National Ethical Guidelines for Bio-Medical Research Involving Children (2017)

National Ethical Guidelines for
Biomedical Research
Involving Children

Indian Council of Medical Research
2017Disclaimer:
Care has been taken to present the information accurately and inline with the latest government
guidelines. However, in view of ongoing changes in government regulations and the constant
flow of new information, the reader is urged to check the latest notifications/rules/ regulations
provided by the Government of India from time to time.
Published by the Division of Publication and Information on behalf of the Secretary DHR & DG, ICMR, New Delhi.
Printed at M/s Royal Offset Printers, A-89/1, Naraina Industrial Area, Phase-I, New Delhi-110028 Phone: 011-25797524,Compiled & Edited by:
Dr. Reeta Rasaily
Published by:
Director General
Indian Council of Medical Research
New Delhi- 110029
October 2017
Production Controller:
J. N. Mathur
ICMR, New DelhiMessage
It is important to include children in clinical research including clinical
trials so that the benefit of new therapy can also be applied to children as
soon as possible. Traditionally children are often the last to benefit from
advances in medicine. However, because of their inherent vulnerability the
potential risk from participation in research studies must be anticipated
and adequate precautions taken. These guidelines have been developed
specifically to address ethical issues of conducting research in children.
We hope that these guidelinesare put into practice in every institution
conducting research in children and the scientific community, public at large
get immensely benefited.
I am grateful to Prof. V.K.Paul and Dr. H.P .S.Sachdev under whose stewardship these
guidelines were developed and all members of expert review committee who have contributed
their time and ideas generously.
Soumya Swaminathan
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Dr. Soumya Swaminathan
MD, FASc, FNASc, FAMS
Secretary to the Government of India
Department of Health Research
Ministry of Health & Family Welfare
&
Director-General, ICMR
Indian Council of Medical Research
Department of Health Research
Ministry of Health & Family Welfare
V. Ramalingaswami Bhawan, Ansari Nagar
New Delhi-110 029 (INDIA)º´ÉɺlªÉ +ÉxÉÖºÉÆvÉÉxÉ ÉÊ´É£ÉÉMÉ
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Tele. : (Off.) +91-11-26588204, 26589620; Fax (Off.) : +91-11-26588662, E-mail: dg@icmr.org.inForeword
Children are unique biologically and in their interphase with the
environment. This is true in fetal life and throughout childhood. The
findings in adults cannot be automatically assumed to be true in children.
This applies to the way therapeutics and preventive modalities are taken
up and metabolised. Children are vulnerable and carry a greater risk of
harm during research. Many new technologies that can provide cures for
incurable disease also pose major ethical concerns. In countries where
effective literacy is still not common, we have a far greater responsibility to
ensure that the participants and their care givers understand, with utmost
clarity, the research and procedures that researchers propose.
Practice of the right kind requires norms and guidelines that are articulated with sublime
clarity. An institutional mechanism to administer and oversee research practice is critical at an
institutional level. Monitoring of data safety and quality through data monitoring committees
compliments the work of the ethics committees. In modern research privacy and confidentiality
are important to preserve. Biological specimens must be obtained when the knowledge to be
gained is likely to advance medical care, how these are used must have the explicit approval of
the subjects of research. It is therefore, gratifying that the Indian Council of Medical Research, the
nodal agency in the country has developed ethical guidelines for biomedical research involving
children. These are written with clarity, based on scientific and ethical principles, and balanced in
providing guiding principles and processes and practices for achieving compliance with these with
the guidelines. As someone concerned with bringing the fruits of research to our children as well
as to ensure their safety and security, I complement the council for this outstanding contribution.
It is for us, researchers to ensure that the guidance becomes the practice in every institution of the
country. We need research for children but only under the best ethical norms.
Dr. MK BhanForeword
In this era of evidence based medicine, it is imperative to conduct
robust and ethical research in neonates, infants, children and adolescents
to improve our understanding of disease and provide optimal healthcare.
However, professionals and parents often feel apprehensive about asking
this vulnerable population to take part in research because of greater
potential risks or burdens. Furthermore, young children are not in a
position to make autonomous decisions regarding their participation in
research, which puts them at risk of coercion or undue influence.
It is therefore mandatory that biomedical research involving
children zealously protects their interests, especially from an ethical
perspective. Ethics could be considered as codified practices and procedures performed by the
practitioners of the profession. Institutional Ethical Committees thus need to refer to consensus
recommendations to arrive at meaningful decisions. Adult based guidelines are not ideal for this
purpose because special concerns related to children are usually not addressed in detail. Realising
this felt need, several developed countries have formulated their ethics guidelines for biomedical
research involving children. However, there is a need to adapt these recommendations to the
Indian context to overcome challenges of applying universal ethical principles in the multicultural
Indian society with a diversity of health-care systems with varying standards.
In 2006, the Indian Council of Medical Research developed an updated, third version entitled
“Ethical Guidelines for Biomedical Research on Human Participants”. These guidelines contain
only a small section pertaining to research in children, which does not address in detail several
ethical perspectives of conducting biomedical research in neonates and children. This monograph
is intended to accomplish this important task and serve as the reference manual for ethical
committees in the national context. These consensus recommendations were formulated through
a rigorous and robust methodology including review of pertinent national and international
guidelines, multiple stakeholders’ input and public scrutiny. It is hoped that this timely publication
will fulfil the objectives with which it was conceived.
Prof. H.P .S. Sachdev,
Acknowledgement
For the first time The Indian Council of Medical Research has come out with the guidelines
separately for Biomedical Research involving children. We acknowledge with gratitude the
contributions made by ICMR Advance Center on Newborn Health Research at All India Institute of
Medical Sciences under leadership of Professor Vinod Kumar Paul in creating the draft guidelines
for biomedical research involving children.
We gratefully acknowledge contribution of Dr. Suvasini Sharma and Dr. Naveen Sankhyan for
preparing the initial draft. We are indebted to all members of the core committee and members
of expert group for their valuable contributions in finalizing the draft guidelines. Special thanks to
Dr. Vasantha Muthuswamy and Dr. Roli Mathur for their constant guidance and final editing of the
draft guidelines.
We are grateful to Secretary Department of Health Research and Director General ICMR –
Dr. Soumya Swaminathan and Dr. V.M. Katoch (Former Secretary DHR & DG ICMR) for their
continued support and guidance.
We gratefully acknowledge the contribution of Mr. Devesh Lodhy for designing the cover
page and assistance of Mr. J. N. Mathur for final printing and publishing the guidelines.
Dr. R.S. Sharma
Scientist G & Head Div. of Division of
RBMCH, ICMR, New DelhiDr. Reeta Rasaily
Scientist F,
Division of RBMCH, ICMR, New Delhi
Contents
Abbreviations
Section 1 10
   1.1 Introduction 10
   1.2 Needs and challenges of clinical research in children 11
     1.2.1 Why is biomedical research necessary in children? 11
     1.2.2 Challenges of biomedical research involving children 12
   1.3 The process of developing ethics guidelines for research involving children 12
   1.4 Scope of the guidelines 13
   1.5 General guidelines for research in children 14
Section 2: Risk 13
   2.1 Assessment of benefit and risk in research in children 15
   2.2 Classification of Risks 16
Definitions: 16
     2.2.1 Less than Minimal Risk 16
     2.2.2 Minimal risk 16
     2.2.3 Minor increase over minimal risk or Low risk 16
     2.2.4 More than minimal risk or High risk 17
   2.3 Concept of relative versus absolute interpretation of risk 17
   2.4 Determinants of risk 17
   2.5 Pain, distress, and fear minimization in children during research 17
   2.6 Type of assays and sample collection 18
  2.7 Paediatric formulations to be used in paediatric studies 18
  2.8 Guidelines for ethical approval based on degree of risk 18
Section 3: Consent and Assent 19
   3.1. Informed consent 19
     3.1.1 General principles of informed consent 19
     3.1.2 Waiver of consent 21
     3.1.3. Concerns regarding informed consent 22
  3.2 Children’s assent 23     3.2.1 Age and method of obtaining assent 23
     3.2.2 Waiver of assent 23
     3.3.3 Content of assent forms 24
Section 4: Safeguard Systems 25
   4.1 Ethics committee (EC) 25
   4.2 Experience of investigator and research setting 26
   4.3 Data and safety monitoring board (DSMB) 27
   4.4 Data protection and confidentiality 28
   4.5 Bio-banking of samples: 28
   4.6 International collaboration and data sharing 28
Section 5: Compensation 28
  5.1 Compensation for participation 28
  5. 2 Compensation for accidental injury 29
Section 6: Special situations 29
   6.1 Research in neonates 29
  6.2 Research in HIV positive children 30
  6.3 Vaccine studies in children 30
   6.4 Ethical issues in genetic research 30
   6.5 Research involving children in an emergency situation 30
   6.6 School-based research 31
   6.7 Internet /Telephone based research in children 31
   6.8 Community Based Research in Children 31
   6.9 Research involving adolescents (12-18 years) 32
Section 7: Annexures 33
   7.1 Glossary 28
   7.2 Web Resources 34
Index 35
Bibliography 38
Members of the Expert Committee on Drafting and Reviewing of guidelines 40 Abbreviations
Acquired immunodeficiency syndrome – AIDS
All India Institute of Medical Sciences – AIIMS
Central Drugs Standard Control Organization – CDSCO
Data and Safety Monitoring Board (DSMB) – DSMB
Deoxyribonucleic acid – DNA
Department of Health Research – DHR
Drug Controller General of India – DCGI
Ethics committee – EC
Government of India – GOI
Health Ministry’s Screening Committee – HMSC
Human immunodeficiency virus – HIV
Indian Council of Medical Research – ICMR
Legally acceptable/authorized representative – LAR
Participation information sheet – PIS
Principal investigator – PI
Ribonucleic acid – RNANational Ethical Guidelines for Biomedical Research involving Children
10
SECTION 1
1.1 Introduction
Biomedical and health research includes basic, applied and operational research studies
designed primarily to increase scientific knowledge about diseases and conditions (physical or
socio-behavioural), their detection, cause and strategies for health promotion, prevention, or
amelioration of disease and rehabilitation.
Biomedical research involving children is needed for the benefit of future generations of humanity.
It leads to advances in medical care which can potentially improve the health and quality of life
of children. As we near the end of the second decade of the 21st century, we have numerous
opportunities to develop interventions to promote health, and prevent and treat diseases that
affect children. This can only be achieved through experimentation. Research and innovation
is therefore the core of the endeavour to generate and translate knowledge into clinical care.
However, at the same time, we cannot expose children to undue harm by participating in research
studies
As per the Declaration of Helsinki, 2013, some research populations (such as children) are
particularly vulnerable and have increased likelihood of incurring additional and greater harm.
Vulnerable means an individual or group of people who are not in a position to make autonomous
decisions regarding participation in research, for example, children, students, prisoners, mentally
challenged individuals and others. This set of participants cannot give or refuse consent for
themselves and they may be at risk of coercion or undue influence. All vulnerable groups need
specifically considered protection. In vulnerable populations, biomedical research is justified only
if it is based on the health priorities of that population.
Ethics are codified practices and/or procedures performed by the practitioners of the profession.
The conduct of biomedical research involving children raises a number of ethical issues. The first
issue is that children lack autonomy : that is, the cognitive and emotional level of maturity and
the legal status to consent to research participation on their own behalf. Any research on children
must consider the level of their physical, cognitive, emotional, and psychosocial development.
Animal studies and research on adults should precede studies with children to minimize research
risks except in situations where the disease occurs only in children. These concepts underlie the
basic ethical principles of beneficence and non-maleficence . However, any system for protecting
children involved in research should not unreasonably impede research on children that may
potentially be beneficial to them in the future. This goes against the basic ethical principle of
justice . The concept of justice means that distribution of the potential benefits and harm of
participating in research should be fairly distributed. For example, a vulnerable set of patients
(such as children from poor socio-economic strata being treated in government hospitals) should
not be unduly exposed to research risks, just because they are available and their parents are not
fully aware of their rights.11National Ethical Guidelines for Biomedical Research involving Children
There are also special cha llenges regarding research in developing countries. In resource-constraint
settings where parents have low levels of literacy, children are even more vulnerable. The concept
of research is not well understood by most parents and research is often confused with treatment
(therapeutic misconception ), or seen as a way of accessing new therapies or better clinical care.
The parents may also be unduly susceptible to financial inducements to participate in research
because of their poor socio-economic status. Overuse of these vulnerable groups is a special
concern when they are unlikely to benefit from the knowledge gained from research. Research
in resource-poor countries has been found unjust when it does not consider the needs of those
societies and countries. For instance, a study being conducted in children of a developing country
with potential beneficiaries of the intervention being children from rich nations is bound to raise
concerns. India faces additional challenges given the multicultural society and diversity of health-
care systems of considerably varying standards.
1.2 Needs and challenges of clinical research in children
Medical research involving children is essential for advancing child health. In many situations,
research findings of studies in adults cannot simply be extrapolated to children and research
involving children is essential if children are to benefit from advances in biomedical sciences and
technology.
1.2.1 Why is biomedical research necessary in children?
Some of the reasons why biomedical research may be necessary in children are as follow:
1. The disease may affect only children, for example, hyaline membrane disease, birth asphyxia,
neonatal hyperbilirubinemia, extrahepatic biliary atresia, infantile spasms, infantile tremor
syndrome, Kawasaki disease, etc. Such diseases have no adult counterparts and therefore,
it is necessary to carry out research in children to advance our knowledge of these diseases.
Additionally, even if the same disease affects both children and adults, the pathophysiological
processes and responses to treatment in children may differ from those in adults, hence, we
cannot simply extrapolate the medications approved for adults to children. Some diseases
such as nephrotic syndrome, hypertension and rheumatoid arthritis affect both adults and
children, but the pathophysiological basis and clinical approach is very different in both.
2. The physiology of children is different from that of adults, and the pharmacokinetics of many
drugs is age-dependent based on the maturation of the drug metabolism pathways. For
example, children metabolize many drugs much more rapidly as compared to adults; hence,
the dosage of the drug (per kg of body weight) that needs to be given is much higher in
children. The absorption of drugs also varies with age. Pharmacokinetics and toxicity profile
varies with growth and maturation from infancy to adulthood.
3. The adverse effects of many drugs may also be different in children as compared to adults.
For instance, tetracyclines cause teeth discoloration in young children and aspirin use is
associated with Reye’s syndrome in children. National Ethical Guidelines for Biomedical Research involving Children
12
4. Age appropriate delivery vehicles and formulations (such as syrups ) are needed for accurate,
safe and palatable administration of medicines to infants and children.
5. The pathophysiology of many disorders is dependent on a child’s growth, development
and adaptive plasticity. Examples include adaptive changes in the motor system following a
perinatal stroke.
6. Research in children is also one of the ways to understand some adult diseases that are
thought to have their origins in early life. The natural history of the disease may be understood
better and it may lead to potential preventive interventions in early life.
1.2. 2 Challenges of biomedical research involving children
1. Diseases in children may be rare, and there may not be sufficient numbers of affected
patients to answer the research questions. This may lead to difficulties in having adequately
statistically powered studies to evaluate an effective treatment. For this reason, large multi-
centric studies lasting many years may be needed, which are not always feasible. To overcome
this difficulty studies in children often benefit from and require alternative and innovative
study designs that incorporate multiple regions, high number of study sites relative to the
number of patients to be enrolled, and realistic timelines to allow them to be feasible and to
collect relevant data specific to the population being studied.
2. It is usually difficult to find funding for research in children. As the market for paediatric drugs
and treatments is quite small compared to the adult ones, pharmaceutical companies do not
find it sufficiently remunerative to fund research in children.
3. The ethical concerns regarding research involving children, which include lack of autonomy
and inherent vulnerability, make it more difficult to perform research in children and obtain
appropriate informed consent.
4. Research in children is not just about performing research on individual patients. As parents
and families are involved, there is a need to take account of familial and socio-cultural
concerns while planning the research.
5. Research procedures and settings need to consider children’s physical, cognitive, andemotional
development. Developmentally appropriate outcomes need to be studied. Followup studies
(which may take years) are often needed to see the long-term outcomes of high risk neonates.
1.3 The process of developing ethics guidelines for research involving children
The Indian Council of Medical Research brought out the Policy Statement on Ethical Considerations
involved in Research on Human Subjects in 1980 and revised these guidelines in 2000 as the
Ethical Guidelines for Biomedical Research on Human Subjects . The third version called the Ethical
Guidelines for Biomedical Research on Human Participants was developed in 2006 and the latest
version, developed in 2017, is called the National Ethical Guidelines for Biomedical and Health 13National Ethical Guidelines for Biomedical Research involving Children
Research Involving Huma n Participants . These guidelines have a section pertaining to research
involving children, however, a need was felt to develop more comprehensive guidelines which
pertain to the specifics of ethics in biomedical research involving children. This endeavour was
undertaken under ICMR Advance Center for Newborn Health Research at All India Institute of
Medical Sciences, New Delhi.
As a first step, the existing national and international guidelines for biomedical research in children
were reviewed. Separate guidelines available for paediatric biomedical research in other countries
include the Institute of Medicine guidelines in the USA, the Medical Research Council guidelines
in the United Kingdom, and the European Union guidelines. All these guidelines were reviewed
for a better understanding of the ethical principles of biomedical research in children. Meetings
were also conducted with experts in the field of bioethics to develop a consensus on guidelines
in the Indian context. These guidelines have been developed and finalized after the expert group
discussions and consensus development.
1.4 Scope of the guidelines
This document covers the ethical and legal issues that researchers need to consider when carrying
out biomedical research in neonates and children. The aim is to set out general principles that can
be applied in most situations rather than to cover every possible situation. These guidelines need
to be used in conjunction with the current National Ethical Guidelines for Biomedical Research
involving Human Participants, Indian Council of Medical Research (ICMR) Government of India
and are meant for use by researchers, ethics committees and other involved stakeholders.
While these guidelines cover general biomedical research involving children, the definition
of ‘child’ has been variable according to various legal and social contexts. As per the National
Commission for Protection of Child Rights, a child is defined as a person from 0 to 18 years of age
(http://ncpcr.gov.in/).
These guidelines are sub-serving to the Constitution of India and the legislature. If the research is
a regulatory clinical trial under the Drugs and Cosmetics Act, 1940, and its rules and amendments
therein, the researchers should follow the requirements as stated under the Act.
For regulatory purposes, clinical trial means a systematic study of new drug(s) in human subject(s)
to generate data for discovering and/or verifying the clinical, pharmacological (including
pharmacodynamics and pharmacokinetic) and /or adverse effects with the objective of determining
safety and /or efficacy of the new drug (including drugs, biologicals, devices )
As per the Drugs and Cosmetics Rules, 1945:
Definition of new drug : For the purpose of this part, new drug shall mean and include- 2[(a)
A drug, as defined in the Act including bulk drug substance which has not been used in the
country to any significant extent under the conditions prescribed, recommended or suggested
in the labelling thereof and has not been recognized as effective and safe by the licensing
authority mentioned under rule 21 for the proposed claims:National Ethical Guidelines for Biomedical Research involving Children
14
Provided tha t the limited use, if any, has been with the permission of the licensing authority.
(b) A drug already approved by the Licensing Authority mentioned in Rule 21 for certain claims,
which is now proposed to be marketed with modified or new claims, namely, indications,
dosage, dosage form (including sustained release dosage form) and route of administration.
(c) A fixed dose combination of two or more drugs, individually approved earlier for certain
claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio
of ingredients in an already marketed combination is proposed to be changed, with certain
claims, viz. indications, dosage, dosage form (including sustained release dosage form) and
route of administration (See items (b) and (c) of 3[Appendix VI] to Schedule Y to the Drug and
Cosmetics Rules, 1945).
[As per Rule 122DA: no clinical trial for a new drug, whether for clinical investigation or any clinical
experiment by any institution, shall be conducted without approval of Drug Controller General
of India (DCGI). The exception to the rule is for academic research as described below as per
notification issued by Government of India)
Academic Research
The Government of India, vide GSR No.313 (E) dated 16.03.2016, stated that:
No permission for conduct of clinical trial intended for academic purposes in respect of approved
drug formulation shall be required for any new indication or new route of administration or new
dose or new dosage form where – (a) the trial is approved by the Ethics Committee; and (b) the
data generated is not intended for submission to licensing authority. “The Ethics Committee shall
however inform the licensing authority about the cases approved by it and also about cases where
there could be an overlap between the clinical trial for academic and regulatory purposes and
where the said authority does not convey its comments to the Ethics Committee within a period
of thirty days from the date of receipt of communication from the Ethics Committee, it shall be
presumed that no permission from the licensing authority is required.
Regulatory guidelines are dynamic and subject to frequent changes, hence researchers are
advised to consult the latest guidelines from the Central Drugs Standard Control Organization
(CDSCO) website (www.cdsco.nic.in/) at the time of planning and commencing their research.
For details regarding clinical trials and regulations, please refer appendix .
1.5 General guidelines for research in children
The following guidelines should be followed when conducting research in children:
• Research proposals should be scientifically sound.
• The equation between the potential benefit and the risk or potential harm should be at least
as favourable for the proposed research procedure as for the alternatives available to the
children.15National Ethical Guidelines for Biomedical Research involving Children
• There should be benefit to children in general and, in most cases, to the individual child
subject.
• The need for the study should be justified by a thorough review of literature.
• The research should be conducted by a team of investigators who have the requisite expertise.
One or more members of the team should be a paediatrician and/or have prior experience of
conducting research involving children.
• Research involving children should take into consideration the unique physiology, anatomy,
psychology, pharmacology, social situation and special needs of children and their families.
• Research involving children must be conducted in a child-friendly environment, as far as
possible.
• In general, drugs should be tested for safety, pharmacokinetics, and at least initial indications
of efficacy in adults established before they are tested in children. It may often be appropriate
to defer paediatric testing until adult testing has reached Phase III or beyond, when substantial
data are available on the safety and efficacy of a drug in adults. However, there may be
situations where studies involving children would be needed without prior adult studies, for
example, surfactant use in premature babies with respiratory distress syndrome.
SECTION 2: Risk
2.1 Assessment of benefit and risk in research involving children
During the journey in quest of n