not intended
intended to
to benefit
the risk presented 'byr interventions rnot
with
and
commensurate
the individual child-subject is low <.-- . the importance of the knowledge to be gained; ana
to provide therapeutic
interventions that are intended
least
as advantageous to the
benefit are likely to be at
available alternative
individual child-subject as any ;
the child's refusal to
research subjects
Essential information for prospective
‘
:e in
an individual's consent to particrpat
Before requesting
individual
with
the
research, the investigator must provide the — she is capable of
following information, in language that he or
not
only
be
communication
should
understanding.
The
their
social
scientifically accurate but should be sensitive to
and cultural context:
that each individual Is invited
Invited to participate
partic
in research.
The aims and methods of the l
research
sno
--individual.
fully explained to the concerned
(------»s participation;
the expected duration of the subject
to
bej expected to result
the benefits that might reasonably
outcome
of
the
research;
the subject or to others as an o-t--subject,
th €5
discomfort
to
any
foreseeable
risks
or
any
associated with participation in the research;
; or courses of treatment that
any
any alternative procedures
as the procedure or
might be as advantageous to the subject
treatment being tested;
the extent to which
which confidentiality
confidentiality of
of records in which the
subject is identified will be maintained,
nf the investigator ’s responsibility, if any, to
the extent
provide medical services to the subject for.e
injury/illness resulting from the research free of charg ,
a result of
research subjects who suffer physical injury as care as an
their participation are entitled to medical
institutional responsibility;
to participate and
that the individual is free to refuse
V
11
will be free to withdraw from the research
at any time
without penalty or loss of benefits to which he or she would
otherwise be entitled.
All possible means of coercion
or
Or. lndlrect rewards for participation should be
scrupulously avoided.
Equitable distribution of burdens and benefits
ft-*.— ——
-rn-e^a b;or
or communities
of
should be selected in
that the
of
the
research
equitably
justification is required
inviting
(prisoners,
nurses,
selected,
- u
e
th6 means of protecting their rights and
slliallvUdLad st£ictly applied.
Persons who are economically or
advantaged should not be used as research subjects to
benefit those who are financially better off.
Pregnant or Nursing women as research subject
orJ?ursin9 women should in no circumstances be the
t .of genetic research unless the research carries no more
of Pho
31 riuk •t° the fetus or nursing infant and the object
uie research is to obtain new knowledge about the fetus
women3should iactation.
As a general rule, pregnant or nursing
triZVs
1
not. be. subiects of any Clinical Trials except such
designed to protect or advance the health of
ShToh
nursing women or fetuses or nursing infants, and for
^Mo4c'nen WhO are not Pregnant or nursing would not be suitable
blUJJ ects..
Confidentiality of data
The investigator must establish secure safeguards for the
confidentiality of the research data.
Subjects should be told of
. to
the
investigator’s
ability
to
rsafeguard
ability
to
fr-rnn rh
’
1S ne.cessary to protect researchers and subjects
from possible coercion/inducement to participate in the study.
Academic institutions
.
------- companies require a ! ‘
---------- ; between scientific responsibilites
of
researchers
and
business
interests
(e.g.
ownership
or
part-ownership of a ccompany developing a new product) .
In cases
where the review board determiners*
•
x. •
" T--- -—-3 that a conflict of interest may
risearch6 1
lnte,3rity of a project or cause harm to
integrity
TnlbT+^h- partlclPants'
the board should advise accordingly,
al^ro
nTd self
-regulatory processes to monitor,
self-regulatory
monitor. prevent
and resolve such conflicts of
- interest.
• ■
•
Prospective
participants
in
12
research
should
also
be
informed of the sponsorship
«— - •
of research, so Cl.
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,
I
does not include agreements with
individuals, families,
families, groups
communities or populations that
foresee technology transfer
local training, joint ventures,
provision of health care or
of information infrastructures,
reimbursement costs of travel and
loss of twages
—
and the possible
use of a percentage of
any royalties for humanitarian
------ purposes.
SPECIFIC PRINCIPIES
I.
HUMAN GENETIC DISEASES/DISORDERS
Pedigree Studies
These involve obtaining history of other
family of the p
members of the
proband under investigations.
It may reveal
information about- the likelihood t*
that individual members of the
family either are carriers of genetic
_J defects or may be affected
by the disease.
Special privacy and
concerns
genetic rfamily studies
special
]
between the
—‘ participants,
mind that
that within
within
families each person is an It should be kept in mind
an
individual
t
’
_*
------ wl-w deserves to keep the
information about himself
or herself confidential.’ Family members
are not entitled to know
each
each other
other’’ss diagnosis. ’ Before
revealing medical or
information
>
'* at>out individuals to
other family members, personal
in/estigator
• must obtain the consent of the
individual.
in our country revealing
the information that Se
wife
has
balanced
that
chromosomal
translocation
(leading
recurrent abortions or
ch
“
* tha genetic syndrome in I
she is a carrier of
single
gene i.e. f^r
'X' linked
hlslanTlsllng
divorce""i^rof
disease, rmay^1lead to the
-1
asking
for
a
‘
the fact that —
ini some of the
mspite of
cases, the husband himself
carrier of a i
recessive
general principles
Counselling require the ]--’
j
e
S»'i^
h
b
°?.
“
ej spouses, necessary
necessary
-care must be taken not toPr
end
—-1 UP ln breaking the families..
Subject recruitment
The familial
Hpan16 °f the
rne
research cohorts involved
pedigree
in
studies
a
a challenge
challenge for
recruitment rto^arti
£
that
are free of elements that
the decision
participate.
The
very nature
nature of the rpcpamh
4?^
*1*
’
met.overy
exerts pressure
f«xly members
members
take part
part, beoaull
on
ramily
to
take
complete
the
more
pedigree,
the
more
'
the
more
reliable
the
information will be.
resulting
Problems which could arise when 1.
Revealing who else in the f ' 2
family agreed to participate may
lead to breach of confidentiality.
13
2.
A proband is used for revealing his personal interest
he/she may put undue pressure on relatives to enroll in the
study.
3.
Direct recruitment (by telephone calls) may however De seen
as an invasion of privacy by family members.
4.
Contact through personal physicians
health care will be compromised if
participate.
may imply that their
they do not agree to
Defining risks and benefits
Potential risks and benefits should be discussed thoroughly
with prospective subjects.
In genetic research, the primary
risks outside
of gene therapy are psychosocial rather than
physical.
Adequate
counselling should be given to subjects on the
meaning of the genetic information they receive.
Genetic
counselling should be done by persons qualified and experienced
in communicating the meaning of genetic information.
II.
GENETIC SCREENING
Definition :
A search in a population to identify individuals
who may have, or be susceptible to, a serious genetic disease or
who t though not at risk themselves, are gene carriers and thus
may be at risk of having children with a particular genetic
disease.
Depending on the nature of the genetic defect that is
identified and its pattern of inheritance, siblings and other
blood relations as well as existing and future offsprings may be
Thus the status of genetic information raises, ethical
affected.
questions that differ significantly, from the normal rules and
standards applied to the handling of personal medical records,
Adequately 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
to what
whether or not to agree
is proposed and they must be
free to withdraw
from
the investigation at any time.
The Disorder to> be screened and its inheritance pattern
screening
should be explained as also the reliability of the
test, the procedure for informing individuals of the results,
information about the
what will be done with the samples,
and a
implication of a positive screening test (abnormal)
14
warning to pregnant women that genetic screening may reveal
unexpected and awkward information, for example about paternity.
Confidentiality should be maintained in handling of the
results with an emphasis on the responsibility of individuals
with a positive (abnormal) result to inform partners and family
members.. It should be emphasised that consent for screening or a
subsequent confirmatory test does not imply consent to any
specific treatment or to the termination of a pregnancy.
General guidelines have to be followed for vulnerable
individuals i.e minors,
students,
mentally ill,
prisoners,
subordinates:,
people who do not speak the language of the
investigator etc.
Genetic counselling should be readily available for those
being screened.
Confidentiality of medical
information is
protected by law but this is not absolute,
Information may be
disclosed where it is in the public interest to do so.
Screening New Borns :? Screening of new borns should be
to
allowed
detect
only
those
genetic
diseases
like
phenylketonuria where the serious effects
of the disease could
be prevented, by a special diet or treatment . The same applies to
investigations
to
detect
genetic,
chromosomal,
metabolic
chromosomal,
abnormalities, etc. if general principles mentioned earlier are
followed.
The other diseases can be screened as and when
interventions/therapy is made available in future.
>
Prenatal, testing : It is aimed at detecting the presence of
genetic or chromosomal abnormalities in fetuses.
Examination of
the genetic make up of the fetus is done through amniocentesis,
chorionic villi sampling, placentocentesis, cordocentesis (blood
sampling from the umbilical cord) and skin and other biopsies,and
also examination of blood samples
from the mother. Embryoscopy
may be used to detect external malformations.
Anonymous testing:
Researchers may conduct anonymous testing or
screening on the general population in order to establish the
prevalence of genetic anomalies and deleterious genes.This is now
possible by PCR(polymerase chain reaction) amplification which
uses a single blood spot or a small sample of blood for multiple
tests
Blood spots collected in screening newborns for treatable
disorders could be used to collect epidemiologic information
about genetic predispositions to disorders of late onset.
In
cases where the information derived from stored specimens might
be useful to individuals, the code of anonymity may be broken.
All the criteria mentioned in the general principles
like
informed consent, confidentiality etc. should be observed.
Genetic Registers • Computer based genetic registers are subject
to Data
Protection Act but there
is
need
for
additional
safeguards for all genetic registers,
including storage of
information in a safe place and manner, restriction of access to
only those specifically responsible for the register, and the
15
removal of
identifying
research purposes.
inf conation
data
when
are
used
for
It may be done
The practice of genetic screening in employment:
employees
i.e.
only when justified and in the interest of the
Sickle Cell Disease screening for those in aviation industry who
are likely to be exposed to
atypical atmospheric conditions. An
employer may use genetic screening procedures with the consent of
entrants (This issue is not decided
in many countries).
This
screening may be only for a disorder which might be harmful to
the
employee or any disorder which may jeopardise other people
in the relevant function or job. (Any possibility of direct or
indirect threat to the job should be scrupulously avoided.)
Subject
to
prior
consultation
with
workplace
representatives, and with appropriate Health authorities, it is
recommended that genetic screening of employees for increased
occupational risks ought only to be contemplated where-
i)
there is strong evidence of a clear connection between the
working environment and the development of the condition for
which genetic screening is to be conducted;
ii)
which seriously endangers
the condition in question is one
<
is
one in which an affected
the health of the employee or
a
serious danger to third
employee is likely to present
parties; ;
iii) the condition is one for which the dangers cannot be
eliminated or significantly reduced by reasonable measures
or
respond
to
the
modify
taken
by
the
employer
to
environmental risks.
<
Insurance companies should adhere to the current policy of not
requiring any genetic tests as a prerequisite of obtaining
This is forbidden by law in some countries .e.g. USA.
insurance.
Public policy & genetic screening
There is a very great need for improving public: awareness
There should be a central
and understanding of human genetics,
coordination and monitoring mechanism for a genetic screening
programme in the iinterest of the public, the majority of which
have rittle knowledge of genetics.
III. THERAPEUTIC APPROACHES INCLUSIVE OF GENE THERAPY
Genetic disorders which require nutritional replacement
therapy like phenylketonuria do not pose any ethical problem.
Replacement with animal products should follow the rules as
stipulated for other diseases.
Gene Therapy
The goal
*
of
human
genetic research
16
is
to
alleviate
human
of this
------ and logical part
suffering.
Gene therapy is a proper
ethical
codes
to all the <---effort.
Gene therapy should be subject
■*
that apply to research
1------- involving patients.
i)
somatic gene therapy 1S .^1® g^^g^iowed^or^he purpose
types of Genetic Engineering
onc. Hi-ease when it is an ethical
of preventing or treating a ser10
21 irted to the alleviation
therapeutic option
^should
It should be restrioted to
__x
threatening or
aLeiiir
to
) ”
in 'per-ltfO
individual patients <
change normal
— — human traits.
of the
Safety should be ensured especially because
gene insertion. It
possibility of unpredicted consequences of
should
provide for
should provide
for long
long term_
term -rveiiiance.
surveillance. Jnforme^consent^ust
as
be taken especially regarding u.----children could be candidates for therapy.
therapy.
attempted at present because
ii) Germ Line therapy should not be evaluate the risk to future
there is insufficient knowledge to is a more valid reason than
generation.
Unpredictable, outcome acquiring undue powers.
fear of unscrupulous people in power
for altering human traits
iii) Enhancement Genetic Engineering
insufficient information
should not be attempted as we possess attempts to alter/enhance
at present to understand the effects or
the genetic machinery of humans.
or ethical for parents to give for
It is not wise, safe their normal offspring
in order to
example growth hormone to
basketball players. Similarly it
produce very large football or
engineering for improvement 01
would be unethical to use genetic if specific gene/genes are
memory etc even
intelligence,
identified in future..
for
personality, character,
j
iv) Eugenic Genetic Engineering
fertility,
intelligence
and physical,
-3, fertility,
formation of body organs
ics
are
enormously
complex,
mental and emotional characteristics
unknown genes that interact in
E-ZLcr.z,
Dozens, perhaps hundreds, of contribute to each such
trai .
totally unknown ways, probably
interact with these genetic
Environmental
influences also
,The concept of remaking a
backgrounds, in poorly understood ways,
is not realistic and has
human i.e. eugenic genetic engineering
unscrupulous p€iople in
grave risksi of this being misused by
power. This
f--- should not be allowed.
and international COLLABORATIVE
ISSUES RELATED TO NATIONAL
IV.
RESEARCH
Tt is important that all research with human subjects
adequately" protect the rights and
^o^guidTlTnes of
human genetic research in India
, tions laid9 down by the
the funding agencies and rules and regulati
r-onnt-rv
Govt, of India if it were conducted wholly within the 1 •
17
International collaborative projects should not only follow
the
sure
that
but
make
the
guidelines
for
collaboration
the
given
by
guidelines
the
investigations
should
follow
to
with
regard
especially
bodies
financial agencies/national
standards
,
international
includes
ethical guidelines.
This
declaration of Helsinki or Nuremberg code. Written descriptions
of the specific procedural implementation of such policies that
have been adopted by the collaborating institutions in their own
countries are required.
Investigators should be very clear as to which part of the
project will be done in a foreign country and also what specific
sample will be taken out of the country for the project. It
should be strictly forbidden to utilise the sample for any other
purpose than for the specific purpose mutually agreed to and
sanctioned by the appropriate authority. To be specific no DNA
from human subjects should be sent out of the country unless it
follows the procedure and guidelines laid down by the Indian
Council of Medical Research/Government of India.
In the event of
failure of agreement the guidelines of the. country (India) shall
prevail.
Commercialization
The human genome« in its natural state is not subject to
private, national or 1transnational ownership by claim of right,
patent or otherwise.
Intellectual property based upon the human
genome may be patented or otherwise recognised in accordance with
national laws and international treaties. Question of patenting
DNA should be clearly stated.
Who should benefit should also be
specified. The percentage benefit to be given/received should be
mentioned in writing through a carefully drawn Memorandum of
Understanding.
V.
HUMAN GENOME DIVERSITY
Deptt. of Biotechnology, Ministry of Science & Technology
>n genomic diversity which envisages
has brought out a document on
the following t
(i)
■—
---------------------------- j.
To support a network of laboratories in India for studying
well-defined
genomic
diversities
of
anthropologically
for
protocols
populations
following a uniform set
of
of
set
collecting information, and screening a uniform
project
genomic
markers
by
inviting
and
implementing
proposals under the framework of this programme.
(ii) To establish a national repository of biological samples
safeguards,
(DNA,
cell
lines
etc.)
with
appropriate
regulations and monitoring.
(iii)To establish and integrate regional and national statistical
databases comprising genomic, epidemiological, cultural and
linguistic data on Indian population.
18
The biological tools, materials and analysis of DNA samples
will be carried out by Indian scientists in Indian laboratories.
The biological samples collected under this programme, as well as
legal and
the data generated,
have a variety of ethical
ethical,,
commercial implications.
Scientists involved in this will follow appropriate ethical
protocols and respect the rights and sensitivities of the
The relevant issues
participating individuals and populations.
pertain to: i) the mechanism for collection of samples, ii) who
can have access to the samples and for what purposes, iii) who
owns the DNA; and iv) to establish measures for quality control
of the laboratories.
VI. RESEARCH RELATED TO DNA BANKING
Primary use
DNA samples should not leave the country without following
the guidelines evolved by the Govt.
of
India with clear
undertaking that it should not be used for any other purpose
other than the original intent for collection.
Secondary use
In every case where a new study proposes to use samples
collected for a previously conducted study, the ethical committee
should consider, whether the consent given for the earlier study
also applies to the new study, whether the objectives of the new
study diverge significantly from the purpose of the original
protocol, and. whether fresh consent has been obtained when the
new study depends on the familial identifiability of the samples.
Internationally the accepted norm is to obtain fresh consent
for any secondary use.
The consequences of DNA diagnosis for
which no treatment is available or for conditions menifesting
late in life e.g. breast cancer, Alzheimer’s etc. should be
seriously considered before embarking on DNA diagnosis.
VII. DNA DIAGNOSIS
The general principles of informed consent, confidentiality
and other criteria used for any investigation in genetics should
be followed.
Preimplantation DNA diagnosis- As there are various types of
investigations in this area this should be reviewed by an ethical
committee.
In children - Parents are advised not to get the diagnosis done
especially in cases like Huntington’s disease till the child
reaches the age of proper ’’consent” to the test.
In adults, the vulnerable population should be kept in mind while
following the general principles.
Unless appropriate counselling
19
services are available DNA
psycho-social implications.
VIII.
diagnosis
is
fraught
with
grave
ASSISTED REPRODUCTIVE TECHNIQUES
Definition
Any fertilization involving human sperm and ova that occurs
outside the human body.
There is no objection ethically as at
the moment for IVF or any other related procedure for conducting
research or for clinical applications.
11 Informed consent ” should include information regarding use
of "spare" 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.
Investigators
j
\ the ownership
\ of the embryos
should clarify
whether they belong to the biological mother or the laboratory.
Abortions should never be encouraged for research purposes.
A National Advisory Board for ethics in reproduction should
be constituted
-- Lit-*—1 which can evaluate research proposals in this
area.
Fetuses as research subjects
Research involving human fetuses
raises special concerns,
The fetus has a unique and inextricable
relationship to the mother,
It cannot consent to be a research
subject.
The fetus may also be an indirect subject of research
when women, who may be pregnant, participate in the research.
Respect for
safeguarding of personal and parental reproductive
choices - Reproductive decisions should be the province of those
who will be directly responsible for the biological and social
aspects of child bearing and child rearing,
Usually this means
the family.
However, when a couple is unable to reach an
agreement,
the mother should have the
final
authority
of
decision.
Women have a special position as care givers for children
with disabilities,
Since the bulk of care
t
falls upon the woman,
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.
cloning (i)
through
Nuclear
transplantation
20
This
seems
to
be
a
possibility in the near future as sheep and monkeys have
already been cloned,
The ethical implications need not be
expanded.
Research on human cloning definitely should be
forbidden by law.
(ii) through embryo splitting:
Embryo splitting is ethically
acceptable provided that the ]resulting embryos are not
damaged or destroyed in the process,.
There are many issues
involved here which require separate discussion.
a.
It is ethically acceptable to use embryo splittingr to
produce embryos for isimult:aneous implantation in the :same
woman.
----- embryos shall be produced from a
(Not more thcfn four
single embryo)
and
to
t )
cryopreserve embryos resulting from
embryo splitting for transfer and
implantation
in a
subsequent IVF cycle, should an initial IVF cycle using
split embryos prove unsuccessful.
b.
It is unacceptable to split embryo and retain
cryopreserved state for the sole purpose of :
them
in a
providing an adult with an identical twin to raise as
his or her own child
having a large family of genetically identical children
retaining a ’’back-up” embryo as a potential replacement
for a child who dies
retaining a ’’back-up” embryo as a potential
£
organ or
tissue donor for
-- • an identical twin already born
retaining a ’' ’back-up” embryo as a potential source of
fetal tissue, organs or ovaries
donation to others
sale to others.
Whether fit is
‘ ethically acceptable to split embryos for the
specific purpose of allowing preimplanation diagnosis; on one of
the resulting embryos if that embryo would be damaged in the
process is debatable.
Research involving human embryos:
*
This
should be permitted with
appropriate safeguards. Studies of ’’normal” embryos will lead to
understanding the process of fertilization,
fertilization, which cannot be
e2tlHe3Y accoinPlished k)y animal research
research..
Additionally, studies
?
abnormal’" embryos are
--a potential source of scientific
information at the molecular level about the origins and
development of genetic disorders, malformations and pediatric
cancers.
To understand the natural history of some genetic
diseases, it will be necessary to obtain sperm and eggs from
parents who are at higher
hicjher risk to transmit these
•t-d« conditions to
offspring, and to study the genetic mechanisms involved compared
21
Bp
U8243
to those in "normal” embryos. Thus, restricting embryo research
only to spare embryos donated after infertility treatment will
not be sufficient.
_ > moral status as infant or
The embryo does not have the same
:
although it deserves respect and moral consideration as a
child
developing form of human life,, This judgement is based on three
pre-implantationi
embryos;
embryos;
absence
of
characteristics
of
no
of
sentience
possibility
individuation,
developmental
(feeling) and a high rate of natural mortality at this stage,
Harm cannot be done to such an organism until the capacity for
sentience has been established. From this perspective there is a
clear difference between the moral statusj of living children and
in research.
The
embryos.
It is possible to damage an embryo
<
sense
only
if
the
damage would become "harmful” in the moral
a
future
sentient
embryo was transferred to a human uterus and
This
person was harmed by the damage once
once done to the embryo..
regulations
forbidding
the
transfer
possibility can be avoided by
a human
human
of any embryo that has been involved in research to
uterus.
Respect for embryo can be shown by (1) accepting limits on
(2) committing to an
what can be done in
in embryo
embryo research,
planned
inter-disciplinary process
orocess of
of peer group review of --process; for
research, and
and (3)
(3) carrying out an informed consent
for
the
's
embryo
donors.
Further,
respect
for
theembryo
< ~
gamete and
regulation
of
the
limited moral status can be shown by careful _ _
’;
against
research,
safeguards
commercial
conditions
of
the
embryo
research,
and
limiting
time
wi
exploitation of
which research can be done to 14 days.
days- This
Restriction
in keeping with the policy in several nations tl at P®™
research with embryos (Australia, Great Britain American College
of Obstetrics and Gynaecology 1986; . Human Fertiiization and
Embryology Authority, 1993; Royal Commission on New RePr^ct^®
Technologies,
1993) until the developmental stage when the
"primitive streak" appears.
At this time, thee
nervous system begins and the embryo begins to become a distinct
individual.
Adoption:
Adopted children or children born from use of donor
gametes, and their social parents, shouldhenze the r J
whatever medical or genetic information about the genetic Parents
that mly be relevant to the child's health, Genetic testing of
adopted children or children awaiting adoption should fall under
the same guidelines as testing of biological children.
IX. HUMAN GENOME PROJECT (HGP)
J
;-- ) is an international research
The human genome project
(HGP)
structure of human
effort, the goal of which is to analyse the estimated 1,00,000
DNA and to determine the locations of the
to analyse the DNA
Another component of the programme isprovide
genes.
comparative
set
of
non-human
model
organisms
to
of a
information that is essential for understanding how the human
genome functions. The project began formally in 1990.
22
V
The investigators have been able to identify and isolate
human genes particularly those associated with diseases.
The
project has the potential for profoundly altering our approach to
medical care from one of treatment of advanced disease to
prevention based on the identification of individuals at risk,
HGP is arguably the single most important organised research
project in the history of biomedicine.
Ethical considerations
Implications of
of questions for -
using this genetic knowledge pose a number
1)
individual and families •- whether
..1 _2.
to participate in testing,
with whom to share the results,, and how to act on them
2)
health professionals - when to offer testing,
how to
ensure its quality, how to interpret the results and to whom
to disclose information
3)
employers,
insurers,
the
courts
and
other
social
institutions - the relative value of genetic information to
the decisions they must make about individuals
4)
for governments - about how to regulate the production,
production
and use of genetic tests and the information they
provide
and how to provide access to
tj testing and counselling
services for society
5)
for society - how to improve public understanding of science
and its social implications and increase participation of
the public m science policy making.
X.
RESEARCHER'S
PRACTICES
RELATIONS
WITH
THE
MEDIA
AND
PUBLICATION
Researchers have a responsibility to make sure that the
public is accurately informed
-- 1 about
-- - results without raising false
hopes or expectations,
Researchers should take care to avoid
talking with journalists or reporters about preliminary findings.
^4--------4
J
Sometimes the media report
potentially
promising research
subsequently cannot be
be validated,
validated.
Sometimes the media lreport
research on animals in such a way that the public thinks that the
step to treatment for humans is
^3 an easy one.
Retractions almost
never appear in the popular press or on television.
Therefore it
is important to avoid premature
reports.
The
best
safeguard
against inaccurate ireporting
_1
is for the researcher to require, as
a condition for talking withi the media,
that the reporter supply
a full written rather than oral version of what will
..ill be reported,
so that the researcher can make necessary corrections.
Investigators publication plans
privacy or <confidentiality of subjects should not threaten the
(publication of pedigrees
can
easily
result
in
the
identification
------- .i
of
studying
23
participants). It is recommended that consent for the publication
shall be obtained separately rather than as part of the consent
to participation in research or treatment.
XI.
AND
GUIDELINES
ON
ETHICAL
ISSUES
FOR
PROFESSIONALS
PRACTITIONERS OF GENETICS IN THE FIELD OF HUMAN GENETICS
General ethical guidelines in medical genetics for health
Respect for person includes
workers and public are outlined.
informed consent, right to referral. full disclosure, protection
of confidentiality and respect for children and adolescents in
the context of genetic testing.
a)
Access to genetics services - Access to genetics services
should not depend upon social class or ability to pay.
Whatever services exist in a nation should be available
Genetic services should be provided
equally to everyone.
first to those whose need for them is greatest.
Hence,
there is a great need to set up genetic centres for
counselling as well as therapy where available.
b)
Non-directive counselling - Genetic counselling should be
non-directive i.e. the couple should be explained the
various options available, while the final choice should be
left to the couple.
Illiterate subjects with no or poor
understanding of scientific facts may be told what other
persons in their situation may opt to do.
c)
T_1
Voluntary approach - It is essential to ensure that the
individual voluntarily approaches genetic services including
genetic counselling, screening for susceptibility to> common
diseases,
occupationally-related
diseases
or
to
and prenatal
testing children,
presymptomatic testing,
diagnosis.
Persons who choose or refuse genetic services
or
discrimination
object
of
should
not
be
the
genetic
stigmatization.
Persons who choose or refuse
testing or services should not be penalized in terms of
health care, employment, or insurance.
The only exception to the rule of voluntary screening
should be newborns, if, and only if, early treatment is
available that would benefit the newborn.
Therefore, the
government may mandate screening for newborns who would be
When this is
harmed by the absence of prompt treatment.
obligation
to
done the government would have the ethical
for
provide prompt, affordable treatment for the disorders
which they screen.
Otherwise the screening would be in
vain.
d)
Disclosure of information - There should be full disclosure
of
clinically
relevant
information
to
patients.
Professionals should disclose all test results relevant to
an individual's own health or the health of a fetus,
including results indicative of any genetic condition, even
if the professional regards the condition as not serious.
24
r
e)
‘, after
■'i child should decide,
Those who will bear and rear the
about
the
effects
information, i
receiving full and unbiased
u.
their
socio-cultural
of the conditions on their family and
even if
situation.
Test results should be disclosed
controversial
or
New
ambiguous
conflicting,
or
be disclosed.
interpretations of test results should also health (e«g«
relevance
to
Test results without direct
in the absence of X-linked
nonpaternity,
fetal sex
necessary to
disorders) may be withheld if this appears
includes
the duty to
Disclosure
protect a vulnerable
vka*.—- party,
'famiiies if new developments arise
recontact individuals or
that are relevant to health.
Duties to family members - In genetics, the true Patient: is
Family members
a family with a shared genetic heritage. information with
x
vch Sth":
••__”1 If children are intended,
shaSe information with their partners.
h-.wc, a
Individuals ha
IMir.ation with their partners. _ Irtwxau.1.*ha^
duty to inform other family members who
may
medical
geneticist may
If an individual will not do so, the i--without
issue a general warning to family members, but
individual.
revealing
information
about
the
affected
duty in
Preserving patient confidentiality is a well-known
it
conflicts
with
medicine.
This duty is mitigated if
to
other
parties.
another well-known duty, preventing harm
f)
parties
Protection of privacy from institutional
institutional third i aT
for harm
not have .eo.ss to such
such
data and Should not be permitted to require genetic tests.
g)
' ' for
,m.Ul al.g»o3ls - This =bouia he Perfor«ed only
the
mother.
reasons relevant to the health of the fetus or ----to select
Prenatal diagnosis should not be performed solely
of an X-linked
absence
or
the sex of the child (in the
female,
disorder). Sex selection, whether for male or
of
those
already
born,
denigrates the fundamental personhood
unbalancing sex
societies
by
and has the power to harm l
___ i to large groups of people
ratios.
The potential harm
- families,
' > 1benefits
to individuals or
outweighs any immediate
-----has already passed legislation
The Government of India
India has
banning diagnosis of sex for non -medical reasons.
* ; for
parents
Prenatal diagnosis can be used to, prepare
prenatal
Therefore,
P-*——
the birth of a child with a disability,
available
to
such
’parents
who
request
it
diagnosis should be
provided
that
they
understand
and
are
but oppose abortion
the risks to the fetus.
willing to accept t.
be performed
In some cases, prenatal diagnosis may be
protect thec^sesltof°f tmorlTidthtnxietyeSor situations where
confirmed paternity testing would benefit the mother s mental
prenatal
25
prenatal paternity testina iwould
' ' ’benefit the mother’s mental
conceive)6.if
occurred ^ile
---- » a couple was trying to
Professionals should :
use^n iJ1iV(O1V4e-d in Prenatalrecognize
diagnosisthe human and economic
J and should limit its
use to situations where there is
a clear benefit.
RESOURCE MATERIAL
1.
The human r
-genome
project & the future of Medicine
Mark S Guyer & Francis S Collins
Human Genome Project, Guyer & Collins,
Vol 147,
P 1143-1151.
Nov 1993,
2.
Nuffield Council on Bioethics U.K.
Genetic screening & ethical issues
3.
Nuffield Council c_.
Z
on Bioethics,
UK
Human tissues Ethical
--- & legal issues
4.
Safeguards for Gene Therapy
Notice Board, The Lancet,, Vol.339, Jan 25,
1992 Page 238
The Prenatal Diagnostic Techniques Act,India
(1994).
DBT Guidelines for Gene Therapy,India (1996)
5.
6.
7.
family
26
ETfflCAL GUIDELINES FOR RESEARCH IN TRANSPLANTATION
INCLUDING FETAL TISSUE} TRANSPLANTATION
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 devised 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, and 1989. 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.
III.
IV.
V.
VI.
Recommendations on existing legislation
Recommendations on Institutional Review Committees
Transplants from live or cadaver donors
Embryonic and foetal tissue and organ transplantation
Xeno-transplantation
Transplantation for cosmetic purposes.
I.
JRECOMMEWDATIONS ON EXISTING LEGISLATIONS
This committee strongly recommends an amendment of the
existing
1 Transplantation of Human Organs Act, 19941 with
transplantation
'Transplantation of Human Organs Rules, 1995' to bring within its
ambit transplantation research,
including transplantation of
foetal tissue or organs, since the existing Act does not permit
this
in clinical practice and is silent on research on
transplantation.
A.
THE SECTION ON BRAIN DEATH AND THE ACCEPTANCE OF BRAIN DEATH
AS THE LEGALLY ACCEPTED DEFINITION OF DEATH MUST BE
DE-LINKED FROM ORGAN TRANSPLANTATION AND MADE UNIVERSALLY
APPLICABLE.
The diagnosis of brain death, as it stands under the Act at
present, is legally valid only when the concerned patient is
a donor of organ(s). This has led to the following anomaly:
When the patient is a potential donor of organ(s), once
a
diagnosis of brain death has been made and the
consent of the legal heirs for organ donation obtained,
the heart, liver, kidneys, pancreas and any other vital
organ can be removed for transplantation.
27
When, however, for some reason,, the patient is not a
donor of organ(s), life support systems cannot be taken
off even after the diagnosis of brain death has been
made as specified in the Act.
This results in
prolongation of agony for the relatives, unnecessary
increase in costs and denial of life support systems
such as ventilators to other patients whose lives might
be saved by them.
B.
EXCLUDE THE SPOUSE FROM THE CATEGORY OF RELATED DONORS OF
ORGANS AS THERE IS NO GENETIC SIMIIaARITY BETWEEN THE SPOUSE
AND THE RECIPIENT.
The organ taken from the spouses is as liable to rejection
as is that from any other unrelated individual.
C.
BRING TRANSPLANTATION RESEARCH INCLUDING TRANSPLANTATION OF
POSTAL TISSUE OR ORGANS WITHIN THE AMBIT OF THIS ACT.
The existing Act does not permit the use of fetal tissues or
organs as transplants in clinical practice and does not
include the area of research on transplantation.
IT.
RBCOmKrnj^TIOifS CW IWSrrrUTIOifAL RK^IW CXMOfTTTKES
Scientific Connittee
1.
Each research proposal should initially be processed by the
local scientific committee. After approval of the scientific
committee has
been obtained,
the proposal should be
scrutinised by the local ethics committee. Special attention
should be paid to all aspects concerning safety and
efficacy.
2.
Strict criteria are recommended for the formation and
function of scientific cowmittses in institutions proposing
to carry out research on organ transplantation.
Such
committees must be composed of at least : two physicians and
two surgeons competent in the field of transplantation of
the tissues or organs to be used; an immunologist with
special interest in tissue-typing and transplantation; a
microbiologist; a biostatistician; a member-secretary who
shall
be
responsible
for
all
administrative
matters
pertaining
to
the
ethics
committee,
including
the
preservation of minutes of each meeting and all other
relevant documents. At least two members of the scientific
committee shall be from outside the institution.
Bthics Committee
1.
We recommend strict criteria for the formation and function
of ethics committees in institutions proposing to carry out
research on organ transplantation. Such committees must be
28
I
least two physiciansf one„io1f1 “whom
JS “fter
composed of at “““and' tl^e “^sXntaV^; look
two Oasie
care
charge of the
two
recipients of organ
of
scientists, one of twhom has experience in
two
senior
nurses,
one
o
J
f
'
tissue
research;
taking
^nsplantation; °fourcompeJenS^n^thical 7^
4
Si^Suer^nnosopSt, social -rker
^oin) ; -
administrator; a member-secretary who shall be responsible
for all administrative matters pertaining
committee, including the Preservation of minutes of each
meeting and all other relevant documents At least three^of
these members must be women to ensure attenti
concerning this sex.
2.
of Health, USA, etc.
When doubt exists, the committees
shall seek the opinion of the Indian Council of Medical
Research, which shall be binding.
3.
4.
5.
These committees must meet regularly, maintain detailed
records on all proposals brought before them and their
decisions on each project with reasons for acceptance or
rejection, reports on follow-up observations on each project
sanctioned, the final report on each project and a copy of
each publication resulting from each project.
These committees must ensure that all records pertaining to
each research project sanctioned are carefully maintained
- • a minimum period of five years
under their supervision for
be the joint
the
completion
of the project. shall
It :---after •!
the
principal
responsibility of the ethics committee and
demand
by any
research officer/s to produce such records on
authorised individual or agency.
soon after
their
These committees must be certified
agencies
according
or
establishment by a Government agency
to procedures laid down by the Ministry
I------- of Health and Family
.
Welfare. This certificate must be renewed
1------ -from time lo time
as specified by the Ministry.
TIT- TRANSPLANTS FROM LIVE OR CADAVER DONORS
DEFINITIONS
Cadaver: A dead body. For purposes of this document,
refers to a dead human body.
the term
Death: This was originally defined as entire and continuous
cessation of respiration and circulation. It has since been
recognised that the heart could continue beating for a time, even
-c
29
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. The salient features are described below:-
Entire, permanent,
permanent, and irreversible cessation of functions
of the brain stem - this is synonymous with brain-stem death,
since the centres for the control of such essential body
functions 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, and 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, arug intoxication, or severe
metabolic upset, must be excluded. Finally,the absence of all
brain-stem reflexes 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. Ail responses have to be absent on at least two occasions
with an interval 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. This
precaution ensures that the patient will not suffer serious
oxygen deprivation while 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.
Gtiidelxnes on Live donor transplants
1.
Donation from a live donor should b€» 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
30
*
binocular vision and produce disfigurement,
permitted in a live donor.
2.
3.
4.
4
it should not be
Surgery on the donor inflicts bodily harm on him or her, the
extenuating circumstances being the saving of another ^un
life. It is imperative that no risk be imposed on the doner
beyond that inherent in surgery and the loss of a vital
organ. Any manner
manner of
of experimentation, though it may be
intended to improve
improve the
the survival of the graft, should be
prohibited if there is; the slightest extra risk to the
pre-treatment
of
the
donor
with
donor.
Examples
are
immunosuppressives or anticoagulants.
Every such research project should be preceded by careful
assessment of predictable risks and compared to foreseeable
benefits;
and
improvement
in
the
success
rate
o
transplantation.
The interests of the donor should always take priority over
those of the recipient of the transplant.
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 him, before his consent is taken.
6.
It follows that the donor should have the legal capacity to
give consent; should 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
1
a
decision
comprehension of the subject to be able to make
and
with full understanding of the consequences. Children
C
with
mentally
incompetent
adults
as
also
individuals
restricted autonomy should not be used as organ donors or as
subjects for such experiments.
7.
for
Since the experiment would have
consequences
recipient too, the donor must be fully informed of
nature of the procedures and the possible effects on
recipient, before consent is taken.
8.
The responsibility of providing the above information to the
donor, and of making sure that he/she understands fully the
' " he or she
implications of what is to be done and what
the.
individual
who directs
on
consents to, rests entirely
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. fThe experiment should be undertaken only
if there is no other method available of finding the answer
to the question raised. Research should also be aimed at
developing means that will benefit the donor.
10.
The
experiment
should
be
so
planned
and
conducted
31
OX
r=/
*>’■
Y'!
as
the
the
the
to
avoid all unnecessary risks to the donor, to the organ to be
transplanted, and to the recipient of the organ.
11.
Proper' precautions should be taken and adequate facilities
should be available to protect the donor from the most
remote possibility of harm.
12.
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.
13 .
If at any time 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.
14 .
This does not preclude any treatment or procedure done on
the organ or tissue after removal from the donor•s body t
aimed at reducing its antigenicity and improving graft
survival.
GiixdeljLEies on Cadaver donor t-jcansplants
1.
Every one of us should give a thought to the need for organ
donation after 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 of the
deceased may be respected after death.
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.
3.
It is important that the medical team use the body only for
the purpose to which the deceased had consented before
death, or to which the family had acceded afterwards.
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.
5.
Under no circumstances
any such procedure.
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 from both
sides: the recipient and his or her family will not be
informed of the identity of the donor, and the family of the
should
32
I
financial
gain
be made
from
the
donor will equally be kept unaware of who receives
of
any
form
avoid
to
donated organ.
This is essential
exploitation by the donor’s family.
Guidelines on recipients; of transplants
1.
The patient with failure of a vital organ is at a particular
disadvantage in developing countries due
due to
to the enormous
cost involved for the available interventions, If the organs
involved are the kidneys, most Indians cannot afford to
maintain themselves on dialysis, Similarly ventilators are
There are no artificial
_____
available at very few centres,
like
the
heart, the lungs and the
supports for other organs
death
is
imminent
and
no
means is available to
liver, so
keep the individual alive short of replacing the organ
concerned. Thus a measure of urgency is introduced into the
search for a donor organ.
2.
desperate patient may consent to procedures which put him
or her at risk. It is all the more important that every
research protocol for transplantation should be carefully
reviewed by a committee of suitably qualified scientists,
jurists and other eminent members of society, so that its
scientific and ethical basis may be impartially evaluated.
3.
The transplant
expertise.
4.
Adequate data management, tissue storage, and surveillance
it is
procedures should be available in a centre before it
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
scientific content of a study and the best interests of the
there be need to choose, the experiment
patient. Should
Should there
abandoned
and the patient should receive the best
should be
treatment possible.
r
research
team
should
have
high
technical
jRecomBeiided reading
1.
(eds): Ethical Problems in
Kjellstrand CM, Dosseter JB,
Dialysis and Transplantation, p 163-168. Dordrecht, Kluwer
Academic Publishers, 1992.
2.
The Nuremberg Code. Trials of War Criminals before the
Nuremberg Military Tribunals under Control Council Law No.
10, Vol 2, pp 181-182. Washington DC, US Government Printing
Office,
1949. World Medical Association, Declaration of
amendment. 41st World Medical Assembly,
Helsinki. Latest amendment.
Hong Kong, 1989.
33
IVa
mBRSTOWIC ARD FOlffTM. tissue and organ transplantation
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 nerve 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 trick the neurones into 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
in an effort at allowing the re-establishment of damaged neural
circuits were started.
The immunological complication that
results whenever any foreign tissue is transplanted into a human
was a barrier.
The use of foetal tissue is one of the means to minimise the
chances of rejection. In the early weeks after conception, foetal
cells multiply rapidly and show very little antigenicity because
it has not yet developed many surface antigens. 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 preserved by cooling
and reanimated, As the technology for developing immortal foetal
cell lines for study of gene regulation, pattern formation in
embryogenesis, models of cell interaction and function, vaccine
development, cell growth and regulation, cancer, and the immune
response was perfected, hopes for the use of these cells as
transplants strengthened.
Non-neural
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 immunodeficiency
disorder. Success has also been reported in the use of foetal
thymus
in
the
reconstitution
of
a
severe
combined
immuno-deficient (SCID) child in Italy. The child is now 17 years
old and exhibits normal immune responses even though his T cells
are 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.
t
DEFINITIONS
Embryonic state: between 15 days and 8 weeks post-conception of a
pregnancy. In the absence of more precise information (i.e.
menstrual cycle length), conception is presumed to have taken
place two weeks after the beginning of
the woman’s last
<
menstrual period. The distinction of the 15-day stage as the
34
I
*
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. At 8 weeks the rudiments of nearly all the
main structures have been laid down and there is a general
appearance of a mammal-to-be with four limbs and a head.
Foetal stage: Subsequent period between 8 weeks and the time the
baby is born, at approximately 38 weeks post-conception (40 weeks
post-last menstrual period). 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 at
least an assault upon it. If doctors wish to perform experiments
legally, they must seek statutory authority.1 (Keown 1993)
Dead fetus:An expelled or delivered foetus that exhibits no heart
beat or spontaneous breathing. Some organs, tissue and cells
remain cilive for varying periods after the moment of death of the
foetus.
Neonate: Newly born, live individual of any gestation period.
Giiid&lln&s on research using foetal tissue or organs
for transplantation in India
1.
Every transplantation or research project involving the use
of embryonic or foetal tissue must be approved by the local
scientific and ethics committees.
2.
All members of the hospital or research staff - medical and
paramedical - directly involved in any of the procedures
will b€> fully informed of the purpose and implications of
the research project.
3.
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.
4.
Tissue for transplantation or research may be obtained from
dead embryos or foetuses, their death resulting from legally
induced or spontaneous abortion.
abortion, Death of an intact embryo
or foetus is defined as absence of respiration and heart
beat.
5.
Voluntary,
informed, written consent will be obtained from
the mother in two stages
s — first for the abortion;
next for
the 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 father’s objection carries no
significance.
35
6.
The mother will not dictate who
tissue taken for transplantation.
7.
Anonymity of donor and recipient will be maintained so that
neither party is aware of the identity of the other.
8.
The procedure of abortion, or its timing, will not be
influenced by the requirements of
the
transplantation
activity. These should be based solely on concern for the
safety of the mother.
9.
Those participating in termination of pregnancy will not, in
any way, be party to the subsequent usage of embryonic or
foetal tissue or profit from such usage.
10.
The procurement of embryos, foetuses
not involve profit or remuneration.
11.
Intact
embryos
or
foetuses
will
not
be
kept
alive
artificially for the purpose of removing usable material.
12 .
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.
13 .
Cells obtained from foetuses will not be patented with
view to making profits from their subsequent usage.
14.
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 follow to the foetus or neonate.
neonate, Since the
exact timing of the clamping of the umbilical cord has a
significant impact on the neonate and early clamping may
cause an abrupt surge in arterial pressure resulting in
in
cerebral
intra-ventricular haemorrhage,
particularly
be
premature
neonates,
normal
clamping
protocol
will
followed when collecting foetal blood for transplantation,
There is a risk that the neonate donor will develop a need
for 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
risks of the donation and written consent obtained from them
on behalf of the foetus.
15.
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 are necessary to sustain organs
till such time as the diagnosis of death is made on the
Retrieval and
basis of cessation of cardiac function,
are
fetus
anencephalic
transplantation
of
organs
of
36
shall
or
receive
the
foetal
their tissue
will
a
ethically permissible qnly after such diagnosis of death is
made.
16.
Whilst the transplantation of tissue from one animal into
__
another
is permissible wheni a rational explanation for such
experimentation has been provided, transplantation of foetal
tissue into man is subject to much greater scrutiny.
17.
No transplantation of foetal tissue into man will
permitted unless the following criteria have been met:
There will be a
transplantation.
detailed
scientif ic
basis
for
be
such
Animal experiments must have shown successful results eradication of disease, elimination or amelioration of
symptoms and signs or successful substitution of
of
deficient
chemicals
and
restoration
normal
These
must be
physiological function by the transplant,
journals
with good
documented in one or more indexed
“
j
peer review mechanisms.
iii. 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.
iv.
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 proceduret specially with
reference to unequivocal demonstration of absence of
any transmission of disease through the transplant.
v.
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.
vi.
the mother must be
After obtaining her consent,
screened for transmissible disease, If possible, the
material to be transplanted must also be similarly
screened.
vii. Trials in human patients will be carried out only at
institutions
having
clinical
and
research
the
facilities needed for such trials, including those
that may be required to treat complications that may
follow such research.
viii.The research group and the institution/s in which they
work will undertake to conduct at free cost the
37
research on their human subjects and also treat
completely any complication that may follow their study
even if it appears several years after the conclusion
of the study.
ix.
The research group will provide the human subjects a
printed document explaining in simple, non-technical
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 of cost any complication that 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.
X.
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 the course of the study.
18.
The local ethics committee must ensure report-back measures
at every stage of research and confirm that a detailed
report on the procedures, findings and conclusions is
submitted to an indexed journal for publication even when
the results are of a negative nature.
19.
As with therapeutic transplantation, constantly updated
local
(metropolitan),
regional
or
national
lists
of
available tissues and organs should be set up to ensure that
optimal use is made of all available donations. These lists
should be made freely available to all authorised research
workers.
Recommended reading
1.
American Medical Association: Code of Medical Ethics
Current opinions with annotations 1996- 1997 Edition,
Council on Ethical and Judician Affairs. American Medical
Association, Chicago 1997 p 191.
2.
Boer GJ: Ethical guidelines for the use of human embryonic
or
foetal
tissue
for
experimental
and
clinical
neurotransplantation and research (The NECTAR guidelines).
Network of European CNS Transplantation and Restoration
(NECTAR). Journal of Neurology 1994;242:1-13.
3.
Council on Scientific Affairs and Council on Ethical and
Judicial Affairs: Medical applications of fetal tissue
transplantation. JAMA 1990;263:565-570.
4.
Coutts Mary Carrington:
21. National Reference
Fetal tissue research. Scope Note
Center for Bioethics Literature.
38
Kennedy
Institute
of
Ethics,
Wasshington, DC 20057. March 1993.
Georgetown
University,
5.
Keown John: The Polkinghorne report on fetal research: nice
recommendations, shame about the reasoning. Journal of
Medical Ethics 1993;19:114-120.
6.
Meinke Sue A: Anencephalic infants as potential organ
sources: ethical and legal issues. Scope Note 12. National
Reference Center for Bioethics Literature. Kennedy Institute
of Ethics, Georgetown University, Washington, DC 20057. June
1989
7.
Michaels
Marian
G,
Trader
J,
Armitage
G:
Ethical
considerations in listing fetuses as candidates for neonatal
heart transplantation. JAMA. 1993;269:401-403.
8.
OPRR NIH: Protecting human research subjects. Institutional
Review Board Guidebook. United States Department of Health
and Human Services. 1993.
9.
Robertson JA: Rights, symbolism and public policy in fetal
tissue transplantation. Hastings Center Report 1988;18:5.
Foetal tissue and organ transplantation Page 5
V.
X^O-TltAffSPKAHTATION
INTRODUCTION
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 scon realised
that unbridled use of simians would lead to possible extinction
of their species. Attention has thus turned to other animals.
DEFINITIONS
Primatess The most highly evolved of animals,
and homo sapiens.
Includes simians
Simians: The monkey species, including the great apes.
biological
sharing
similar
Species:
of
individuals
Group
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 are not permitted any choice.
Tissue: A collection of similar cells, all of which perform the
same function. An example is neural tissues within the brain.
39
Transgenesiss The introduction of a foreign gene into an animal
or organism. The transferred gene is called transgene.
XenO’-transplant: Transplant of tissue or organ from one species
to another. Here, we are principally concerned with transplants
from animal to man.
Eoonoses: Diseases peculiar to animals in the normal course of
as after
events that can,
under special circumstances
xeno-transplant - be transferred to man.
AnijBiJIs that can be used as sources of tissue or organ for jaam
Our immune responses are likely to reject all foreign tissue
us. The chances of rejection are
and organs transplanted into us.
minimised if the source animal is genetically similar to man.
This is the reason for considering the great apes as likely
sources.
Once the apes were ruled out, in order to preserve their
species ,r attention turned to cattle, sheep and pigs, In each of
these species, transplant of unaltered tissue or organ will
certainly lead to rejection.
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 cells obtained from
pigs with encouraging results.
Attempts are on so that pigs be engineered to possess
genetic material similar to that in man. This is done 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?
Equally worrying is the possibility of transferring germs
and viruses peculiar to pigs into man through transplanted
tissues. We are 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 to another and cause untold havoc in the new species,
which has no immunity against them.
Some of the most deadly
viruses currently devastating individuals and groups in some
African countries - that causing Lassa Fever, the Marburg virus,
and the Ebola virus are such examples. They appear to have* spread
40
from bats or other animals to man. The human immunodeficiency
These
virus (HIV) also appears to fall into this category.
questions are still unresolved.
‘ , fungi and viruses, there is
Apart from the known bacteria,
i
for
those
hitherto
unknown
and undetected, especially so
concern
slow viruses, that produce manifestation of the disease
with
years • often decades - after they gain entry into our systems.
Equally disquieting_j is the fact that once an infective
organism makes a -Jjump across species, it may spread like wildfire
in the new species - in this case, man.
consicieraiti oils
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
This anxiety has prompted most
unwanted genetic abnormalities,
countries, to ban all research on transplanting animal organs to
human beings till this issue has been satisfactorily addressed.
Measures proposed include the breeding of successive 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.
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.
Guidelines on xeno-trtinsplantation
1.
Experimental xeno-transplantation must only be permitted
Animal
to
- man
between different animal
species,
transplants must not be permitted at the present level of
knowledge.
2.
Institutional scientific and ethics committees must approve
of such research studies, with special attention being paid
to
their
relevance,
availability
of
facilities
for
extensive,
sophisticated
and
long-term
studies
for
transmission of disease through transplantation.
3.
An advisory committee consisting of reputed scientists in
the field, medical professionals, veterinary experts and
microbiologists must oversee all such transplants.
4.
detailed,
Records
on
all
research
studies
must
be
long
period
scrupulously maintained and kept available for a
of time - perhaps decades.
5.
Safeguarding the interest of the pioneer human recipients
when such transplants are permitted in future.lt is proposed
41
f
extensive studies on the animals to ensure
lnfeCtl°n mUSt be IRade mandatory. The human
recipients of tissues or organs must be carefully followed
up over a long term.
instance,
RecottBended reading
1.
Anonymous: Code for breeding, care, management
]
and housing
of
laboratory
animals.
New
Delhi:
.1:
Indian
Standards
Institute. 1978.
2.
Anonymous: Guidelines for the care and usage of animals in
scientific research. New Delhi: Indian National Science
Academy. 1992.
3.
Anonymous: The UFAW book on the care and management
j--of
laboratory animals. New York: Churchill Livingstone ”.. 1987.
4.
Baker HJ, Lindsey JR, Weisborth SH (Eds,):
The laboratory
rat.Volume II: Research application. New
York: Academic
Press. 1980.
5.
Bhardwaj KR, Purohit DC, Dhawan BN (Eds.): Laboratory animal
ethics
and
technology.
Lucknow:
Central
Drug Research
Institute. 1991.
6.
Coats ME: The germ free
Academic Press. 1968.
VI.
transplantation
animals
in
research.
New
York:
COSMETIC purposes
1.
Research on <transplantation for cosmetic purposes (such as
the creation of a new ear after transferring tissue from the
patient on to a mould which is later implanted into the
subcutaneous tissue of a transgenic mouse) will be governed
by the same principles as those in using donation of tissue
or organ from a live donor.
2.
Donation of tissue should be restricted to renewable tissues
like skin to an extent where such iremoval will not greatly
alter the normal functions of such tissue.
3.
It is imperative that no jrisk
‘
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 therex is the
slightest
extra
risk
to
the
donor.
Examples
are
pre-treatment of
the donor with
immunosuppressives
or
anticoagulants.
4.
Every such research project should be preceded by careful
assessment
of
predictable
risks
in
comparison
with
42
foreseeable benefits 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.
6.
It follows that the donor should have the legal caipacity to
give consent; should 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 so also persons with limited
autonomy should not be subjected to such surgery.
7.
'The experiment should be such as to yield fruitful results
transplantation without
___
for the good of patientts who need
xperiment
should
be undertaken
only
having the donor. The ei_t.
.
if there is no other method available of finding the answ
to the question raised.
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.
10.
> an animal,
Where tissue is to be temporarily transferred to
and
adequate
all necessary precautions should be taken, u.
facilities should be available, to protect the patient from
the most remote possibility of harm.
The subjects should be at liberty to withdraw from the
with
experiment and to abrogate the consent earlier
the
reasons
for
no requirement to offer any explanation of t-- --his or her doing so.
43
STATEMENT OF SPECIFIC PRINCIPLES FOR CLINICAL EVALUATION
OF DRUGS /DIAGNOSTICS/VACCINES/BERBALREMEDIES ETC.
Human
studies
designed
to
evaluate
the
safety,
effectiveness, or usefulness of an intervention include research
on therapeutics, diagnostic procedures and preventive measures
including vaccines.
The type of experimental procedures that a
patient is submitted to has become more complex and varied as the
complexities of medical research have increased.
It is clearly
accepted that it is essential to carry out research on human
subjects to discover better medical and therapeutic modalities
for the benefit of mankind.
It is equally clear that such
research on normal subjects and patients is associated with some
degree of risk to the individual concerned.
The guidelines have
been framed to carry out the evaluation of drugs, vaccines,
devices and other diagnostic materials on human subjects
including herbal remedies, in accordance with basic ethical
principles.
These guidelines are important for the protection
of research subjects against any avoidable risk and to guide the
researchers in the preparation of research proposals/protocols.
For the evaluation of proposed research
framework of guidelines is as follows:
A.
General Ethical Principles
B.
Special Ethical concerns related to
intervention the
1.
Drug Trials
2.
Vaccine Trials
3.
Medical Devices
4.
Diagnostic agents - with special reference to use of
Radioactive Materials and X-rays
5.
Trials with Herbal remedies.
A. GENERAL ETHICAL PRINCIPLES
subjects should be
All
the
research
involving human
conducted in accordance with three basic ethical principles,
namely respect for person/subject, beneficience and justice, The
guidelines laid down are directed at application of these basic
principles to research involving human subjects.
An investigator is the person responsible for the clinical
trial and for the rights, health and welfare of the subjects
recruited for the study.
He/she should have qualification and
in
clinical trial research methods for proper
competence
conduct of the trial and should be aware of and comply with the
legal and ethical requirements of the study protocol.
44
1.
1.1
Conjs&nt o£' Subject
Individual Informed Consent
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 are entitled to choose freely whether to
Informed consent protects
participate in research or not.
choice
and
respect
for
of
the
individual’s
freedom
individual’s autonomy.
When research design involves no more than minimal risk (for
example, where the research involves only collecting data
from subject’s records) the ethical review committee may
waive some or all elements of informed consent.
1.2
Essential information for prospective research subjects
Before
taking the
informed consent
of
subject,
the
investigator must provide the individual with the following
information in the language he or she is able to understand the aims and methods of the research.
the expected duration of the subject participation,
the benefits that might reasonably be expected as an outcome
of research to the subject or to others,
any risk to the subject, associated with study,
maintenence of confidentiality of records,
responsibility of investigators,
provision of free treatment for research related injury,
compensation of subjects for disability or death resulting
from such injury, and
freedom of individual to participate and to> withdraw from
benefits to
research any time without penalty or loss of
<
which the subject would otherwise be entitled.
1.3
Obligations of investigators regarding informed consent
The investigator has duty to*
communicate with prospective subject all the information
There should not be any
necessary for informed consent.
45
restriction on subject’s right to ask any questions related
to study,
and any restriction on this undermines the
validity of informed consent.
deception
exclude the possibility of unjustified deception,
undue
influence 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 prospective subject is adequately
informed.
Investigator
should
not
give
any
iunjustifiable
r
influence
the
assurances to prospective subject,
which may
subject’s decision to participate in the study.
-
as a general rule obtain from each prospective subject a
signed form as an evidence of informed consent (written
informed consent)
preferably witnessed by a person not
related with trial, and in case of incompetence, a legal
guardian or other duly authorised representative should do
so.
renew the informed consent of each subject if there
material changes in the conditions or procedures of
research along the trial.
are
the
The
Intimidation in any form invalidates informed consent,
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.
1.4
Inducement to participate
Subjects may be paid for the inconvenience and time spent,
in connection
i___
and should be reimbursed for expensesi incurred,
They
may
also
receive free
with their participation in research,
be
so large or
medical services.
However,
payments
should
not
However,
the medical services so extensive as to induce prospective
subjects to consent to participate in research against their
All payments, reimbursement and
better judgement (inducement),
medical services to be provided to research subjects should be
approved by the Ethical Committee.
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.
46
2.
Selection of Research Subjects
2.1
Equitable distribution of burdens and benefits
Effort may be made that individuals or communities invited
for research should be selected in such a way that the burdens
and benefits of the research should be equally distributed,
Special
justification
is required for
inviting vulnerable
subjects, whose rights and welfare must be protected.
Vulnerable subjects:- Equitable distribution of the burdens and
benefits of research participation is generally more difficult
when the intended subjects include vulnerable individuals ox'
groups.
These subjects are children, persons with mental or
behavioural disorders, who are incapable of giving informed
consent and prisoners, students, subordinates
subordinates^f service personnel
etc. iwho
'
have reduced autonomy. Adequate justification of their
involvement as research subjects is required.
The quality of the consent of certain social groups requires
careful consideration,
consideration, as their agreement to volunteer may be
unduly influenced by the Investigator.
2.2
Selection
of
subjects:-
pregnant
or
nursing
women
as
research
As a general rule, pregnant and nursing (breast feeding)
women should not be subjects of any clinical trials except such
trials which are designed to protect or advance the health of
pregnant or nursing women or fetuses or nursing infants, and for
which drugs can be tested only in pregnant women.
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
preventive benefits.
Example of such trials are, to test the
efficacy and safety of a drug for reducing perinatal transmission
of HIV infection from mother to child, trials for detecting fetal
abnormalities, trials of therapies for conditions 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.
Research related to termination of pregnancy:Pregnant women
who desire to undergo Medical Termination of Pregnancy (MTP)
could be made subjects for research relating to termination of
pregnancy, as per The Medical Termination of Pregnancy Act, 1971.
Research related to pre-natal diagnostic techniques:In
pregnant women research on prenatal diagnostic techniques should
be limited to detect the fetal abnormalities.
Such research
47
4.
should
take
the
consideration
of
The
Prenatal
Techniques (Regulation and Prevention of Misuse) Act,
2,3
Diagnostic
1994 .
Research involving children
Before undertaking children as subjects for clinical trial,
the investigator must ensure that children will not be involved in research
carried out equally well with adults,
that
might
be
the purpose of the research is to obtain knowledge relevant
to health needs of children.
For a new drug usually the
study in children should always be 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,
a parent or legal guardian
consent on behalf of the child,
each
child has given proxy
the consent of the child should be obtained to the extent of
the child’s capabilities such as in the case of mature
minors, adolescents etc.,
research involving children should be conducted in settings
in which the child and parent can obtain adequate medical
and psychological support,
interventions
intended
to
provide
direct
diagnostic,
therapeutic or preventive benefit for the individual child
subject must be justified in relation to anticipated risks
The risks of interventions that are
involved in the study,
not intended to be of direct benefit to the child subject
must be justified in relation to anticipated benefits to
society.
3.
Confid&ntiaility of Data
3.1
Safeguarding confidentiality
The investigator should
research data,
which might
individual subjects.
safeguard
lead to
the
the
confidentiality
identif ication
of
of
Data of individual subject^ 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
industrial
sponsor
of
research
or
in
cases
of
certain
communicable diseases to health authority.
Therefore,
the
limitations in maintaining the confidentiality of data should be
anticipated and assessed.
48
4.
Coatp&nsat.ion of ll&soazrch Subj&ct;s frost Accld&ntal Injury
Right of subjects to compensation
Research subjects who suffer physical injury as a result of
their participation are 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.
4.1
The sponsor whether a
pay:Obligation of the sponsor to pay:-eutical company, a government, or an institution, should
sb
pharmaceutical
i for
before
the
research
begins,
to
provide
compensation
agree., 1
to
entitled
injury
for which
subjects
are
i------any physical
compensation.
5.
Ethical Review Comittee
All trials involving human subjects must be submitted for
committee of
scientific review and approval of ethical review
in
institute before starting such research.
All the medical colleges and research institutions/centres
involved in clinical research should form scientific and ethical
committees which may be either
combined or be two independent
committees.
The scientific evaluation will assess the technical
excellence of the proposed clinical trial.
5.1
Composition of the Ethical Committee
The ethical committee should be able to provide complete and
adequate review of the research proposals submitted to them.
committee should be headed by a chairman, who should not be head
of the same institution.
Other members should be — one
pharmacologist preferably clinical pharmacologist if available,
one
pathologist,
two
clinicans,
one
or
more
members of
non-clinical departments, one person having knolwedge of law
(preferably a Judge or Lawyer) and a social scientist or
philosopher. The member secretary should be from the Institute
concerned.
The number of persons in an ethical committee be kept fairly
The ethical committee at any institution
small (5-7 members) .
from
should not hesitate to have as its members, individuals
if
required.
If
the
other
institutions or communities
Institutional
Ethical
Committee,
Investigator is a member of the
he/she should not be present when his/her own project is
discussed.
5.2
Basic responsibilities
The ethical committee should meet periodically (at least
twice a year) and review all research proposals an<^o their
progress reports.
Ethical approval through circulation of
reports.
The
research proposal among members should not be resorted to.
basic responsibilities of ethical committee are 49
human
to verify the safety, integrity and
subjects participating in the trials.
rights
of
the
to verify that all proposed interventions, and particularly
the administration of drugs and vaccines or use of medical
devices under development, have been assessed by a competent
expert body as acceptably safe to be undertaken in human
subjects; and
to ensure that all other ethical and scientific concerns
arising from a protocol are satisfactorily resolved both in
principle and in practice.
5.3
Assessment of research proposal
The ethical committee should review every research proposal
it should observe that the research proposal
on human subjects.
is scientifically sound, the possible risks to the subjects are
is
justified
by
the
expected
benefits,
informed
consent
are
satisfactory and procedures
for selection
of
subjects
equitable and properly documented.
The protocol should include clear research objectives and rationale for undertaking the
investigation in human subjects in light of the existing
knowledge,
precise description of methodology of the proposed research,
including intended dosages of drugs and planned duration of
treatment,
a description of plans to withdraw
therapies in the course of research,
or
withhold
standard
the plans for statistical analysis of the study,
inclusion and exlusion criteria for admission of subjects in
the study,
procedure for seeking and obtaining informed consent,
safety of proposed intervention and any drug or• vaccine to
and
be tested, including results of relevant 2laboratory
'
animal research, and
for research carrying more than minimal risk, if any, an
account of plans to provide medical therapy for such risk or
injury should be included.
storage
trial.
The
role
and
of
maintenance
ethical
of
all
committee
50
data
is
not
collected
during
the
to
permit
the
only
initiation of research but also to review research during the
course of study.
When there is anticipation of likely injury or
detection of adverse events during the course of study the
termination of study should be recommended.
6'.
Extejmally Sponsasr&d ^Resear-ch
The externally
obligations:-
sponsored
research
entails
two
ethical
The external sponsoring agency should submit the research
proposal according to the standards applied by ethical
committee of sponsoring agency/country with due approval.
The ethical committee of host Institution/country should
satisfy themselves that the proposed research meets their
own ethical requirement before sanctioning approval..
The
decision of the host Institution where the study will be
conducted is ultimate.
B.
T,
ETHICAL CONSIDERATIONS FOR SPECIFIC AREAS
DWG TRIALS
Clinical trial of drugs is a controlled study in human
subjects, designed to evaluate propsectively the safety and
effectiveness of new drugs/new formulations.
The proposed trial should be carried out, only after
aPProval of the Drugs Controller General of India, as is
necessary under The Schedule Y of Drugs and Cosmetic Act, 1940.
The investigator should also get the approval of Ethical
Committee of the Institution before submitting the proposal to
DCI. The guiding principles should be followed irrespective of
whether the drug has been developed in this country or abroad or
whether clinical trials have been carried out outside Indict.
1.
Phases of clinical trials
The following four phases of clinical trials of drug require
ethical clearance
1.1 Phase 1 drug trials:- The objective of phase 1 of clinical
trial is to determine the maximum tolerated dose in healthy adult
male.
To establish the safe dose range, pharmacokinetic,
pharmacodynamic effects, and adverse reactions, if any, with
their intensity and nature.
These studies should be carried out
by investigator trained in clinical pharmacology.
1.2 Phase 2 drug trials:These are controlled studies
conducted
in
a
limited number of
patients
to
determine
therapeutic uses, effective dose range and further evaluation of
safety and pharmacokinetics.
51
1.3 Phase 3 drug trials:The purpose of these trials is to
obtain sufficient evidence about the efficacy and safety of drug
in a larger number of patients, generally in comparison with a
standard drug and/or a placebo as appropriate.
On successful
completion of phase 3 trials the permission is granted for
marketing of drug.
1.4 Phase 4 drug trials:- After approval of drug for marketing,
phase 4 trial or post marketing surveillance is done to delineate
additional information about the drug’s risks, benefits and
optimal use.
Although, this is outside the purview of ethical
committee, it is an important aspect of drug trial on the long
term effects of the drugs.
Throughout the drug trials, the distinction between therapy
and research must be maintained.
A physician/investigator who
participates in research by administering the new drug to
consenting patients must ensure that the patients understand and
remember that the drug is experimental and that its benefits for
the condition under study are unproven.
Use of Placebo in drug
trials has come under severe scrutiny at the present age and
requires careful consideration before approval.
Trials of drugs
without approval of appropriate authority should be dealt
according to law of the land and regulatory agencies.
Model protocols recommended by WHO Guidelines for Good
Clinical Practices (GCP) for trials on pharmaceutical products
and Drugs Controller General of India’s Guidelines for Good
Clinical Trial Regulations are included at the end of the text.
2.
Special concerns for Multicentric Trials
A multicentric trial is conducted simultaneously by several
investigators at different centres following the same protocol
and proformae.
Ideally, these trials should be initiated at the
same time at all the centres.
All the Investigators should give ci written acceptance of
the protocol to be followed for the trial duly approved by
the ethics committee of the host institutes.
Meetings to be organised at the initial and intermediary
stages of the trial to follow uniform procedures; at all
centres.
Training to be imparted to participating
familiarise with the uniform procedure.
Standardisation of methods for recruitment.
laboratory procedures.
to
centres
evaluation and
Control of adherence to protocol including
f
measures to
terminate the participation of some centres,, if necessary.
Specific role of coordinators and monitors.
52
An
j
08243
,
x** / ■f
p
.
-• ■
5.
Medical devices not used regularly have less risk potential
than those used regularly. For example: Intraocular lens vs
contact lenses.
6.
Safety of the procedure to introduce a medical device in the
patient should be considered,
as the procedure itself may
cause harm to the patient.
TV.
DIA^OSTIC AGENTS
USE OF RADIOACTIVE MATERIALS AND X-RAYS
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
materials..
Points for consideration;
can the information to be gained be gathered using methods
that do not expose subjects to more radiation than exposed
normally,
the research be performed on patients undergoing
procedures for diagnostic or therapeutic purposes,
the
safety measures to 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 embryo,
information to subject about possible, if any genetic damage
to offspring,
1
1
*
‘
* ; are considered as drugs
non-radioactive
diagnostic
agents
and same; guidelines should be followed when using them.
V.
CLINICAL EVALUATION OF HERBAL REMEDIES AND MEDICINAL PLANTS
The guidelines given below relate to herbal remedies and
medicinal plants which are to be clinically evaluated for use in
the allopathic system of medicine and which will be used in
allopathic hospitals. The evaluation also will be carried out m
allopathic hospitals and the registration of the plant extract or
compound will follow the procedure laid down by the office of the
Drugs Controller General of India for allopathic drugs.
This
does not pertain to guidelines for ayurvedic drugs or unani drugs
to be clinically evaluated by experts in those systems of
medicine to be eventually used by ayurvedic and unani physicians
in their own hospitals and clinics.
55
All the general principles of clinical trials described
However, there are
-- -However,
earlier pertain also to
herbal remedies.
special features regarding herbal remedies which need to be kept
in mind during their clinical evaluation.
The first feature is that at the time of clinical evaluation
There could
a lot may be known about the plant or its extract,
be extensive literature about use of this in ancient Ayurvedic or
Unani literature and other organised systems or, indeed, the
or the traditional
plant may actually be in use by physicians of
The substance to be
systems of medicine for a number of years.
clinically evaluated will be used as is being used now or as has
been described in the texts.
The second consideration is that it is possible that
clinical evaluation of a plant extract or a compound isolated
from an extract has to be carried out which has never been in use
before and has not ever been mentioned in ancient literature.
The guidelines for these two types of substances cannot be
the same and therefore,
given below are specific guidelines for
substances which could fall into either group.
A.
For plants and herbal remedies currently in use or mentioned
in literature of any organised system of medicine
It is important that the herbal preparation to be clinically
evaluated has been described in an authentic and recognised text
of the particular system of medicine and prepared strictly in the
same way, incorporating GMP norms or standardisation as far as
possible.
It may not be necessary to undertake phase I studies.
No toxicity study may be needed for phase II trial unless there
are reports suggesting toxicity or the use is to be for more than
3 months.
It should be necessary to undertake 2-4 weeks toxicity
study in 2 species of animals in the circumstances pointed out in
the preceding sentence or when a larger multicentric phase III
trial is subsequently planned based on results of phase II study.
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 are
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 not in full control of their senses
all apply to these trials.
These trials have also got to be
approved by the appropriate scientific and ethical committees of
the concerned Institutes.
There is one special aspect which needs to be emphasised.
Since the substance to be tested is already in use in the
Ayurvedic or Unani System of medicine or has been mentioned in
these texts, toxicity testing in animals has been considerably
reduced.
However, it is essential that such clinical trials are
carried out only when a competent ayurvedic or unani physician is
56
15.
16.
17.
18.
19.
code lists, treatment
records, jj—
w
case report form
- andomisat
ion 1 ist and/or
(CRF).
Records
identification
--- ; should permit easy
of
permit auditing and individual 1;P of1 data/Part 1
and
reconstruction
Information on r_‘
’
of the ■■trial
will be Jk5ft andestablishment
when^ /
code, where it
and
how
and by whom
in the event of
-1
it
can be broken
an emergency.
Measures to be implemented
storage of pharmaceutical to ensure the safe handling and
products, and to
control
c-.
promote and
compliance
with
the
prescibed
instructions.
and
other
Description of j ■
on the
statistical
and
s/participants withdrawn from
evaluation of results
on
the
report
on
the trial.
Time schedule for
completion of the trial.
Information to be j--presented to the i*trial subjects including
how they will Jbe informed
consent will be■J obtained. about the trial
rial and how and when
20.
Staff instructions, i . e.
. statement of how ithe staff involved
are to be informed about
the way the trial
conducted and about the
is to be
procedures
for drug usage and
administration.
21.
Ethical considerations
and measures relating to the
trial.
Medical care uf
after the trial and modalities
treatment should
of post-trial
-—1 be defined.
22.
23.
24.
Statements
regarding
regarding
financing,
insurance,/
delegation/distribution of
liability,
r
responsibilities,
<and publication
policy, i.e. when serving as
o a contract.
List of literature
referred to in the protocol.
59
Drugs Controller General of India’s Guidelines for
Good Clinical Trial Protocol
1.
Title: including statement of confidentality.
2.
Unique identity code: with date of version.
3.
Investigator(s):
fax number(s).
4.
Study site: name, address. phone number, fax number.
5.
Statement of confidentality and bona fide disclosure.
6.
Sponsor: name, address, phone number.
7.
Introduction :
references.
8.
Objectives: questions co be answered.
9.
Design of study: noncomparative or comparative; open, single-blind, or double
blind; parallel-group or cross-over.
10.
Study subjects: target population; sample size; criteria of diagnosis,
selection and exclusion; subject information sheets; informed consent form and
procedure; rules for replacement of droptouts and withdrawals.
11.
Study drugs: dosage forms and strengths; lot numbers; packing and labelling;
method of randomisation; supply, storage, dispensing and accounting; dosage
regimens; method of administration; rules for breaking the code, if any;
concomitant treatments allowed and not allowed.
12.
Observations
frequency
a)
b)
c)
d)
f)
name(s),
background
to be made:
degree(s),
of
and
clinical
title(s),
justification
and
address(es ),
for
the
investigational;
Screening and baseline.
Efficacy«
Safety: requirements of reporting
events.
Quality of life assessment, if any.
Healthcare economics, if any.
non-serious
phone number(s),
trial;
method.
and
appropriate
place,
serious
and
adverse
13.
Data recording: source documents; retention and archiving policy.
14.
Statistics: sample size justification; response
analysed with methods and frequency of analyses.
15.
Administrative matters: ethics committee approval; regulatory approval; risk
coverage for subjects, investigator, and institution (with limitations, if
any); source document verification; nature and frequency of audit for protocol
compliance};
policy about preparation of
final report,
authorship and
presentation/publication;
confidentiality;
investigator ’s
and
sponsor's
agreement.
16.
Appendices: Case Report Form: specimen and instructions for completion;
authorised signatories and their specimen signatures; Declaration of Helsinki;
study flow chart; other aid memoirs for reference materials.
definitions;
Note: Any amendment to any section should be approved by
dated, and appended to the protocol.
60
the
ethics
data
to
be
committee.
ETHICAL GUIDELINES FOR EPIDEMIOLOGICAL STUDIES
PREAMBLE:
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 history,
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 classes would mean that a significant number of life style
related diseases such as Ischaemic Heart Disease are increasing.
There is very little information about this and it would be
useful to undertake long term cohort studies in different
population groups.
Epidemiological studies; are generally considered into two
Designs of these
categories - observational and experimental.
based
on
cross-sectional,
case-control
or cohort
studies are
Epidemiological
studies
cover
research,
programme
approaches.
surveillance.
Scope
of
ethical
guidelines
for
evaluation and
studies
is
concerned
with
epidemiological
epidemiological
Ethics in epidemiological studies is multidimensional
research,
medicine,
public
health
and
the
social
clinical
covering
millieau.
Perhaps code of ethics is much better understood for
clinical research, where the interaction between a patient and a
clinical researcher is
is of
of supreme
supreme importance..In epidemiological
the
researcher
is
research 1-- ----------_ dealing with group of individuals and
the questions faced by an epidemiologist are more of professional
nature.
These questions would pertain to interactions with
fellow
individual subjects, sources of funding or employer,
Need
for
code
of
ethics
epidemiologist and the society at large,
for epidemiologists is being recognised globally and the issues
for such a code in the context of epidemiological research in
India deserve attention.
Epidemiological research differs; from clinical research in
the context of larcre
large number of study
siubjects and generally a
s
long time frame.
If some mistakes or aberrations get detected
frame.
during the course of conduct of such studies, repeating 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.
61
tional Epld&niol o^y •
Observational
following type:-
Epidemiological
Research
includes
the
a.
Cross
Sectional
Studies
(Surveys):
This
is primarily
population based and involves selecting stratified random samples
of the population to be representative based on census 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 specif led
condition/disease (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 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 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.
c.
Cohort Studies:
These are longitudinal or prospective
studies of a group of individuals with differing exposure levels
to suspected risk factors. They are observed over a long period
usually several years. The rate of occurrence of the condition of
interest are 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 cohort and it is essential to
identify precisely every individual to be studied. Protection of
individual rights is an important issue.
IT.
Experimental Epideniology:
In experimental epidemiology the investigators alter one or
more parameters under controlled conditions to study the effects
of 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 come under the purview of
clinical evaluation of drugs/devices/products etc.
SPECIAL CONSIDERATIONS FOR EPIDEMIOLOGICAL STUDIES IN INDIA
The C.I.O.M.S/W.H.O guidelines for epidemiological research
assumes that the individuals or population being studied are
capable of giving 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
62
industrialised countries may not be achievable. How the principle
of "do no harm" is ensured under such circumstances without being
paternalistic is a major issue which has to be taken into
consideration in ethical guidelines.
In cohort or survey techniques for incidence and prevalence
of various diseases, a major issue that has to be considered is
how much of intervention 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 which is well established with
regard to preventive aspects, or should you leave them alone so
that the. natural evolution of the disease can be studied? Health
education
or
other
interventions
including
non-health
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
clinic which is readily accessible to the population without any
other intervention.However, it is generally considered unethical
to withhold intervention or services.
Gejaejral Ethlcatl Principles:
General ethical principles of respect for persons, duty to
are
possible harm
maximise possible benefits and minimise
important considerations in ethical guidelines. At the same time
it is essential that all individuals in an epidemiological
research
are treated alike keeping
in mind the
rules of
distributive justice.The welfare of the individual has to be
balanced against the welfare of the community and society at
large.
Specific Ethical Principles applied to Epidemiology:
1.Informed Consent:
When individuals are to be the subject of
any epidemiological studies, the purpose and general objectives
of the study has to be explained to them keeping in mind, their
level of understanding, It needs to be ensured that privacy will
be maintained.
In the context of developing countries, obtaining informed
times
as
consent
has
been
considered
many
on
various
difficult/impracticable/not
meeting
the
purpose
grounds such as
(a)
(b)
sufficiently
are
Whether
the
patients
subjects
or
knowledgeable or competent to understand the meaning of
informed consent?
not at the
Culturally,
decision making will be done,
individual level but at the level of head of the family or
village/community head.
However,
there is no alternative to obtain an informed
individual consent,
What should be the contents of the informed
How much to disclose and
consent also becomes a crucial issue.
63
are to be
the implications of nondisclosure
T„ spit, of obtaining informed
Inforn.a
considered seriously.
“ware
auavp of th°ir' ridhts •
Xn this°contextf the role
and may not be aware of their rights.
i .ant ■anrt
of investigator is crucial and he/she should remain Vigilant and
conscious of his/her obligations towards the subjects/patients ,
all through the 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 etc.
In obtaining the consent of individuals or communities it is
3.
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 disa.gree and refuse to give
consent because of societal pressures. This is something that has
to be carefully avoided.
4.
Particularly in 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 to
consent. Such inducements are not permissible.
However, it is
necessary to provide for adequate compensation for loss of wages
the
and travel/other expenses incurred for participating in tl
—
study.
5.
All
must be
study.
risks involved including the risk of loss of privacy
explained to the participants in an epidemiological
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. It may also be necessary in some
instances to inform the concerned family members about the
results.
For example, as in AIDS, STD etc.
It may not always be
possible to communicate study results to individuals but research
findings and advise should be publicised by appropriate available
means.
In countries
like
India
it
is
important that
the
beneficial results of epidemiological studies are fed into the
health system and necessary training modules should be developed
as part of the epidemiological project.
7.
All attempts should be made to minimise harm to the
individuals and society at large, Special consideration for the
cultural characteristics of the communities which are being
studied is essential to prevent any disturbance to cultural
sensitivities because of the investigation.
8.
Maintaining
confidentiality
64
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.
2.
In all situations where there is likely to be conflicts of
9O
interest it must be ensured that the interest of the individuals
involved in the study are protected at all cost.
10. Scientific Objectivity should be maintained with honesty and
impartiality , both in the design and conducting studyr and in
presenting and interpreting findings. Selective withholding of
data and similar practices are unethical.
Ethical Review Procedures:- In addition to the Research
11.
Review
Procedures,
Ethical
Committee
has
authority
and
Procedures,
responsibility for review and approval of research proposals from
ethical angle. Specific areas to be covered include
(a)
(b)
(c)
(d)
Plan for informed consent
Assess risks and anticipated benefits
Equitableness
Protecting vulnerable subjects.
In all Ethical Review Committees at least one or two
the
principles
of
understanding
of
individuals
with
an
Ethical Committees
epidemiological ethics have to be included,
of
epidimiologists,
should
be
independent
and
comprise
of
e
clinicians, statisticians, social scientist, philosopher, legal
expert and representatives from voluntary groups, Members should
be aware of local, social and cultural norms as this is the most
important social control mechanism.
Ethical Committee members
should be kept informed as to how the ethical guidelines are
actually being implemented. Regulatory mechanism can come from a
core group of the technical monitoring committee which may refer
issues of ethical concern to the ethical committee.
12 . Distinction between research and programme evaluations It is
important to make a distinction between epidemiological research
and programme evaluation. In order to evaluate the beneficial or
other effects of various health related programmes which are
initiated
primarily
by Governmental Agencies,
Longitudinal
are
epidemiological studies may be necessary. These studies
slightly different because they are not prospectively evaluating
issues, but looking at the effects of a programme that is already
initiated. It is ideal that whenever a programme is launched, the
monitoring and evaluating mechanisms should clearly be plemned at
the very beginning so that there is no conflict at a later
later time.
Resource Material
1.
for
Ethical
International
Guidelines
Epidemiological Studies, CIOMS, Geneva, 1991.
65
Review
of
GUIDELINES FOR ASSISTED REPRODUCTIVE TECHNOLOGIES
IN INDIA
I.
II.
TECHNICAL AND SCIENTIFIC ASPECTS
Page No.
1.
INTRODUCTION
67
2.
HISTORICAL PERSPECTIVE
67
3.
OBJECTIVE OF THE DOCUMENT
68
4.
DEFINITION AND SCOPE
68
5.
SCREENING OF INFERTILE COUPLE
68
6.
SELECTION CRITERIA FOR ART
70
7.
COMPLICATIONS
73
8.
FACILITIES
74
9.
^’COORDINATION,
COLLABORATION AND COOPERATION
77
10.
t ESTABLISHMENT OF PROTOCOL AND MAINTENANCE OF
RECORDS
78
11.
ACCREDITATION
79
12 .
REGISTRY
80
ETHICAL AND LEGAL ASPECTS
1.
GENERAL ETHICAL AND LEGAL ASPECTS
1.1
1.2
2.
80
Informed Consent
Selection of Donor
SPECIFIC ETHICAL AND LEGAL ASPECTS
2.1
2.2
2.3
2.4
2.5
2.6
2.7
3.
80
82
Legitimacy of the Child born through ART
IVF-ET and Surrogate Motherhood
Adultary in case of AID
Consummation of marriage in case of AIH
Rights of an unmarried woman to Al
Posthumous AIH through Sperm Banks
Preservation ,
Utilisation
and
Destruction of Embryos
SAMPLE CONSENT FORMS
85
66
I.
TECHNICAL AND SCIENTIFIC ASPECTS
1.
INTRODUCTION
The special programme by WHO on human reproduction has
estimated that there are 60 to 80 million infertile couples
worldwide. It has also been variously estimated that between 6 10% of the couple are infertile.
In India, the stable
family
structure and the desire for children is the norm; there is also
a social stigma associated with infertility. As a result of these
two there is an ever increasing
demand for dignostic and
therapeutic interventions in infertile couple.
The advent of
technologies of Assisted Reproduction have not only enhanced the
possibility of pregnancy but have also made women conceive in
situations which would have not have been possible a decade ago.
However many of these technologies require enormous technical
expertise and infrastructure, carry a success rate below 30% even
in the best of hands, are expensive, and tax the couple’s
There is an
endurance physically, emotionally and economically,
urgent need to draw up necessary guidelines, so that optimum
benefit of these newer technologies are made available to
at affordable
appropriate persons by skilled team of experts,
identified facilities for Assisted
health and economic cost, at
Reproductive Technology in our country.
2.
HISTORICAL PERSPECTIVE
The first report of successful extracorporeal fertilization
and cleavage of the human egg is that of Rock and Menkin in 1944.
Thirty years later the successful extracorporel fertilisation and
cleavage of a donor egg and transfer into a recepient uterus was
reported.
It was only in 1978 that the first ’’test-tube baby”
was born due to the efforts of Edwards and Steptoe.
An earlier
attempt had resulted in an ectopic pregnancy.
In 1979 Schettles
reported the intratuba1 transfer of freshly aspirated oocytes at
the time of tubal anastomosis.
This had been preceded the
following day by cervical insemination.
The patient delivered
normally at term.
In 1983 Tesarik reported the first pregnancy
after tubal microsurgery and transfer of oocyte and sperm into
the fallopian tube in the same sitting.
Asch and workers
reported a pregnancy and birth following laparoscopic placement
Devroey reported the first
of sperm-oocyte mixture in 1984.
pregnancy and birth by the technique of Zygote Intrafallopian
With increased success rates of ovarian
Transfer in 1986.
oocyte retrieval and invitro fertilization and
stimulation,
development, the problem of dealing with excess oocytes and
been
tackled
effectively
by
cryopreservation.
embryos
has
Trounson reported the first human pregnancy following thawing of
frozen embryos in 1983.
Cryopreservation is also of use in cases
of oocyte donation.
Micromanipulation of gametes has been
utilised for those situations with severe male factor, in the
presence of previous failed fertilization and in the presence of
antibodies
impeding
sperm-oocyte
interaction.
The
first
pregnancy was reported by this technique in 1988.
67
3e
OBJECTIVE OF THE
DOCUMENT
of
4.
13
tO
and
Since
of the
DEFINITION and scope
is defined as Manipulating the
u.. oocyte
of
gametes
or
embryos
again
into the body*
. ’.. The technology covers_ the following procedures :
i)
In vitro fertilisation and embryo transfer
(IVF-ET)
ii)
Gamete intrafalloppian transfer
(GIFT)
iii) Zygote
fintrafalloppian
Transfer
(ZIFT)/Preembryo
Transfer/Pronuclear
----- r stage Embryo Transfer (PROST)
iv)
Transfer of gamate/embryo and
surrogate motherhood.
v)
Micromanipulation of gametes
Although strictly speaking
°21Y the above categories fit the
description of Assisted
?Assisted
'
Reproductive Technologies, other a 11iod
techniques
nart
m S° tO. be cons}dered because these are often used
as a
a part
considered for ART^Thesl aTlied^^h1^ couP.les before they
they are
ART.
aki. mese allied techniques include :
i)
Intrauterine insemination
Sperm Intrafallopian Transfer
iii) Sperm Intraovarian Transfer
iv)
Intraperitoneal Sperm Transfer
5.
SCREENING OF INFERTILE COUPLE
In India most couples imarry
---- young, As and when a couple
anxious to conceive seek medical help,
a simple examination of
both the husband and wife should
be
irrespective of
done irresoective
preceding period of infertility.
if menstrual history,
sexual
histcn-y, physical examination
---3 couple and semen
analysis3 report are normal findings of the
the couple
couDle may be reassured,
counselled and r
requested to report back if there is
within
2 years
.’3 of cohabitation (if the age of no conception
woman is more
than thirty years,
then
the period as
1
year of
cohabitation, This advise istake
given mainly to avoid unneccessary
investigations and invasive
procedures.
Detailed finvestigations without i ‘ ‘
waiting any further and if
required, referral to centres carrying
out IVF could be carried
out immediately under the following conditions:
68
wife is healthy and is more than 35 years of age
severe endometriosis
genital tuberculosis
irreparable damage to or absence of Fallopian tubes
frozen pelvis
absence of ovary
primary ovarian failure - azoospermia, severe oligo,
asthe no or teratozoospermia, in the husband
absense of uterus
Preliminary investigationsi and management for infertile
couple can readily be
< carried out at District Hospitals, Urban
Medical
Colleges
and appropriately equipped Private
Clinics,
The
following
minimal
investigations need to be carried
Clinics,
to ascertain the cause of infertility.
out
Husband: (In 4 0%
of infertility)
of
infertile
couples
male
factor
is
a
cause
Physical examination both systemic and1 local to detect
infertility or
any problem that might be the cause of
c
modify the management of infertility.
both morphological and
Semen analysis including
functional tests should be carried out ; if any
abnormality detected repeat tests may be done after
suitable intervals. Abnormal finding on repeated semen
investigation
fey
examination warrants
full
scale
appropriate specialist to ascertain the cause and
institute necessary treatment.
Screening for infections including Syphilis, Hepatitis
B and HIV and appropriate management.
If needed appropriate endocrinological
and therapy.
investigations
Wife :
Physical examination both systemic and local to detect
any problem that might be the cause of infertility or
modify the management of infertility.
Detection
and timing of ovulation by BBT, cervical
mucus study, ultrasonography, premenstrual endometrial
biopsy and histopathological examination.
Assessment
of
tubal
patency
by
appropriate
investigations
including
Hysterosalpingography,
*
- ---- T if
Diagnostic ultrasound, laparoscopy or .hysteroscopy
if
specific problems and
required to find out/ rule out
to' assess response to therapy .
Screening for
local
factors
69
including
cervical mucus
related problems and lower genital tract infections and
instituting appropriate therapy.
Screening for reproductive tract
infections including
Syphilis, Chlamydia, Tuberculosis, Hepatitis B and HIV
and appropriate management.
If needed appropriate
and therapy.
endocrinological
investigations
Preliminary screening and management of infertile couple are
to be carried out at hospitals/clinics
where trained and
interested
Gynaecologists/Andrologists;/Endocrinologists
and
investigation facilities are available. Once the cause of
infertility had been identified, simple management procedure can
be taken up by trained Gynaecologist/Andrologist.
First line
management
with
appropriate
therapy
including
ovulation
induction with or without artificial
insemination using
husband•s semen (repeated atleast upto 6 cycles) should be
attempted in suchi centers and only those couples
who are not
responding, may then be referred to AR Centres.
6.
SELECTION CRITERIA
i)
Selection Criteria for
Transfer* (IVF-ET) :
1.
2.
3.
4.
5.
6.
7.
8.
9.
1.
FOR ART
In Vitro
Fertilization
and
Embryo
Tubal Disease
Emclome t r i o s i s
Unexplained infertility
Immunological factors
Cervical factor
Male factor
Ovarian disorders
Uterine disorders
In association with donor eggs and donor embryos
Tubal Disease
I.V.F./E.T. can be offered where microsurgical techniques
for tubal and peritoneal disease have failed or are unlikely to
benefit the patient.
The choice between I.V.F. and Microsurgery
would be dictated by the presence of peritubal adhesions,
condition of the tubal wall,, condition of the ciliary epithelium
and degree of fimbrial damage.
Patients who have already
undergone tuboplasty and those with inaccessible ovaries would be
more suitable for I.V.F.
In cases of history of ectopic
I. v. F. would be a better option.
pregnancy, I.V.F.
2.
Endometriosis
I.V.F. is a suitable option for women with moderate to
severe endometriosis and in those where medical and surgical
therapy have failed and sometimes is even offered for mild to
moderate
endometriosis
in
the
presence
of
other
factors
70
contributing to infertility.
3.
Unexplained infertility
Couples who have prolonged unexplained infertility would
benefit from I.V.F. as many factors such as subtle ovulation
defects,
defects in ovum pick-up,
gamete transport,
tubal
environment, sperm abnormality, oocyte abnormality may come to
light when I.V.F.. is used.
4.
Immunological factor
I.V.F. can be considered when there are antisperm antibodies
in the male or the famale and when other technigues such as
immunosuppression, use of condoms, intrauterine insemination and
other therapeutic measures have failed.
5.
Cervical factor
I.V.F. can be offered for cervical factor only if repeated
attempts (6 to 8 cycles) of intrauterine insemination have failed
and other therapies have not resulted in pregnancy.
6.
Male factor
I.V.F.-E.T. is logical therapy in the presence of low
concentrations of sperm (less than 10 million/ml.), low motility
(less than 3 0%) and in the presence of abnormal morphology
(greater than 60% of abnormal forms as per Yovich) . In severe
male factor, assisted fertilization by means of Micromanipulation
and sperm injection can be offered even in obstructive and
non-obstructive cases
cases..
No universally accepted minimal sperm
concentration for IVF success exists. In severe oligospermia,
teratospermia,
cryptospermia,
azoospermia
(obstructive/nonobstructive) intracytoplasmic sperm injection can
be employed using either ejaculated or epididiymal sperm.
7.
Ovarian disorders
I.V.F.
E.T. can benefit patients with hypogonadotropic
anovulation,
deficiency,
oligoovulation,
and
luteal
phase
although IVF is rarely indicated when these disorders exist as
IVF - ET can be used for women with
isolated conditions.
luteinized unruptured follicle syndrome in polycystic ovarian
disease.
8.
Uterine disorders
uterine
agenesis,
congenital
Patients
mullerian
with
severe
intrauterine
adhesions
anomalies,
and
women
with
refractory to surgical lysis; of the adhesions as well as
IVF, transfer their embryos
hysterectomized patients can, through
•
to a surrogate mother.
71
9.
In association with donor eggs and donor embryos
Women who have undergone either premature menopause or
timely menopause and women in the perimenopausal age group who do
not show proper recruitment of follicles and who have other
existing causes of infertility can avail of the option of donor
eggs and donor embryos.
Also women with genetic disorders, those
who have undergone radiation therapy and with ovaries which are
not accessible by ultrasound due to severe adhesions can avail of
donor eggs.
ii)
Selection Criteria for Gamete Intrafallopian Transfer(GIFT):
The
experimental
background
for
gamete
intrafallopian
transfer is the ability of the fallopian tube toserve as the
site for capacitation and fertilization in
beings.
— human
----- ----z,_.
Earlier
experiments by GIFT were carried out on monkeys who had undergone
tubal
resection and
ligation.
In
1979
Shettles reported
pregnancy after intratubal transfer of freshly aspirated oocytes
at the time of tubal reanastomosis combined with cervical
insemination.
Asch and colleagues reported the first pregnancy
and birth using laparoscopic GIFT.. Indiccitions are almost similar
to that of IVF-ET.
iii) Choosing between IVF - ET
&
GIFT
Deciding
on
which
1technique
to
utilise
must
be
individualised for each patient,.
The advantages of IVF over GIFT
are documentation of fertilization, less trauma and anaesthetic
risk.
There is no exposure to excess quantities of carbon
dioxide in IVF as happens during laparoscopic insufflation with
GIFT.
It has been suggested that GIFT is more natural as
f er uilisation OCCUrS
une ya
in the tubal mupuxxa,
ampulla,
the
gametes are
minimally exposed in vitro and early embryo development: occurs in
a natural environment.
iv)
Zygote Intra Fallopian Transfer (ZIFT)
This is an offshoot of the IVF and GIFT procedures where the
first ]pregnancy
------was reported by Devroey.
This procedure entails
the transfer of preembryos into the falloppian tube either
laparoscopically or by transvaginal retrograde cannulation of the
fallopian
tubes
either
by
ultrasound
or
by
hysteroscopic
guidance.
v)
Microassisted Fertilisation
Subzonal
insemination
(SUZI),
Intracytoplasmic
Intracytoplasmic
Sperm
injection (ICSI)
. and Assisted hatching_ need
micromanupulation
.
__
_____
_
__
i of
gametes.
sperm injection directly into the oocyte
outside the body,
this is replaced
injection of sperm into the cytoplasm of by ICSI which involves
the oocyte under certain
conditions such as aging ova, in elderly women, repeated failure
of implantation at IVF and in males factor infertility. Assisted
hatching of embryo by drillingr a hole in the zona pelucuda is
72
I
resorted
rates.
pr i or
to
embryo
transfer
for
improving
implantation
Finally, the choice of the procedure used eg. IVF-ET, GIFT,
ZIFT, PROST etc. is made depending upon the needs of the couple,
availability of facilities, experience and expertises of the
gynaecologist/embryologist .
7.
COMPLICATIONS
AR procedures carry a small risk both to the mother and the
offspring . It is essential that these risks are defined and
appropriate counseling done. AR
explained to
the couple and
initiated only after they understand these
procedures are to be
Some of the most commonly
and still want to undergo AR.
encountered problems include :
1.
Multiple Gestation
The reported incidence of multiple gestation ranges from 2030 %. Incidence of twin in the range of 10- 20 % may have to be
accepted as inevitable but specific ettorrs
efforts are to be made to
the
incidence
of
triplets
and
multple births of
higher
reduce
order. Most of the AR practitioners do not tranfer more than
three oocytes for GIFT and more than three embryos for IVF-ET at
one sitting ;» the remaining embryos, if any, are cryopreserved
and if required tranferred at a later cycle.
2.
Ectopic Pregnancies
for AR
Ectopic pregnancy rates range from 0 to 8%
in
procedure
especially
apppropriate
choice of
procedures;
pregnancy
reduce
the
ectopic
disease
may
tubal
persons with
rates.
3.
Spontaneous Abortions
Spontaneous abortion rates range from 20 to 35%.
Abortion
rates rise
with increasing
age of the mother and in multiple
pregnancies especially presence of three or more foetuses.In
cases where more than three foetuses are present many AR experts
advise selective embryo reduction.lt is essential that the
advantages of embryo reduction (better chances of the survival of
the other foetuses and the fact that they are likely to be born
nearer term, with better birth weight) and disadvantages (the
possibility that there might be an increased risk of abortion
following the procedure) have to be explained to the couple and
then informed consent taken before embryo reduction is attempted.
4.
Preterm Births
There is a higher risk of premature/ low birth weight
in the presence of multiple
following AR especially
delivery
./foetuses.
73
5.
Ovarian Hyperstimulation Syndrome
The
use
of
superovulation
for
Assisted
Reproductive
Technology entails the risk of Hyperstimulation for some women
(0.2 —8.0%). This is determined by the hormonal profile of the
woman, the Estradial values (greater than 2000- pg./ml.), the
dose for the. trigger of ovulation, the ability to aspirate all
the follicles at the time of oocyte retrieval and a host of other
factors.
The Programme. Director should be fully aware of the
means of avoiding hyperstimulation and also of treating it.
Careful monitoring and management will reduce the risk of this,
as well as the morbiditv
morbidity associated with hvoerstimulatinn.
hyperstimulation.
In addition
to these specific
complications
persons
undergoing
various
AR
procedures
incur
associated
with
the
operative
and
anaesthestic
involved in AR.
8.
of AR, the
the
risks
procedures
FACILITIES
Assisted Reproduction requires the availability of
1.
2.
Manpower with expertise and qualifications.
Infrastructure such as Equipment/Supplies/Space.
i)
Manpower - Expertise and qualifications
The organisation and implementation of an ART programme
calls
for
significant
teamwork
with
close
collaboration,
coordination and cooperation between concerned and commited
clinicians, endocrinologists, ultrasonographists, embryologists
and a team of supportive paramedical and laboratory workers. All
members of the team should have a commitment to the programme
Which Often Calls for
__ irregular working hours anvi
xu
and iiqxui
hard work
It
is essential that right from the inception of the programme there
is clear cut documentation on the responsibilities of each of the
team members.
The following personnel form an ideal team.
a)
Clinical Director (Clinical Science! : The Director is the
Team Leader and is overall incharge of the clinical as well as
the laboratory aspects of Assisted Reproduction Technology,
He
or she could be a gynaecologist with adequate training in
endoscopy, oocyte retrieval, administration and laboratory and
would
be
required
to
liaison
with
the
clinical
faculty,
laboratory
faculty,
secretary,
nurse,
anaesthetists,
RIA
laboratory, psychiatrist and operating room staff.
The director
should be: competent to tackle any emergency arising from clinical
situations and in the laboratory.
He should be fully aware of
use of hazardous material eg. liquid nitrogen,
The Director has
the following major responsibilities :
- obtaining informed consent for all procedures,
- selection of patients for various Assisted Reproduction
procedures,
the decision to repeat/ change over to other methods/advise
74
termination of further attempts at AR procedures,
- to tackle any emergency arising from clinical situations
and in the laboratory,
- maintanance of records and ensuring confidentiality,
- periodic analysis of data anc^ Review of the activities and
appropriate
corrective measures as and when necessary,
- laison with the state/central govt agencies,
- submission of appropriate data e.g. the pregnancy rates to
the Accreditation authority or licensing authority or
Registry.
b)
Laboratory Director (Basic Science)
: Post-graduate in
reproductive biology with adequate training and experience in the
Andrology and Embryology laboratory,
laboratory, quality control, media
preparation,
semen
examination
and cryopreservation,
His
administrative duties would include purchase of equipment and
supplies f hiring of laboratory personnel and formulate all
laboratory policies.
His qualifications would be a M.Sc.,
preferably a Ph.D. and M.D. desirable.
c)
Technologists (Lab) :
Laboratory personnel trained in
media preparation and quality control, serum collection and
preparation, maintenance of equipment and supplies, maintenance
of log books, performance of quality control, and ability to
identify
oocytes,
fertilization
and
cleavage
(sperm-egg
interaction) and semen analysis and preparation procedures. They
should be Science graduates with the above skills and also have
basic understanding of cultural conditions. The laboratory staff
should have adequate protection from blood products and semen.
All couples entering the IVF programme should be pre-tested for
HIV and Hepatitis-B in order to protect the laboratory personnel.
d)
Nurse Coordinator : A qualified Nurse with experience in
Gynaecology and Infertility fields. She would be responsible for
daily blood collection,
obtaining endocrine assay reports,
maintenance of equipment in the operation theatre, scheduling of
appointments and sonography examinations and assisting in oocyte
retrieval and embryo transfer.
Counsellor : The role of the counsellor is well acknowledged
e)
in the treatment of infertility as clinical research suggests
that the infertile couple is at risk for sexual dysfunction,
psychiatric co-morbidity and marital conflict.
Psychological
evaluation and intervention should be offered to couples and
should be available on request. The counsellar should be a person
with thorough understanding of ART procedures and benefits and
problems associated with them. He should be able to give a clear
picture about the centre, services offei’ed, cost and present
pregnancy rate.
In developed countries specially trained counsellors are
usually available and counselling is taken as an essential
In the Indian context
pre-requisite for couple seeking ART.
especially
in smaller centres which have just been opened,
specific trained counsellor may not be readily available; in such
75
a situation, the Gynaecologist, Andrologist and Embryologist or
the Para medical personnel who had the know- ledge, time,’skill,
and interest in counselling can be entrusted with the task of
counselling the couple. It is essential that every effort should
be made to explain the procedures that are going to be used and
their
consequences to the couple, assess their response and
needs before ART procedures are initiated.
f)
Secretary s The secretary would be responsible for patient
appointments, answering inquiries and letters and administrative
duties.
g)
Ancillary Services : These would include
Anaesthetist,
Radio immunoassay Laboratory and
Technical staff in the Operation theatre and Laboratory.
The entire programme of ART stresses on the importance of
team effort.
The individuals have to work dynamically in groups,
Professional burnout can occur in this highly and intensely
personal technololgy and hence the leader or director of the
group has responsibility and privilage of holding the group
together..
ii)
Equipments , Supplies and
a)
Space :
Space
The
space
requirements
for
isolation
of
Embryology,
Andrology Laboratories and Operation Theatre should be met.
These
areas
should
be
supplied
by
clean,
filtered,
air-conditioned air.
Ideally speaking the laboratory should be
under a positive pressure environment and should be walled off
from other areas.
Other rooms would include Interview rooms,
Examination room, Sonography room, Recovery room, Patient waiting
area. Toilet areas. Waste collection areas, Autoclave room and
Semen collection room.
The walls in the Operation Theatre and
room,
the Laboratory should be easily washable and disinfected.
Carpeting is not permitted, Aerosols and pest control should not
be used in the Laboratory.
b)
Equipments :
The following equipments are mandatory for ART Programme :
Horizontal laminar flow hood.
Stereo microscope..
Inverted microscop
_ e•
Phase contrast microscope.
Water jacketed CO2 incubator with CO2 regulator and at least
3 CO2 cylinders.
Osmometer.
vii) pH meter.
i)
ii)
iii)
iv)
v)
VP.
76
yiii)Centrifuge and ultracentrifuge.
ix)
Water bath.
x)
Analytical balance.
xi)
Refrigerator.
xii) Millipore water purification system..
xiii) Stage warmer.
xiv) A Makler Chamber for semen analysis or haematocytometer.
To set up ART 7lab,
*
equipments are desirable.
c)
cryogenic
unit
and
micromanupulation
Supplies :
i)
Semen containers.
Tissue culture flasks.
iii) Disposable pipettes.
iv)
Culture tubes and Embryo transfer catheters.
v)
Oocyte retrieval needles and tubes.
Culture dishes.
vi)
vii) Organ culture dishes.
viii) Ultrapore filters.
ix) Microscope slides and cover slips.
X)
Rubber bulbs.
pH buffer.
Xi)
xii) Osmometer fluid.
xiii) Pipette tips.
xiv) Disposable syringes (Liverlock), 1ml z 2ml, 5ml, disposable
needles.
xv)
Cryopreservation vials and straws.
xvi) Spirit lamp,
xvii) Cartridges for water purification system,
xviii)Tissue
culture
medium
and
chemicals
associated
with
preparation of tissue culture media.
Note - All material used
toxic to sperm and embryo.
9.
in the ART
Laboratory
should
not
be
COORDINATION, COLLABORATION AND COOPERATION
Assisted Repropductive technology is highly specialised and
needs financial,
1technical and clinical backup,
"
After setting up
the facility, its smooth functioning calls for proper liason,
understanding and trouble shooting alongwith coordination and
cooperation from all areas.
In many metropolitan cities Of India the expertise and
facilities needed are available
in different institutions
situated a few kilometers apart and they may be able to work
together
even though they are all not working under the same
roof in the same institution.
The
Institutions
where
the
experts
from
different
specialities
work,
have
all
the
necessary
expensive
sophisticated equipments,
In the existing situation of economic
constraints it might be worthwhile
--- to set up AR clinics in an
77
area where an operation theatre and embryology laboratory are
The
present in the close proximity in the same institution,
infrastructure available in the neigbouring institutions can be
‘. This
utilised optimally for diagnositc procedures needed for AJU
in
which
may be the most efficient and cost effective manner i.. yhic ART
This arrangement however
programme may be initiated in India.
requires personal commitment of the individuals concerned and the
commitment from the respective Institutions that the facilities
<
will be made available on a continuous basis to the couple
In-charge
seeking
AR.
In
such
situation,
the
shall
be
Co-ordinator of the Institute,
(Director or Dean or person
designated as; Head)
JU.
10.
JU
••■•*** JI
——
ESTABLISHMENT
—’ — -
—
OF PROTOCOLS AND MAINTENANCE OF RECORDS
All protocols used in the laboratory for I.V.F. and related
These
procedures must be documented and available as manuals.
manuals should be revised periodically.
periodically.
Log books for the
maintenance and periodic overhauling of all equipment should be
The entire procedure from the ovarian stimulation
maintained.
to the oocyte retrieval and oocyte and sperm
protocol
preparation including evaluation of the morpholgy of the gametes,
transfer,
their number, timing of insemination, date of embryo
"
“
embryos
or
gametes
transfered
and
the
fate
of the
number of
Abnormal pre-embryos such as
gametes imust be documented.
L
embryos
should
not
be
transfered.
Cryopreserved
polyploid
The
material must be labelled indexed and stored properly.
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 date of receipt of the reagents entered on the box
containing the reagents.
Asepsis should be maintained at all
times.
Each couple undergoing treatment should have a minimal
screen for HIV and Hepatitis.
ISera of patients used for embryo
The Laboratory personnel
culture should not be interchanged,
should be offered vaccinations for Hepatitis B. Gloves should be
worn at all times.
Clothes specific for use in the laboratory
Regular shoes should not be taken into the
should be provided.
Laboratory.
Preparation of culture media should be. done in
water
and
dedicated
dedicated
containers
using
ultrapure
reagents.
The media should be checked for pH and osmolarity,
Facilities for proper refrigeration and freezing should be
available, back-up of
electrical supply and voltage stabilisers
<
should be available in areas prone to electrical failures.
Mouth pipetting is not permissible and only mechanical
pipetting is allowed.
Eating, drinking, smoking within the
precints of the Laboratory should be prohibited.
Contaminated
material
should be disposed off
in
the proper
fashion.
Biological material should be handled with care and disposed off
after sealing.
It is essential that all documentation regarding every
patient treated in the centre is maintained meticulously cind all
precautions
are taken to
ensure that confidentiality is
:—
78
t
maintained. It is preferable that a networking of the centres
attempted right now when only a
involved in ART Programmes are
few centres are doing ART, so that as more and more centres take
up
the programme the net work will grow and the Regional and
National data on the ART programme will automatically become
available.
11.
ACCREDITATION
It is estimated that at the moment there are about 50
Some have been well established
centres offering AR in India,
and have been functioning for some years. Others are in various
stages of being established.
In order to ensure quality of care it is imperative that a
proper accreditation procedure is followed in establishement of
AR centres. All AR centres should follow standardised protocols
and guidelines.
There should be a strict internal and external
quality control programme for all AR centres. A team consisting
of gynaecologists, embryologists, andrologists, legal and ethical
experts along with the social scientists may be included in the
accreditation committee.Representatives of various professional
bodies in the specialities connected with AR procedures such as
the Federation of Obstetric and Gynaecological Societies of India
(FOGSI) and Indian Society for Assisted Reproduction (ISAR) may
also be included in the accreditation committee. In addition the
opinion of these professional bodies and organisations such as
Indian Council of Medical Research (ICMR) and Drug Controller of
India (DCI) should be saught on the
recommendations of the
accreditation committee.
The aim of the accreditation procedure is to ensure that :
the institutions providing AR do maintain the quality
of care expected
infertile
exploited
couple
get
good
quality
care
and
are
not
the. institutions offering AR do get the needed support
especially in terms of streamlined procedures for
import of needed drugs, reagents and equipment.
Appropriate expert panel would inspect the AR centres as a
centre
before
the
is
part
of
accreditation
procedure
_x_
also
periodically
after
it
starts
operationalised
and
functioning. The accreditation committee will review the existing
infrastructure and facilities, the track record of the centre.
records,
the upkeep of the
records. security arrangements for gamete,
“ *‘j
and make
embryo storage and maintanance of the confidentiality
authorities
their
recommendations
to
the
appropriate
for
providing
Appropriate
legal/executive
procedures
accreditation to these centres will have to be evolved and
Centres require ready
implementing agencies; identified. AR
access to reagents, drugs and equipment many of which have to be
79
imported in order to provide patient care, Steps may have to be
evolved to assist accreditted ART centres by streamlining the
procedures that these centres have to adapt for import, so that
their requirements are met without undue delay and additional
expenses.
Some of the accreditted centres can be utilised for
training postgraduates or interested specialists from the related
specialities so that in a phased manner AR facility becomes more
widely available in the country.
Some of the accreditted ART
centres could also take up research studies on specific aspects
of AR based on approved protocols.
12.
REGISTRY
A national registry pertaining to all centres who are
accredited by the licensing authority should be maintained and
should contain records of treatment cycles and outcome.
LEGAL
ASPECTS
OF
II.
ETHICAL
AND
TECHNOLOGIES
1.
GENERAL ETHICAL AND LEGAL ASPECTS
ASSISTED
REPRODUCTIVE
There is a certain element of risk associated with AR
procedures.
It is therefore necessary to ascertain the
therapeutic value of the AR procedure in each case.
1.1
Informed Consent
After duly counselling the couple/oocyte/semen donor, an
informed and written consent should be taken from both the
spouses as well as the oocyte donor, as the case may be.
They
should be explained the various risk factors associated with the
procedures in simple
simple, language and the words that they can
understand.
These include risks associated with
ovarian
hyperstimulation, anaesthestic procedures, invasive procedures
like laparoscopy, aspiration of ovum.
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.
1.2
Selection of Donor
The doctor assumes the responsibility in selection of the
suitable donor in terms of following:
*
Complete physical examination of the donor should bedone to
ascertain the good health of the donors of semen, oocyte or
embryo.
*
The donor should be healthy with a good quality eggs
sperms and preferably with proven fertility record.
80
or
*
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.
•k
Blood group of the proposed donor and donee should be tested
with respect to Rh compatibility.
*
No person
suffering
from any
sexually
transmitted
disease
(e.g. syphilis, gonorrhea, chlamydia, herpes, HIV
etc.)t
infectious disease
(e.g. hepatitis - B, HIV)
or
genetically transmissible disease should be used as donor.
*
Sexually transmitted diseases should be ruled out not more
than one
week
before
the
seminal
fluid
is obtained.
It is preferable that donated semen is cryo-preserved and
used only after 6 months as this would enable
the
centre
to retest the donor after 3 months for HIV and eliminate the
potential risk of HIV transmission in the ’window’ period of
HIV infection.
*
Identity of the donor as well as the recipient should be
protected from each other.
the records
However
all
of the donor
to
trace
preserved in
order
must be
should be
him/her
in case of any eventuality
and
confidential.
★
Confidentiality of the entire procedure and its outcome
should
be
relative
is
advisable and
therefore
no
accepted as a sperm donor besides avoiding the claims
of parenthood and inheritance rights.
*
Written
consent
of the
donor should be taken towards
unrestricted use of sperms or oocytes for AR, as well
not
as an undertaking
from him/her that he/she will
In case
attempt to seek the identity of the recipient.
of the donor is married, to take the written consent of
the spouse, if possible.
*
It is also desirable to restrict the use of semen from
the same donor to 10 pregnancies to avoid the possibil
ity of an incestuous relationship occurring among the
offsprings at a later date.
*
In
case
of
any health
the
oocyte
donor, incurring
problems during the process of donation,
the costs of
the
subsequent
borne by the
care
should
be
health
whether
potential
irrespective
of
recipient , couple
*In
they receive oocyte donation as planned or not.
case of
unused
surplus
embryos,
consent of the
concerned
couple
should
be
obtained
to
cryopreserve
such embryos for donation to other needy couples.
Such
embryo donations should be kept anonymous.
81
2•
SPECIFIC ETHICAL AND LEGAL ISSUES INVOLVED IN ART
2.1
Legitimacy of the Child born through ART
A child born through AR is presumed to be the legitimate
child of the couple having been born 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
theix' anonymity should be protected.
2.2
IVF-ET and Surrogate Motherhood
There are no medicolegal problems posed by IVF-ET with egg
and sperm of married couple.
With either egg or sperm donated,
it is governed on the same lines as AID with the married partner
being 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 motherhood:
1.
Surrogate motherhood should be legal only when it is coupled
with authorized adoption.
2.
It should be rebuttably presumed that a woman who carries
the child and gives birth to it is its mother.
3.
The intending parents should have a preferential right to
adopt the child subject to six week’s postpartum delay for
necessary maternal consent.
4.
It should be legal only if medically certified as the only
solution to infertility or any other
medical bar on
pregnancy, by the intending mother.
5.
It should be supervised by a qualified consultant to enforce
adequate genetic screening.
6.
The contract for surrogacy despite reasonable payment of
compensation on completion of adoption would be valid
subject to surrogate’s right to retain the baby if she so
desires.
The only remedy for the genetic father then would
be to claim for custody on the grounds of the best interest
of the child.
7.
Abortion under the Abortion Law on the medical ground should
be an inviolate right of the surrogate and the adopting
parents have no claim over the amounts already paid.
2.3
Adultery in case of AID
AID in a married woman with the consent of the husband does
not amount to adultery on part of the wife or the donor, as there
is no sexual intercourse involved.
AID without the husband’s
consent can be ground for divorce or judicial separation.
82
2.4
Consummation of Marriage in case of AIR
Conception of the wife through AIH does not necessarily
amount to consummation of marriage and a decree of nullity would
still be granted in favour of the wife on the ground of impotency
of the husband or his willful refusal to consummate the marriage.
However, such a decree could be excluded on the grounds of
approbation .
2.5
Rights of An Unmarried Woman to AID
There is no legal bar on an unmarried woman going for AID.
However,
universally it is recommended that AID should be
performed only on married women and that too with the written
consent of her husband, two parent family being always better for
the child whose interests will
always
outweigh all
other
interests.
Besides, child born to a single woman through AID is
deemed to be illegitimate.
2.6
Posthumous AIR through Sperm Bank
Though the Indian Evidence Act, 1872 says that a child born
within 280 days after dissolution of marriage (by death or
divorce) is a legitimate child since that is considered to be the
gestation period, it is pertinent to note that this Act was
enacted as far back as 1872 when one could not even visualise
The law needs to take note of these advancements.
A child
ART.
born to a single woman is already not in a very happy position,
in our society specially; why doubly damn him by branding him as
illegitimate?
a child born to a
Considered opinion is that
woman with the sperms of her <deceased husband artificially
be a legitimate child
inseminated should be considered[ to
notwithstanding the existing law of presumptions under our
move
alongwith
medical
Evidence.
Act.
The
law needs
to
advancements and suitably amended so that it does not give rise
to dilemnic or harsh situations.
2.7
Preservation, Utilisation and Destruction of Embryos
While passing The Human Fertilisation and Embryology Act
1990, the British Parliament accepted the Warnock
Committee
recommendations prohibiting research on or keeping alive any live
embryo over 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 embryos deposits.
Under this law, early this month nearly 3000 frozen embryos were
destroyed in the UK after the expiry of 5 year statutory limit
and no consent coming forth from the parents to extend the limit
by further 5 years.
In a case of dispute arising between the couple since
divorced, after the preservation of embryos, over the right of
the ’woman to conceive the child and seeking custody of the
embryos, a recent judgement has gone in favour of the woman, the
83
husband having consented to the conception at the time of
fertilisation.’ However
However,, the child born in such a case would be
deemed to be an illegitimate child.
Resource Material
Guidelines for Human Embryology and Andrology Laboratories.
Fertility & Sterility.October 1992, Supplement 1, vol.58,
No.4 (IS & IIS).
Fertility
Guidelines for Gamete Donation.
February, 1993, vol.59, No. 2 (IS & 5S).
Human Fertilisation and
Ethics, London, 1993.
Embryology
Authority
&
Sterility
Code
of
Ontario Law Reform Commission's Report on Human Art i f i c ia1
Reproduction - Related Matters of Canada.
American
Fertility
Society's
’’Ethical
Considerations
of
Technologies” 1986 and 87.
84
Ethics
the
Report
Committee
Reproductive
New
3.
SAMPLE CONSENT FORMS FOR AR PROCEDURES
3.1
CONSENT FORM
We,
and
Mr.
hereby give consent
Mrs.
to
to donate sperms of Mr.
for
Mrs..
purpose
of
artificial insemination with donor’s sperms and we agree that
we
will
have
no
legal
claim
on
baby
the
by
Mrs.
procedure of artificial insemination.
Mr.
Mrs.
DONOR
SPERM DONATION
85
born
the
to
above
3.2
We,
CONSENT FORM
and
Mrs.
state that
Mr.
we are lawfully married and have no children.
We desire that
should
be
are
both
desirous that we should have a child by that means.
The
Mrs.
artificially inseminated with donor
sperms
as we
procedure of artificial insemination has been explained to us
and we hereby give consent to such cirtificial insemination.
1/
hereby
request
to
you
my
inseminate
wife
Mrs .
will take responsibility of bring-
1/ Mr.
ing
up
the
child
born
by
my
wife
Mrs.
above procedure.
Mr.
Mrs.
RECIPIENT
ARTIFICIAL INSEMINATION
86
3.3
CONSENT FORM
We,
Mrs.
and
state that
Mr.
we are lawfully married and have no children.
Mrs.
artificially
inseminated
as
we
are
should have a child by that means.
both
We desire that
should
be
that
we
desirous
The procedure of arftifi-
cial insemination has been explained to us and we hereby give
consent to such artificial insemination.
We agree that identity of the donor for the purpose of such
insemination is not to be disclosed to us.
We ourselves are
not able to procure such donor and agree to accept such donor
for the jpurpose as you may procure.
We understand that since
fresh samples may be used, small risk of getting AIDS infec
tions cannot be ruled out.#
Mr.
Mrs.
RECIPIENT
ARTIFICIAL INSEMINATION WITH
UNKNOWN DONOR
# All ART Centres should only use frozen sperms
87
CONSENT FORM
3.4
and
This is to certify that I
my
hereby
husband
consent to
donate my
infertile
oocytes to any
give
couple who
wishes to receive them.
The procedure
of
oocyte collection
is
explained
to
us
in
as
detail and I understand the risk involved in the procedure
well as premedications and protocols for monitoring of ovula-
tion induction.
The identity of recipients of the oocytes will remain unknown
to us and we will not have any claim on offsprings that will
be produced by donation of my oocytes.
Mrs.
Mr.
(Signature)
DONOR
OOCYTE DONATION
88
3.5
We,
CONSENT FORM
Mrs.
and
Mr.
state that
we are lawfully married and have no children.
We desire that
Mrs.
should
have
IVF-ET/GIFT by oocyte/embryo donation as we are both desirous
that we should have a child by that means.
IVF-ET/GIFT
has
been
explained
The procedure of
us
and
we
hereby
the
donor
for
the
purpose
of
not to
be
us.
We
to
give
consent to such treatment.
We
agree
that
oocyte/embryo
identity
donation
is
of
ourselves are not able to procure
disclosed
to
such donor and agree to
accept such donor for the purpose as you may procure.
Mrs.
Mr.
(Signature)
RECIPIENT
OOCYTE/EMBRYO DONATION
89
3.6
CONSENT FOR EMBRYO REDUCTION
We,
Mr.
&
Mrs.
hereby
give
fully
Embryo
Reduction,
informed
to
consent
attempt
the
for
the
procedure
reduction,
of
of
our
to
We have been informed that this procedure can lead to the
termination of the whole pregnancy or failure to reduce the
number of embryos to the desired number of continuation of
the pregnancy with the original number of embryos.
We do not hold the doctors responsible for any other future
complications in this pregnancy.
We have been explained that since this procedure is done in
the first trimester, therefore it is not possible to detect
the
future
anatomical
or
functional
abnormalities
of
the
embryos and therefore a selective reduction may not be possi
ble.
We solemnly pledge that we are giving this consent without
any pressure and with full awareness of the consequences.
Mr.
Mrs.
(Signature)
90
L.3JP. '• 1
3.7
COUSEW FOMM FO3R 80RROGATE MOTHER
We,
Mrs.
and
state that
Mr.
we
Eire
lawfully
married.
We
give
Mrs.
consent
that
should
have
IVF/ET by embryos of Mrs.
The procedure of
and we
IVF/ET has been explained to us
hereby give consent to such treatment.
We agree that we will have no legal claim on the baby born by
that procedure and we will hand over the child to the genetic
parents on birth of the baby.
is
Mrs.
volunteering
to
become
surrogate
mother
purely
to
Mrs.
Mr.
Mrs.
(Signature)
SURROGATE MOTHER
91
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help
3.8 CONSENT FORM ? Participation in IVF Program
Note : This Consent Form should be signed at the time
of the initial consultation with the IVF team.
1.
hereby authorize and direct. Dr.
and such assistants as may be selected by
to
and
treat
me
to
administer
him/her
withthe
______ in accordance
with
attached IVF protocol, which have been discusscsd with
me, and I here by consent to such treatment.
2.
I understand that the purpose of my participation in
the program is to attempt to become pregnant by means
of in vitro fertilization, and embryo transfer because
I have been unable to become pregnant due to conditions
which have not been, treatable by other currently
available methods and procedures.
3.
I understand from my reading of the attached IVF bro
chure and counselling by the IVF team physician that
the following is an outline of the IVF process and
procedures which will be followed during my participa
tion in the programme :
I
of
medications
assist
to
my
a•
Administration
ovulation.
b.
Frequent blood tests,
ultrasound studies to
ovulation.
c.
Admission to the hospital for a laparoscopy or
ultrasound retrieval when my ovulatory process is
at the appropriate state, as determined by the IVF
team, in order to obtain as many eggs as possible
from my ovaries (usually one to four).
d.
Mixtures of my eggs with my husband • s sperm
attempt to allow fertilization, to occur.
e.
Transfer of my fertilized egg into
medium outside the uterus for growth.
f.
Transfer of the embryo(s) into my uterus by means
of a small plastic tube following several cell
divisions.
g-
Frequent blood tests through the remainder of my
cycle to determine hormone levels and whether
pregnancy has occured.
92
pelvic examinations and
determine development of
a
to
different
4.
I am advised of all the reasonably known risks and
consequences associated with this treatment.
Those
reasonably known risks and conseiquences have been fully
explained to me.
5.
I am advised that there are no
i
guarantees that I will
become pregnant through my participation ini the IVF
program or that, if I do achieve pregnancy, a successful full-term pregnancy will result.
6.
I understand that the factors that may prevent my
becoming pregnant or carrying a fetus to• full-term
during my participation in the IVF program include, but
are not limited to, the following:
7.
a)
The time of ovulation may not be accurately pre
dictable, or ovulation may not occur in the moni
tored cycle, thereby precluding any attempt at
obtaining an egg.
b)
The attempt to obtain an egg may be unsuccessful.
c)
My husband may be unable to obtain a semen specimen.
d)
Fertilization or splitting of the egg outside the
uterus may fail to occur.
e)
A laboratory accident may result in the loss of an
egg.
f)
Following successful establishment of pregnancy,
there is the possibility of miscarriage, ectopic
pregnancy (tubal pregnancy), or stillbirth.
I
understand that should
I carry the
fetus to full-
term, ’there
*’
are no guarantees that congenital anomalies
(birth defects) will not: occur.
8.
I understand that the chances of multiple pregnancy are
higher by this procedure than by natural conception.
9.
I understand that there is indication in the scientific
literature that the occurrence rate of any of the
events stated in paragraph 6(f) or 7 is increased or
decreased by the procedure.
93
10.
I understand that according to information currently
available from other in vitro fertilization centers,
pregnancies resulting from the procedure occur at a
maximum of 20 percent per cycle attempted.
I also
understand that the Fertility Clinic program does not
guarantee that its success rate will be similar to that
of other programs.
11.
I. understand that I am free to discontinue participa
tion in the program at any time, either verbally or in
writing, and that my decision to discontinue will in no
way prejudice other treatment that I may receive from
the Fertility Clinic.
I also understand that if I
decide to discontinue participation in the IVF program,
I will be responsible for all expenses incurred during
the periods cf time prior to such discontinuation and
which relate to my treatment in the program.
12.
I understand that this consent extends from the
original period of my participation in the program
until the program is completed or until I decide to
discontinue participation.
13.
I understand that should the results of my treatment or
any aspect of it be published in medical or scientific
journals, all possible precautions will be taken to
protect my anonymity.
I grant permission to the IVF
team to publish in professional journals statistics
(relating to my case, provided my name is not used.
Date :
Patient:
Time :
Spouse :
Witness :
Physician Obtaining
Consent :
I
■
G/SGPNOV97/11-12-97
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4
PARTC
APPENDICES
1.
Code of Ethics of the Medical Council of India
2.
The Nuremberg Code
3.
World Medical Association - D<jclaration of Helsinki
1
Appendix I
Code of Medical Ethics framed under section 33 of the Indian
Medical Council Act 1956
At the time of registration, each applicant shall be given a copy of the following
declaration by the Registrar concerned and the applicant shall read and agree to
abide by the same:
DECLARATION
1 I solemnly pledge myself to consecrate my life to the service of humanity.
2. Even under threat, I will not use my medical knowledge contrary to the laws
of humanity.
3. I will maintain the utmost respect for human life from the time of conception.
4. I will not permiit considerations of religion, nationality race party politics or
social standing to intervene between my duty and my patient.
5. I will practise my profession with conscience and dignity.
6. The health of my patient will be my first consideration.
7. I will respect the secrets which are confided in me
8. I will give to my teachers the respect and gratitude which is their due.
9. I wMI maintain by all means in my power, the honour and noble traditions of
medical profession.
10. My colteagues will be my brothers.
I make these promises solemnly, freely and upon my honour.
CODE
Genera/ Principles
1. Character of the Physician. The prime object of the medical profession is to
render serviice to humanity; reward of financial gain is a subordinate
consideration. Who-so-ever chooses this profession, assumes the obligation to
conduct himself in accord with its ideals. “A physician should be an upright man,
instructed in the art of healings”. He must keep himself pure in character and be
diligent in caring for the sick. He should be modest, sober, patient, prompt to do
whole duty without anxiety; pious without going so far as superstition conducting
himself with propriety in his profession and in all the actions of his life.
i
4
2. The physician’s responsibility. The principle objective of the medical
profession is to render service to humanity with full respect for the dignity of
man. Physicians should merit the confidence of patients,entrusted to their care,
rendering to each a full measure of service and devotion. Physician should tfy
continuously to improve medical knowledge and skill and should make available
to their patients and colleagues the fcenefHs of their professional attainments.
The physician should practice methods of healing founded on scientific basis
and should not associate professionally with anyone who violates this principle.
The honoured ideals of the medical profession imply that tine responsibilities of
the physicians extend not only to individuals but also to society.
3. Advertising. Solicitation of patients directly or indirectly, by a physician, by
groups of physicians or by institutions or organisations is unethical. A physician
shall not make use of or aid or permit others to make use of him (or his name) as
subject of any form or manner of advertising or publicity through lay channels
either alone or in conjunction with others which is of such a character as to invite
attention to him or to his professional position, skill, qualification, achievements,
attainments, specialities, appointments, associations, affiliations or honours
and/or of such character as would ordinarily result in his self aggrandisements
nor shall he give to any person who-so-ever, whether for compensation or
otherwise, any approval, recommendation, endorsement, certificate, report or
statement with respect of any drug, medicine, nostrum remedy, surgical, or
therapeutic article, apparatus or appliance or any commercial product or article
with respect of any property, quality or use thereof or any test demonstration or
trial thereof, for use in connection with his name, signature, or photograph in any
form or manner of advertising through lay channels nor shall he boast of cases,
operations cures or remedies or permit the publication of report thereof lay
channels. A medical practitioner is permitted a formal announcement in press
regarding the following:
(1)
(2)
(3)
(4)
(5)
(6)
On starting practice.
On change of type of practice.
On changing address.
On temporary absence from duty.
On resumption of another practice.
On succeeding to another practice.
4, Payment of professional services. The ethical physician, engaged in the
practice of medicine, limits the sources of his income received from professional
activities to service rendered to the patient. Remunerations received for such
services should be in the form and amount specifically announced to the patient
at the time the service is rendered
cure no payment”.
It is unethical to enter into a contact of "no
2
f
-A
5. Patent and copy rights,. A physician may patent surgical instruments,
appliances and medicine or copy right applications methods and procedure.
The use of such patents or copy right or the receipt of remuneration from them
which retards or inhibits research or restricts the benefits derivable therefrom
are unethical.
6.
Running an open shop (dispensing of drugs and appliances by
physicians). A physician should not run an open shop for sale of medicine for
dispensing prescriptions prescribed by doctors other than himself or for sale of
medical or surgical appliances It is not ethical for a physician to prescribe or
supply drugs, remedies or appliances as long as there is no exploitation of the
patient.
7. Rebates and commission., A physician shall not give, solicit, or receive nor
shall he offer to give, solicit or receive any gift, gratuity, commission or bonus in
consideration or return for the referring, recommending or procuring ot any
patient for medical, surgical or other treatment. A physician shall not directly or
be any subterfuge participate in or by a party to act of division, transference,
assignment, subordination, rebating, splitting or refunding of any fee for medical,
surgical or other treatment.
The provisions of this para shall apply with equal force to the referring,
recommending or procuring by a physician or any person, specimen or material
for diagnostic, or other study or work. Nothing in this section, however, shall
prohibit payment of salaries by a qualified physician to other duly qualified
person rendering medical care under his supervision
8. Secret remedies. The prescribing or dispensing by a physician o* secret
medicines or other secret remedial agents of which he does not know the
composition, or the manufacture or promotion of their use is unethical.
9. Evasion of legal restrictions. The physicians will observe the laws of the
country in regulating the practice of medicine and will not assist others to evcade
such laws. He should be cooperative in observance and enforcement of sanitary
laws and regulations in the interest of public health. A physician should observe
the provisions of the State Acts like Drugs Act. Pharmacy Act, Poisons Act and
Dangerous Drugs Act and such other Acts, Rules, F-iegulations made by the
Central Govt./State Govts, or local Administrative Bodies for protection and
promotion of public health.
3
Duties of Physicians to their Patients
10. Obligations to the sick. Though a physician ss not bound to treat each and
eveiy one asking his services except emergencies for the sake of humanity and
the noble traditions of the profession, he should not only be ever ready to
respond to the calls of the sick and the injured, but should be mindful of the high
character of his mission and the responsibility he incurs in the discharge of his
professional duties. In his ministrations, he should never forget that the health
and the lives of those entrusted to his care depend on his skill and attention. A
physician should endeavour to add to the comfort of the sick by making his visits
at the hour indicated to the patients.
11.
Patience, delicacy and secrecy.
Patience and delicacy should
characterize the physician. Confidence concerning individual or domestic life
entrusted by patients to a physician and defects in the disposition or character of
patients observed during medical attendance should never be revealed unless
their revelation is required by the laws of the State. Sometimes, however, a
physician must determine whether his duty to society requires him to employ
knowledge, obtained through confidences to him as a physician, to protect a
healthy person against a communicable disease to which he is about to be
exposeci. In such instance, the physician should act as he would desire another
to act toward one of his own family in like circumstances.
12. Prognosis. The physician should neither exaggerate nor minimize the
gravity of a patient’s condition. He should assure himself that the patient, his
relatives or his responsible friends have such knowledge of the patient’s
condition as will serve the best interests of the patient and the family.
13. The patient must not be neglected. A physician is free to choose whom
he will serve. He should, however, respond to any request for his assistance in
an emergency or whenever temperate public opinion expects the service. Once
having undertaken a case, the physician should not neglect the patient, not
should he withdraw from the case without giving notice to the patient, his
relatives or his responsible friends sufficiently long in advance of his withdrawal
to allow them to secure another medical attendant. No provisionally or fully
registered medical practitioner shall wailful commit an act of negligence that may
deprive his patient or patients from necessary medical care.
Duties of the Physician to profession at large
14.
Upholding the honour of the profession.
uphold the dignity and honour of his profession.
4
A physician is expected to
15. Membership in medical society. For the advancement of his profession, a
physician should affiliate with medical societies and contribute his time, energy
and means so that these societies may represent the ideals of the profession.
16. Safeguarding the profession. Every physician should aid in safeguarding
the profession against admission to it of those who are deficient in moral
character or education. Physician should not employ in connection with his
professional practice any attendant who is neither registered not enlisted under
the Medical Acts in force and should not permit such persons to attend, treat or
perform operations upon patients in respect of matters regarding professional
discretion or skill as it is dangerous to public health.
17. Exposure of unethical conduct. A physician should expose, without fear
or favour, incompetent or corrupt, dishonest or unethical conduct on the part of
members of the profession. Questions of such conduct should be considered,
first before proper medical tribunals in executive sessions or by special or duly
appointed committees on ethical relations, provided such a course is possible
and provided also that the law is not hampered thereby. If doubt should arise as
to the legality of the physician’s conduct, the situation under investigation may
be placed before officers of the law, and the physician investigators may take
the necessary steps to enlist the interest of the proper authority.
Professiona/ Services of Physicians to each other
18. Dependence of physicians on each other. There is no rule that a
physician should not charge another physician for hts service, should cheerfully
and without recompense give his professional services to physicians or his
dependents if they are in his vicinity.
19. Compensation for expenses. A physician should consider it as a pleasure
and privilege to render gratuitous service to all physicians and their immediate
family dependents When a physician is called from a distance to attend or
advice another physician or his dependents, reimbursement should however be
made for travelling and other incidential expenses.
Duties of Physician in consultation
20.. Consultation should be encouraged. In case of serious illness, especially
in doubtful or difficult conditions the physician should request consultation.
5
21. Consultation for Patient's Benefit. In every consultation, the benefit to
the patient is first importance All physicians interest in the case should be
candid with the patient, a member of his family or responsible friend.
22. Punctuality in consultation. Utmost punctuality should be observed by a
physician in meeting for consultation.
23. Conduct in consultation. In consultations no insincerity, rivalry or envy
should be indulged in.
All due respect should be observed towards the
physician in-charge of the case and no statement or remark be made, which
would impair the confidence reposed in him. For this purpose no discussion
should be carried on in the presence of the patient or his representatives.
24. Statement to patient after consultation, (a) All statements of the patient
or his representatives should take place in the presence of all the physicians
consulting, except as otherwise agreed; the announcement of the opinion to the
patient or his relations or friends shall rest with the medical attendant.
(b) Differences of opinion should not be divulged unnecessarily bit when
there is irreconcilable difference of opinion the circumstances should be frankly
and impartially explained to the patient or his friends It would be open to them
to seek further advice should they so desire.
25. Treatment after consultation.. No decision should restrain the attending
physician from making such subsequent variations in the treatment any
unexpected change may require, but at the next consultation, reasons for the
variations should be stated. The same privilege, with its obligations, belongs to
the consultant when sent for in an emergency during the absence of attending
physician. The attending physician may prescribe at any time for the patient, the
consultant only in case of emergency.
26. Consultant not to take charge of the case. When a physician has been
called as a consultant, none but the rarest and most exceptional circumstances
would justify that consultant taking charge of the case. He must not do so
merely on the solicitation of the patient or friends.
27. Patients referred to specialists. When a patient is referred to a specialist
by the attending physician, a statement of the case should be given to the
specialist, who should communicate his opinion in writing in a closed cover
direct to the attending physician.
6
1
Duties of physician in cases of interference
28. Appointment of substitute. Whenever a physician requests another
physiciai i to attend his patients during his temporary absence from his practice,
professional courtesy requires the acceptance of such appointment in consistent
with his other duties. The physician acting under such an appointment should
give the utmost consideration to the interests and reputation of the absent
physician. All such patients should be restored to the care of the latter upon his
return.
29. Visiting another physician's case. A physician called to visit a patient
who has recently been under the care of another physician in the same illness,
should not take charge of, nor prescribe for such patient except in case of
emergency when he should communicate to the former explaining the
circumstances under which the patient was seen and treatment given, or when
the physician has relinquished his case, or when the patient has notified such
physician to discontinue his services.
When it becomes the duty of a physician occupying an official position to
see and report upon an illness or injury, he should communicate to the physician
in attendance so as to give him an option of being present. The medical officer
should avoid remarks upon the diagnosis of the treatment that has been
adopted.
30. Engagement for an obstetric case. If a physician agrees to attend a
woman during her confinement, he must do so. Inability to do so on an excuse
of any other engagement is not tenable except when he is already engaged on a
similar or other serious case. When a physician who has been engaged to
attend an obstetric case is absent and another is sent for and delivery
accomplished, the acting physician is, entitled to his professional fees, but
should secure the patient’s consent to resign on the arrival of the physician
engaged
Duties of physician to the public
31. Physician as citizens. Physicians, as good Citizens, possessed of special
training should advise concerning the health of the community wherein they
dwell. They should bear their part in enforcing the laws of the community and in
sustaining the institutions that advance the interests of humanity. They should
operate especially with the proper authorities in the administration of sanitary
laws and regulations.
7
32. Public health. Physicians, especially those engaged in public health work,
should enlighten the public concerning quarantine regulations and measures for
the preventlion of epidemic and communicable diseases.
At all times the
physician should notify the constituted public health authorities of every case of
communicable disease under his care, in accordance with the laws, rules and
regulations of the health authorities. When an epidemic prevails, a physician
must continue his labour without regard to the risk to his own health.
33. Pharmacists. Physicians should recognize and promote the practice of
pharmacy as a profession and should recognise the cooperation of the
pharmacist in education of the public concerning the practice of ethical! and
scientific medicine.
DISCIPLINARY ACTION
1. The Medical Council of India desires to bring to the notice of the registered
medical practitioners the following statement upon offences and form of
professional misconduct, which may be brought before the appropriate Medical
Council for disciplinary action in view of the authority conferred upon the Medical
Council of India and/or State Medical Councils as provided under Indian Medical
Council Act, 1956, or State Medical Councils Acts as may be subsequently
amended.
2. The appropriate Medical Council may award such punishment as deemed
necessary or may direct the removal altogether or for a specified period from the
Register, the name of any registered practitioner who has been convicted of any
such offence as implied in the opinion of the Medical Council of India and/or
State medical Councils, a defect of character or who after an enquiry at which
opportunity has been given to such registered practitioner to be heard in person
or by pleader, has been held by the appropriate Medical Council to have been
guilty of serious professional misconduct. The appropriate Medical Council may
also direct that any name so removed shall be restored.
3.
It must be clearly understood that the instances of offences and of
professional misconduct which are given do not constitute and are not intended
to constitute a complete list of the infamous acts which may be published by
erasure from the Register, and that by issuing this notice the Medical Council of
India and/or State Medical Councils are in no way precluded from considering
and dealing with any form of professional misconduct on the part of a registered
practitioner. Circumstances may and do arise from time to time in relation to
which theres may occur questions of professional misconduct which do not come
8
within
any
V n « Pri
n of
i Hthese categories.
caTegories. Every
Every care should be taken that the code is not
of ndH Ih 6rfPIK 0 SUCh instances as in a|l others, the Medical Council
of India and/or State Medical Councils have to consider and decide uoon the
facts brought before the Medical Council of India and/or State Medical Councils.
a•
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—J
— 8
< a
LIST
nrS>rti^l!ery
imProPer conduct or association with a patient Anv medical
improperconductwifol8' 'T Ptrofessional P°sition bV committing any adultery or
patforrt is liable for .P”1 'ent or by maintainmg an improper association with a
Council Act I956 L/,- £
rZ aCt'°n aS Pr°vided under the lndian M^ical
r otate Medical Acts, as may be subsequently amended.
2. Conviction by Court of Law for offences involving moral turpitude.
!n ““ca,es’ «ePor,s
°«™ Documents
Registered
be calted upon or reouesi
b0L,nd by law 10 0lve. or may from time to time
documents of kindrpri^h
tO 9'Ve certlflcates' notification, reports and other
XXn °u< e m Xp , ?C,e;.S'9ned by them in ^^ir professional capacity for
suDsequunt use in the courts of justice or for administrative purposes etc.
reports- SUCh d°Cumerits inc|ude among other certificates, notifications,
(d! Under'
^aC;Cir1at'0n Acts and the regulations made thereunder,
ifo L ndt h r
7 CtS and thS re9ulatiori "^de thereunder.
i,e) under the Education Acts.
fd) Under th! w T Hea,f£ AC,S
the °rder made thereunder.
J U nder the Woi kmen s Compensation Act.
(h)
f ) Under the Acts and order relating to the notification of infectious
diseases.
(I) Under the Employee's State Insurance Act.
(k Undp?mp
W!h S'Cl< benefit insurance and friendly societies.
(Kj under the Merchant shipping Act.
() For procuring the issuing of passports.
(m) oublfooffiS attenda?ce in courts °f Justice, in public services, in
public offices or in ordinary employments
(n) In connection with Civil and Military matters
°
With matters under the control of Ministry of the
pensions.
9
(ii)
Any registered practitioner who shall be shown to have signed or
given under his name and authority and such certificate,
notification, report of document of a kindred character which is
untrue, misleading or improper relating to the several matters
above specified or otherwise, is liable to have his name erased
from the Register.
(iii)
A Registered medical practitioner shall maintain a Register of
Medical Certificates giving full details of certificates issued. When
issuing a medical certificate always enter the identification marks of
the patient and keep a copy of the certificate. So not omit to note
down the signature or thumb-mark, address and identification
marks of the patient on the medical certificate or report.
4.
Contravening the provisions of the Drugs Act and regulation made
thereunder.
5. Selling Schedule poison to the public under the cover of his own qualification
except to his patient.
6. Performing or enabling unqualified person to perform an abortion or any
illegal operation for which there is no medical, surgical or psychological
indication.
7. A physician should not issue certificates of efficiency in modern medicine to
unqualified or non-medical person.
(Note: The foregoing does not apply so as to restrict the proper training and
instruction of bonafide students, legitimate employees of doctors, midwives,
dispensers, surgical attendants, or skilled mechanical and technical assistants
under the personal supervision of physicians).
8. A physician should not contribute to the lay press articles and give interviews
regarding diseases and treatments which may have the effect of advertising
himself or soliciting practices, but is open to write to the lay press under his own
name on matters of public health hygienic living or to deliver public lectures, give
talks on the radio broadcast for the same purpose and send announcement of
the same to the lay press.
9. As institution run by a physician for a particular purpose such as a maternity
home, a sanatorium, a house for the crippled or the blind, etc. may be advertised
in the lay press, but such advertisements should not contain anything more than
the name of the institution, type of patients admitted, facilities offered
10
J
and the residential fees.
Name of either the superintendent or the doctor
attending should not appear in the advertisement.
10. It is improper for a physician to use an unusually large signboard and
write on it anything other than his name, qualifications obtained from a Unwersity
or a statutory body, titles and name of his speciality. The name should be the
contents of his prescription papers. It is improper to affix a sign-board on a
chemist’s shop or in places where he does not reside or work.
11. Do not disclose the secrets of a patient that have been learnt in the
exercise of your profession Those may be disclosed only in a Court of Law
under orders of the presiding judge.
12.
Refusing on religious grounds alone to give assistance in our
12.
conduct of sterility, birth control craniotomies on living children and therapeutic
abortions when there is medical indication; unless the medical practitioner feels
himself/herself incompetent to do so
13. Before performing an operation the physician should obtain in writing
the consent from the husband or wife, parent or guardian in the case of a minor,
or the patient himself as the case may be. In an operation which may result in
sterility the consent of both husband and wife is needed.
14. Do not publish photographs or case reports of your patients in any
medical or other journal in a manner by which their identity could be made out
without their permission. Should the identity be not disclosed his consent is not
needed.
15. If you
running a nursing home and if you employ assistants to
help you the u’^nate responsibility rests on you.
16. No physician must exhibit publicly the scale of fees. But there is not
ejection to the same being put in the physicians’ consulting or waiting room.
Oft
17
No physician shall use touts or agents for procuring patients.
18 Do not claim to be a specialist unless you have put in a good few
years of study and experience or a special qualification in that branch. Once
you say you are one, do not undertake work outside your speciality even for your
friends.
n
Appendix II (a)
THE NUREMBERG CODE
1.
The voluntary consent of the human subject is absolutely essential.
The means that the person involved should have legal capacity to give
consent; should be so situated as to be able to exercise free power of
choice, without the intervention of any element of force, fraud, deceit,
duress, over-reaching, or other ulterior form of constraint or coercion; and
should have sufficient knowledge and comprehension of the elements of
the subject matter involved as to enable him to make an understanding
and enlightened decision. This latter element requires that before the
acceptance of an affirmative decision by the experimental subject there
should be made known to him the nature, duration, and purpose of the
experiment; the method and means by which it is to be conducted; all
inconveniences and hazards reasonably to be expected; and the effects
upon his health or person which may possibly come from his participation
in the experiment
The duty and responsibility for ascertaining the quality of the conseint
rests upon each individual who initiates, directs or engages in the
experiment. Jt is a personal duty and responsibility vyhich may not be
delegated to another with impunity
2
The experiment should be such as to yield fruitful results for the good of
society, unprocurable by other methods or means of study, and not
random and unnecessary in nature
3
The experiment should be so designed and based on the results of
animal experimentation and a knowledge of the natural history of the
disease or other problem under study that the anticipated results will
justify the performance of the experiment
4.
The experiment should be so conducted as to avoid all unnecessary
physical and mental suffering and injury.
5.
No experiment should be conducted where there is an a priori reason to
believe that death or disabling injury will occur, except, perhaps, in those
experiments where the experimental physicians also serve as subjects.
6.
The degree of risk to be taken should never exceed that determined by
the humanitarian importance of the problem to be solved by the
experiment.
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7.
Proper preparations should be made and adequate facilities provided to
protect the experimental subject against even remote possibilities of
injury, disability, or death.
8.
The experiment should be conducted only by scientifically qualified
persons. The highest degree of skill and care should be required through
all stages of the experiment of those who conduct or engage in the
experiment.
9.
During the course of the experiment the human subject should be at
liberty to bring the experiment to an end if he has reached the physical or
mental state where continuation of the experiment seemed to him to be
impossible.
10.
During the course of the experiment the scientist in charge must be
prepared to terminate the experiment at any stage, if he has probably
(sic) cause to believe, in the exercise of the good faith, superior skill and
careful judgement required of him that a continuation of the experiment is
likely to result in injury, disability, or death to the experimental subject.
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Annex I
Appendix II (b)
WORLD MEDICAL ASSOCIATION DECLARATION
OF HELSINKI
Recommendations guiding physicians in biomedical research
involving human subjects
Adopted by the 18th World Medical Assembly
Helsinki, Finland, June 1964
and amended by the
29th World Medical Assembly Tokyo, Japan, October 1975
35th W'orld Medical Assembly
Venice, Italy. October 1983
and the
41 st World Medical Assembly Hong Kong, September 1989
INTRODUCTION
It is the mission of the physician to safeguard the health of the people. His or
her knowledge and conscience are dedicated to the fulfillment of this mission.
The Declaration of Geneva of the World Medical Association binds the physician
with the words “ The health of my patient will be my first consideration, "and the
International Code of Medical Ethics declares that, “A physician shall act only in
the patient s interest when providing medical care which might have the effect of
weakening the physical and mental condition of the patient.’7
The purpose ot biomedical research involving human subjects must be to
improve diagnostic, therapeutic and prophylactic procedures and
and the
understanding of the aetiology and pathogenesis of disease.
In current medical practice most diagnostic, therapeutic or prophylactic
procedures involve hazards. This applies especially to biomedical research.
<
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Medical progress is based on research a fundamental distinction must be
recognised between medical research in which the aim is essentially diagnostic
or therapeutic for a patient, and medical research, the essential object of which
is purely scientific and without implying direct diagnostic or therapeutic value to
the person subjected to the research.
Special caution must be exercised in the conduct of research which may affect
the environment, and the wtslfare of animals used for research must be
respected.
Because it is essential that the results of laboratory experiments be applied to
human beings to further scientific knowledge and to help suffering humanity, the
World Medical Association has prepared the following recommendations as a
guide to every physician in biomedical research involving human subjects. They
should be kept under review in the future. It must be stressed that the standards
as drafted are only a guide to physicians all over the world. Physicians are not
relieved from criminal, civil and ethical responsibilities under the laws of their
own countries.
I. BASIC PRINCIPLES
1.
Biomedical research involving human subjects must conform to generally
accepted scientific principles and should be based on adequately
performed laboratory and animal experimentation and a thorough
knowledge of the scientific literature.
2.
The design and performance of each experimental procedure involving
human subjects should be clearly formulated in an experimental protocol
which should be transmitted for consideration, comment and guidance to
a specially appointed committee independent of the investigator and the
sponsor, provided that this independent committee is in conformity with
the laws and regulations of the country in which the research experiment
is performed.
3.
Biomedical research involving human subjects should be conducted only
by scientifically qualified persons and under the supervision of a clinically
competent medical person.
The responsibility for the human subject
must always rest with a medically qualified person and never rest on the
subject of the research, even though the subject has given his or her
consent.
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4.
Biomedical research involving human subjects cannot legitimately be
carried out iunless
‘
the importance of the objective is in proportion to the
inherent risk to the subject.
5.
Every biomedical research project involving human subjects should be
preceded by careful assessment of predictable risks in comparison with
foreseeable benefits to the subject or to others Concern for the interests
of the subject must always prevail over the interests of science and
society.
6.
The right of the research subject to safeguard his or her integrity must
always be respected. Every precaution should be taken to respect the
privacy of the subject and to minimize the impact of the study on the
subject’s physical and mental integrity and on the personality of the
subject.
7.
Physicians should abstain from engaging in research projects involving
human subjects unless they are satisfied that the hazards involved are
believed to be predictable. Physicians should cease any investigation if
the hazards are found to outweigh the potential benefits.
8
In publication of the results of his or her research, the physician is obliged
to preserve the accuracy of the results. Reports of experimentation not in
accordance with the principles laid down in this Declaration should not be
accepted for publication.
9.
n any research on human beings, each potential subject must be
adequately informed of the aims, methods, anticipated benefits and
potential hazards of the study and the discomfort it may entail. He or she
should be informed that he or she is at liberty to abstain from participation
?n the study and that he or she is free to withdraw his or her consent to
participation at any time The physician should then obtain the subject’s
freely-given informed consent, preferably in writing.
10. When obtaining informed consent for the research project the physician
should be particularly cautious if the subject is in a dependent relationship
to him or her or may consent under duress. In that case the informed
consent should be obtained by a physician who is not engaged in the
investigation and who is completely independent of this official
relationship.
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11.
In case of legal incompetence, informed consent should be obtained from
the legal guardian in accordance with national legislation.
Where
physical or mental incapacity makes it impossible to obtain informed
consent, or when the subject is a minor, permission from the responsible
relative replaces that of the subject in accordance with national
legislation.
Whenever the minor child is in fact able to give a consent, the minor’s
consent must be obtained in addition to the consent of the minor’s legal
guardian.
12. The research protocol should always contain a statement of the ethical
considerations involved and should indicate that the principles enunciated
in the present Declaration are complied with.
II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE
(Clinical research)
1. In the treatment of the risk person,, the physician must be free to use a
new diagnostic and therapeutic measure, if in his or her judgement it
offers hope of saving life, reestablishing health or alleviating suffering.
2
The potential benefits, hazards and discomfort of a new method should be
weighed against the advantages of the best current diagnostic and
therapeutic methods.
3. In any medical study, every patient including those of control group, if any
should be assured of the best proven diagnostic and therapeutic
method.
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4.
The refusal of the patient to participate in a study must never interfere
with the physician-patient relationship.
5.
If the physician considers it essential not to obtain informed consent, the
specific reasons for this proposal should be stated in the experimental
protocol for transmission to the independent committee (1.2)
6.
The physician can combine medical research with professional care, the
objective being the acquisition of new medical knowledge, only to the
extent that medical research is justified by its potential diagnostic or
therapeutic value for the patient.
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111.
NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN
SUBJECTS
(Non-clinical biomedical research)
1. bi the purely scientific application of medical research carried out on a
human being, it is the duty of the physician to remain the protector of the
life and health of that person on whom biomedical research is beinq
carried out.
2.
The subjects should be volunteers — either healthy persons or patients for
whom the experimental design is not related to the patient’s illness.
3.
1 he investigator or the investigating team should discontinue the research
if in his/her or their judgement it may, if continued, be harmful to the
individual.
4. In research on man, the interest of science and society should never take
precedence over considerations related to the well-being of the subject
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