Ethical Guidelines for Biomedical Research Involving Children

National Ethical Guidelines for Biomedical Research Involving Children

Indian Council of Medical Research 2017
Disclaimer:
Care has been taken to present the informa on accurately and inline with the latest government guidelines. However, in view of ongoing changes in government regula ons and the constant ow of new informa on, the reader is urged to check the latest no ca ons/rules/ regula ons provided by the Government of India from me to me.
Compiled & Edited by:
Dr. Reeta Rasaily
Published by:
Director General
Indian Council of Medical Research New Delhi- 110029
October 2017
Produc on Controller:
J. N. Mathur
ICMR, New Delhi
Published by the Division of Publica on and Informa on on behalf of the Secretary DHR & DG, ICMR, New Delhi. Printed at M/s Royal O set Printers, A-89/1, Naraina Industrial Area, Phase-I, New Delhi-110028 Phone: 011-25797524,

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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
Message
It is important to include children in clinical research including clinical trials so that the bene t of new therapy can also be applied to children as soon as possible. Tradi onally children are o en the last to bene t from advances in medicine. However, because of their inherent vulnerability the poten al risk from par cipa on in research studies must be an cipated and adequate precau ons taken. These guidelines have been developed speci cally to address ethical issues of conduc ng research in children. We hope that these guidelinesare put into prac ce in every ins tu on conduc ng research in children and the scien c community, public at large get immensely bene ted.
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 commi ee who have contributed their me and ideas generously.
Soumya Swaminathan Secretary, DHR & DG, ICMR
Tele. : (Off.) +91-11-26588204, 26589620; Fax (Off.) : +91-11-26588662, E-mail: dg@icmr.org.in
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Indian Council of Medical Research
Department of Health Research Ministry of Health & Family Welfare
V. Ramalingaswami Bhawan, Ansari Nagar New Delhi-110 029 (INDIA)

Foreword
Children are unique biologically and in their interphase with the environment. This is true in fetal life and throughout childhood. The ndings in adults cannot be automa cally assumed to be true in children. This applies to the way therapeu cs and preven ve modali es 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 e ec ve literacy is s ll not common, we have a far greater responsibility to ensure that the par cipants and their care givers understand, with utmost clarity, the research and procedures that researchers propose.
Prac ce of the right kind requires norms and guidelines that are ar culated with sublime clarity. An ins tu onal mechanism to administer and oversee research prac ce is cri cal at an ins tu onal level. Monitoring of data safety and quality through data monitoring commi ees compliments the work of the ethics commi ees. In modern research privacy and con den ality 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, gra fying that the Indian Council of Medical Research, the nodal agency in the country has developed ethical guidelines for biomedical research involving children. These are wri en with clarity, based on scien c and ethical principles, and balanced in providing guiding principles and processes and prac ces 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 contribu on. It is for us, researchers to ensure that the guidance becomes the prac ce in every ins tu on of the country. We need research for children but only under the best ethical norms.
Dr. MK Bhan

Foreword
In this era of evidence based medicine, it is impera ve to conduct robust and ethical research in neonates, infants, children and adolescents to improve our understanding of disease and provide op mal healthcare. However, professionals and parents o en feel apprehensive about asking this vulnerable popula on to take part in research because of greater poten al risks or burdens. Furthermore, young children are not in a posi on to make autonomous decisions regarding their par cipa on in research, which puts them at risk of coercion or undue in uence.
It is therefore mandatory that biomedical research involving
children zealously protects their interests, especially from an ethical
perspec ve. Ethics could be considered as codi ed prac ces and procedures performed by the prac oners of the profession. Ins tu onal Ethical Commi ees thus need to refer to consensus recommenda ons 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 recommenda ons to the Indian context to overcome challenges of applying universal ethical principles in the mul cultural 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 en tled “Ethical Guidelines for Biomedical Research on Human Par cipants”. These guidelines contain only a small sec on pertaining to research in children, which does not address in detail several ethical perspec ves of conduc ng biomedical research in neonates and children. This monograph is intended to accomplish this important task and serve as the reference manual for ethical commi ees in the na onal context. These consensus recommenda ons were formulated through a rigorous and robust methodology including review of per nent na onal and interna onal guidelines, mul ple stakeholders’ input and public scru ny. It is hoped that this mely publica on will ful l the objec ves with which it was conceived.
Prof. H.P.S. Sachdev,

Acknowledgement
For the rst me The Indian Council of Medical Research has come out with the guidelines separately for Biomedical Research involving children. We acknowledge with gra tude the contribu ons made by ICMR Advance Center on Newborn Health Research at All India Ins tute of Medical Sciences under leadership of Professor Vinod Kumar Paul in crea ng the dra guidelines for biomedical research involving children.
We gratefully acknowledge contribu on of Dr. Suvasini Sharma and Dr. Naveen Sankhyan for preparing the ini al dra . We are indebted to all members of the core commi ee and members of expert group for their valuable contribu ons in nalizing the dra guidelines. Special thanks to Dr. Vasantha Muthuswamy and Dr. Roli Mathur for their constant guidance and nal edi ng of the dra 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 con nued support and guidance.
We gratefully acknowledge the contribu on of Mr. Devesh Lodhy for designing the cover page and assistance of Mr. J. N. Mathur for nal prin ng and publishing the guidelines.

Dr. R.S. Sharma
Scien st G & Head Div. of Division of RBMCH, ICMR, New Delhi
Dr. Reeta Rasaily
Scien st F,
Division of RBMCH, ICMR, New Delhi
Contents
Abbrevia ons
Sec on 1 10 1.1 Introduc on 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 Sec on 2: Risk 13 2.1 Assessment of bene t and risk in research in children 15 2.2 Classi ca on of Risks 16 De ni ons: 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 rela ve versus absolute interpreta on of risk 17 2.4 Determinants of risk 17 2.5 Pain, distress, and fear minimiza on in children during research 17 2.6 Type of assays and sample collec on 18 2.7 Paediatric formula ons to be used in paediatric studies 18 2.8 Guidelines for ethical approval based on degree of risk 18 Sec on 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 Sec on 4: Safeguard Systems 25 4.1 Ethics commi ee (EC) 25 4.2 Experience of inves gator and research se ng 26 4.3 Data and safety monitoring board (DSMB) 27 4.4 Data protec on and con den ality 28 4.5 Bio-banking of samples: 28 4.6 Interna onal collabora on and data sharing 28 Sec on 5: Compensa on 28 5.1 Compensa on for par cipa on 28 5.2 Compensa on for accidental injury 29 Sec on 6: Special situa ons 29 6.1 Research in neonates 29 6.2 Research in HIV posi ve children 30 6.3 Vaccine studies in children 30 6.4 Ethical issues in gene c research 30 6.5 Research involving children in an emergency situa on 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 Sec on 7: Annexures 33 7.1 Glossary 28 7.2 Web Resources 34 Index 35 Bibliography 38 Members of the Expert Commi ee on Dra ing and Reviewing of guidelines 40
Abbrevia ons

Acquired immunode ciency syndrome
All India Ins tute of Medical Sciences
Central Drugs Standard Control Organiza on Data and Safety Monitoring Board (DSMB) Deoxyribonucleic acid
Department of Health Research
Drug Controller General of India
Ethics commi ee
Government of India
Health Ministry’s Screening Commi ee Human immunode ciency virus
Indian Council of Medical Research
Legally acceptable/authorized representa ve Par cipa on informa on sheet
Principal inves gator
Ribonucleic acid
– AIDS

– AIIMS

– CDSCO

– DSMB

– DNA

– DHR

– DCGI

– EC

– GOI

– HMSC

– HIV

– ICMR

– LAR

– PIS

– PI

– RNA

National Ethical Guidelines for Biomedical Research involving Children
SECTION 1
1.1 Introduc on
Biomedical and health research includes basic, applied and opera onal research studies designed primarily to increase scien c knowledge about diseases and condi ons (physical or socio-behavioural), their detec on, cause and strategies for health promo on, preven on, or ameliora on of disease and rehabilita on.
Biomedical research involving children is needed for the bene t of future genera ons of humanity. It leads to advances in medical care which can poten ally 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 opportuni es to develop interven ons to promote health, and prevent and treat diseases that a ect children. This can only be achieved through experimenta on. Research and innova on is therefore the core of the endeavour to generate and translate knowledge into clinical care. However, at the same me, we cannot expose children to undue harm by par cipa ng in research studies
As per the Declara on of Helsinki, 2013, some research popula ons (such as children) are par cularly vulnerable and have increased likelihood of incurring addi onal and greater harm. Vulnerable means an individual or group of people who are not in a posi on to make autonomous decisions regarding par cipa on in research, for example, children, students, prisoners, mentally challenged individuals and others. This set of par cipants cannot give or refuse consent for themselves and they may be at risk of coercion or undue in uence. All vulnerable groups need speci cally considered protec on. In vulnerable popula ons, biomedical research is jus ed only if it is based on the health priori es of that popula on.
Ethics are codi ed prac ces and/or procedures performed by the prac oners of the profession. The conduct of biomedical research involving children raises a number of ethical issues. The rst issue is that children lack autonomy : that is, the cogni ve and emo onal level of maturity and the legal status to consent to research par cipa on on their own behalf. Any research on children must consider the level of their physical, cogni ve, emo onal, and psychosocial development. Animal studies and research on adults should precede studies with children to minimize research risks except in situa ons where the disease occurs only in children. These concepts underlie the basic ethical principles of bene cence and non-male cence. However, any system for protec ng children involved in research should not unreasonably impede research on children that may poten ally be bene cial to them in the future. This goes against the basic ethical principle of jus ce. The concept of jus ce means that distribu on of the poten al bene ts and harm of par cipa ng in research should be fairly distributed. For example, a vulnerable set of pa ents (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.

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National Ethical Guidelines for Biomedical Research involving Children
There are also special challenges regarding research in developing countries. In resource-constraint se ngs 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 o en confused with treatment (therapeu c misconcep on ), or seen as a way of accessing new therapies or be er clinical care. The parents may also be unduly suscep ble to nancial inducements to par cipate in research because of their poor socio-economic status. Overuse of these vulnerable groups is a special concern when they are unlikely to bene t from the knowledge gained from research. Research in resource-poor countries has been found unjust when it does not consider the needs of those socie es and countries. For instance, a study being conducted in children of a developing country with poten al bene ciaries of the interven on being children from rich na ons is bound to raise concerns. India faces addi onal challenges given the mul cultural 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 essen al for advancing child health. In many situa ons, research ndings of studies in adults cannot simply be extrapolated to children and research involving children is essen al if children are to bene t 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 a ect only children, for example, hyaline membrane disease, birth asphyxia, neonatal hyperbilirubinemia, extrahepa c biliary atresia, infan le spasms, infan le 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. Addi onally, even if the same disease a ects both children and adults, the pathophysiological processes and responses to treatment in children may di er from those in adults, hence, we cannot simply extrapolate the medica ons approved for adults to children. Some diseases such as nephro c syndrome, hypertension and rheumatoid arthri s a ect both adults and children, but the pathophysiological basis and clinical approach is very di erent in both.

2. The physiology of children is di erent from that of adults, and the pharmacokine cs of many drugs is age-dependent based on the matura on 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 absorp on of drugs also varies with age. Pharmacokine cs and toxicity pro le varies with growth and matura on from infancy to adulthood.

3. The adverse e ects of many drugs may also be di erent in children as compared to adults. For instance, tetracyclines cause teeth discolora on in young children and aspirin use is associated with Reye’s syndrome in children.

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National Ethical Guidelines for Biomedical Research involving Children
4. Age appropriate delivery vehicles and formula ons (such as syrups ) are needed for accurate, safe and palatable administra on of medicines to infants and children.

5. The pathophysiology of many disorders is dependent on a child’s growth, development and adap ve plas city. Examples include adap ve 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 be er and it may lead to poten al preven ve interven ons in early life.

1.2. 2 Challenges of biomedical research involving children
1. Diseases in children may be rare, and there may not be su cient numbers of a ected pa ents to answer the research ques ons. This may lead to di cul es in having adequately sta s cally powered studies to evaluate an e ec ve treatment. For this reason, large mul – centric studies las ng many years may be needed, which are not always feasible. To overcome this di culty studies in children o en bene t from and require alterna ve and innova ve study designs that incorporate mul ple regions, high number of study sites rela ve to the number of pa ents to be enrolled, and realis c melines to allow them to be feasible and to collect relevant data speci c to the popula on being studied.

2. It is usually di cult to nd funding for research in children. As the market for paediatric drugs and treatments is quite small compared to the adult ones, pharmaceu cal companies do not nd it su ciently remunera ve to fund research in children.

3. The ethical concerns regarding research involving children, which include lack of autonomy and inherent vulnerability, make it more di cult to perform research in children and obtain appropriate informed consent.

4. Research in children is not just about performing research on individual pa ents. 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 se ngs need to consider children’s physical, cogni ve, andemo onal development. Developmentally appropriate outcomes need to be studied. Followup studies (which may take years) are o en 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 Considera ons 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 Par cipants was developed in 2006 and the latest version, developed in 2017, is called the Na onal Ethical Guidelines for Biomedical and Health

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National Ethical Guidelines for Biomedical Research involving Children
Research Involving Human Par cipants. These guidelines have a sec on pertaining to research involving children, however, a need was felt to develop more comprehensive guidelines which pertain to the speci cs of ethics in biomedical research involving children. This endeavour was undertaken under ICMR Advance Center for Newborn Health Research at All India Ins tute of Medical Sciences, New Delhi.
As a rst step, the exis ng na onal and interna onal guidelines for biomedical research in children were reviewed. Separate guidelines available for paediatric biomedical research in other countries include the Ins tute 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 be er understanding of the ethical principles of biomedical research in children. Mee ngs were also conducted with experts in the eld of bioethics to develop a consensus on guidelines in the Indian context. These guidelines have been developed and nalized a er 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 situa ons rather than to cover every possible situa on. These guidelines need to be used in conjunc on with the current Na onal Ethical Guidelines for Biomedical Research involving Human Par cipants, Indian Council of Medical Research (ICMR) Government of India and are meant for use by researchers, ethics commi ees and other involved stakeholders.
While these guidelines cover general biomedical research involving children, the de ni on of ‘child’ has been variable according to various legal and social contexts. As per the Na onal Commission for Protec on of Child Rights, a child is de ned as a person from 0 to 18 years of age (h p://ncpcr.gov.in/).
These guidelines are sub-serving to the Cons tu on of India and the legislature. If the research is a regulatory clinical trial under the Drugs and Cosme cs 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 systema c study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmacodynamics and pharmacokine c) and /or adverse e ects with the objec ve of determining safety and /or e cacy of the new drug (including drugs, biologicals, devices )
As per the Drugs and Cosme cs Rules, 1945:
De ni on of new drug : For the purpose of this part, new drug shall mean and include- 2[(a) A drug, as de ned in the Act including bulk drug substance which has not been used in the country to any signi cant extent under the condi ons prescribed, recommended or suggested in the labelling thereof and has not been recognized as e ec ve and safe by the licensing authority men oned under rule 21 for the proposed claims:

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National Ethical Guidelines for Biomedical Research involving Children
Provided that the limited use, if any, has been with the permission of the licensing authority.
(b) A drug already approved by the Licensing Authority men oned in Rule 21 for certain claims, which is now proposed to be marketed with modi ed or new claims, namely, indica ons, dosage, dosage form (including sustained release dosage form) and route of administra on.
(c) A xed dose combina on of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the rst me in a xed ra o, or if the ra o of ingredients in an already marketed combina on is proposed to be changed, with certain claims, viz. indica ons, dosage, dosage form (including sustained release dosage form) and route of administra on (See items (b) and (c) of 3[Appendix VI] to Schedule Y to the Drug and Cosme cs Rules, 1945).
[As per Rule 122DA: no clinical trial for a new drug, whether for clinical inves ga on or any clinical experiment by any ins tu on, shall be conducted without approval of Drug Controller General of India (DCGI). The excep on to the rule is for academic research as described below as per no ca on 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 formula on shall be required for any new indica on or new route of administra on or new dose or new dosage form where – (a) the trial is approved by the Ethics Commi ee; and (b) the data generated is not intended for submission to licensing authority. “The Ethics Commi ee 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 Commi ee within a period of thirty days from the date of receipt of communica on from the Ethics Commi ee, 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 Organiza on (CDSCO) website (www.cdsco.nic.in/) at the me of planning and commencing their research. For details regarding clinical trials and regula ons, please refer appendix.
1.5 General guidelines for research in children
The following guidelines should be followed when conduc ng research in children:
• Research proposals should be scien cally sound.

• The equa on between the poten al bene t and the risk or poten al harm should be at least as favourable for the proposed research procedure as for the alterna ves available to the children.

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National Ethical Guidelines for Biomedical Research involving Children
• There should be bene t to children in general and, in most cases, to the individual child subject.

• The need for the study should be jus ed by a thorough review of literature.

• The research should be conducted by a team of inves gators who have the requisite exper se. One or more members of the team should be a paediatrician and/or have prior experience of conduc ng research involving children.

• Research involving children should take into considera on the unique physiology, anatomy, psychology, pharmacology, social situa on 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, pharmacokine cs, and at least ini al indica ons of e cacy in adults established before they are tested in children. It may o en be appropriate to defer paediatric tes ng un l adult tes ng has reached Phase III or beyond, when substan al data are available on the safety and e cacy of a drug in adults. However, there may be situa ons 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 bene t and risk in research involving children
During the journey in quest of new knowledge and science, every study entails some risk to the par cipant which should be balanced against the likelihood of an cipated bene t. The rela onship between the risk a par cipant is likely to face and the an cipated bene t is a very important considera on in the ethical conduct of biomedical research. A research “equipoise” between bene t and risk must be planned when considering biomedical research.
Risk or harm is a very important considera on in research involving children. Risk refers to a poten al harm that can occur to the child as a direct or indirect consequence of the research procedure. Research may include any procedure the par cipant undergoes for research including ques onnaires, inves ga ons such as blood sampling, bone marrow aspira on, liver biopsy etc., or therapeu c interven ons such as medica on or surgery, over and above the rou ne standard of care for the pa ent. The risks entailed in research procedures need to be considered when they are over and above the rou ne care of the par cipant.
Harm occurring from par cipa ng in research may be physical (such as pain from a needle prick for blood sampling), psychological (such as fear of separa on from parents) or social (such as missing school and friends etc). Risks must be assessed in rela on to bene ts. A bene t is a good

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National Ethical Guidelines for Biomedical Research involving Children
outcome. The bene t is usually poten al, which means posi ve but uncertain outcome. The bene t may be direct, as in a direct bene t to the par cipant; or indirect. Examples of direct bene ts include the possibility of recovery, reduc on in pain, improvement in disease severity, etc. Indirect bene ts include the opportunity to understand more about the disease, develop social rela onship with other pa ents, etc. Payments for par cipa on should not be considered in the bene t-risk- ra o. Also, pa ents and par cipants may consider other bene ts such be er access to doctors, access to inves ga ons which are not otherwise freely available, being special pa ents as part of research, etc. These indirect bene ts may be more misunderstood by illiterate pa ents from poor socioeconomic strata.
It needs to be emphasised that these research risks should be over and above the risks cons tuted by the standard of care. Risk assessment needs to be done for those procedures that are addi onal to the standard prac ce, which means they are over and above those procedures that the child would anyway undergo during normal care.
2.2 Classi ca on of Risks
De ni ons:
Risks may be classi ed as less than minimal, minimal, minor increase over minimal or low and more than minimal or high risk. These are however just broad guidelines. As explained later, the categoriza on of risk may vary from child to child even within the same research procedure, depending on the situa on. It is therefore necessary to exercise individual judgement.
2.2.1 Less than minimal risk
Probability of harm or discomfort an cipated in the research is nil or not expected. For example, research on anonymous or non-iden ed data/samples, data available in the public domain, meta-analysis, etc.
2.2.2 Minimal Risk
Minimal risk is de ned as those which may be an cipated as harm or discomfort not greater than those ordinarily encountered in daily life or during the performance of rou ne physical or psychological examina ons or tests. This includes procedures such as ques oning, observing, and measuring the anthropometric parameters (such as height and weight) in children, provided that procedures are carried out in a child friendly way, respec ng the child’s wishes, and that consent has been given by appropriate persons. Procedures with minimal risk include history taking, physical examina on, chest X-ray, obtaining bodily uids without invasive interven on, for example, taking saliva or urine samples, etc. It is expected that the harm caused by the minimum risk level research would be very slight and temporary.
2.2.3 Minor increase over minimal risk or Low risk
Low risk is de ned as a slight increase in the poten al for harm or discomfort beyond or more than minimal risk (as de ned in rela on to the normal experiences of average, healthy, normal

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National Ethical Guidelines for Biomedical Research involving Children
children). These include procedures that might cause no more than transient pain or tenderness, small bruises or scars, or very slight, temporary distress, such as a blood test, oral seda on for diagnos c procedures, etc.
2.2.4 More than minimal risk or High risk
All research procedures which have a risk over and above low risk are classi ed as high risk. These include procedures such as lumbar puncture, lung or liver biopsy, intravenous seda on for diagnos c procedures, etc.
2.3 Concept of rela ve versus absolute interpreta on of risk
The rela ve interpreta on takes into account the child’s underlying condi on and the treatment and risks she or he undergoes in daily life. For instance, a child with leukaemia rou nely undergoes bone marrow aspira ons and chemotherapy. Therefore, the rela ve interpreta on may claim that bone marrow aspira ons and chemotherapy (otherwise high-risk interven ons) may be within ‘minimal risk’ for such a child. Bone marrow aspira ons for research in this situa on may be considered minimal risk’ in such children. A rela ve interpreta on theore cally allows high-risk studies to be approved as minimal-risk studies in children who undergo high-risk interven ons in their rou ne life. In contrast, healthy children who experience low levels of risk in daily life would have a correspondingly low risk threshold for assessing whether a study presented minimal risk. Therefore, in children, an absolute interpreta on of the minimal risk may be be er.
2.4 Determinants of risk
1. Age and developmental status: Risk assessment in children must take into account their age, developmental status and maturity. For example, taking 10 ml blood sample may be low risk for a 10-year-old but high risk for a preterm neonate.

2. Underlying medical condi on: In some cases, a research procedure that may be of minimal or low risk to a healthy child could be of high risk to a child with underlying medical condi on. For example, intramuscular injec ons that may be safe for healthy children are risky for children with clo ng disorders. Ethics commi ees should ensure that children with underlying medical condi ons that place them at risk due to research procedures are excluded from the study.

3. Cumula ve characteris cs of risk during research: Determina ons about risk should consider the cumula ve characteris cs of research interven ons or procedures and the me period for which they are done. For example, a single chest X-ray is a minimal risk procedure, but if the child has to undergo mul ple chest X-rays over a short dura on of me, the risk category should be higher.

2.5 Pain, distress, and fear minimiza on in children during research
Both pain and emo onal discomfort should be prevented as much as possible. When unavoidable, it should be adequately managed and reduced. To do this, non-invasive procedures should be

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National Ethical Guidelines for Biomedical Research involving Children
preferred. The environment of the study should be as child-friendly; and the child should not be separated from his/her parents as far as possible.
2.6 Type of assays and sample collec on
In research in children, due considera on should be given to the number and type of body uid assays and inves ga ons.
• Blood samples should be age and/or bodyweight appropriate. Depending on the nature of the study the ethics commi ee may obtain an independent opinion from a paediatrician regarding the safety of blood volumes proposed to be drawn for the purpose of the study.

• The samples should be obtained using appropriate facili es and materials.

• Alterna ve sampling (for example, urine or salvia sampling) for pharmacokine c studies should be preferred when possible. However, the ability to use alterna ve samples may depend on the valida on of the analy cal methodology and clinical u lity of measurements made in these matrices.

• For blood and ssue assays, micro volumes and micro-assays should be used, whenever possible.

• For painful and/or invasive procedures standard pain relief methods should be employed.

• Timing of sampling should be coordinated with the rou ne standard of care sampling of the pa ents to avoid repeated needle pricks.

• Sampling should be performed by trained sta .

• The number of a empts for sampling should be limited. Timing of sampling and number of sampling a empts should be de ned in the protocol. For example, it is recommended that a er one unsuccessful a empt, another experienced person should take over the procedure.
2.7 Paediatric formula ons to be used in paediatric studies
Formula ons used in a study should be described in the protocol. Age-appropriate formula ons should be used to avoid the risk of adverse reac ons (for example, young children choking on tablets), the risk of dosing errors or inaccuracy. Whenever available, paediatric formula ons should be used. Excipients used for the formula on should take into considera on the age of the children included in the study (for example, benzyl alcohol is contraindicated in neonates). Condi ons to avoid bacterial contamina on and degrada on of the medicinal product should be speci ed in the protocol.
2.8 Guidelines for ethical approval based on degree of risk
For research procedures that are intended to provide poten al direct diagnos c, therapeu c or preven ve bene t for the individual child par cipant, a risk category higher than minimal risk may be jus ed. For studies having interven ons not intended to directly bene t the individual child par cipant, the risk-levels should be minimum risk or low risk.

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National Ethical Guidelines for Biomedical Research involving Children
SECTION 3: Consent and Assent
3.1. Informed consent
In research involving children, the tradi onal method of informed consent where decisions about research par cipa on are made by those with the legal and intellectual capacity to make such choices for themselves cannot be implemented, as children usually lack this capacity. Instead, the authority to allow a child’s par cipa on in research rests with parents or a legally acceptable/ authorized representa ve (LAR), as the case may be. A LAR is an individual or judicial or other body authorized under applicable law to consent on behalf of a prospec ve par cipant to par cipate in research or to undergo a diagnos c, therapeu c, or preven ve procedure as per research protocol. However, inves gators must seek to involve children in discussions about research and obtain their assent to par cipa on as in accordance with their developmental level and decision making capacity. The parental/LARs’ permission for the child’s par cipa on in the research is termed as ‘consent’, whereas the child’s agreement to par cipate is termed as ‘assent’.
3.1.1 General principles of informed consent
Informed consent protects the individual’s freedom of choice and respect for the individual’s autonomy and is given voluntarily to par cipate in research or not. Adequate informa on about the research is given in simple and unambiguous language in a document known as the informed consent form with par cipant/ parent /LAR informa on sheet. A copy of this informa on sheet should be given to the parents /LAR as well as children from whom assent is being taken. A signed copy of the informed consent/assent form must be kept by the inves gator.
The par cipant informa on sheet should have following components as may be applicable:
Essen al Elements of an Informed Consent Document
1. Statement men oning that it is research.

2. Purpose and methods of the research in simple language.

3. Expected dura on of the par cipa on and frequency of contact with es mated number of par cipants to be enrolled, types of data collec on and methods.

4. Bene ts that might reasonably be expected as an outcome of research to the par cipant or community or to others.

5. Any foreseeable risks, discomfort or inconvenience to the par cipant resul ng from par cipa on in the study.

6. Extent to which con den ality of records could be maintained i.e. the limits to which the researcher would be able to safeguard con den ality and the an cipated consequences of breach of con den ality.

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National Ethical Guidelines for Biomedical Research involving Children
7. Freedom of individual to par cipate and to withdraw from research any me without penalty or loss of bene ts which the par cipant would otherwise be en tled to.

8. Free treatment and/or compensa on of par cipants for research-related injury and harms.

9. The iden ty of the research teams and contact persons with address and phone numbers (PI/ Co-PI for queries related to the research and Chairperson/Member Secretary or helpline for appeal against viola ons of ethical principles and human rights)

In addi on, the following elements may also be required depending on the type of study:
1. Any alterna ve procedures or courses of treatment that might be as advantageous to the par cipant as the ones to which she/he is going to be subjected to.

2. Payment/reimbursement for par cipa on and incidental expenses depending on the type of study.

3. If the research could lead to any s gma, e.g. HIV and gene c disorders, provision for pre-test- and post-test counselling.

4. Insurance coverage if any, for research-related or other adverse events.

5. Foreseeable extent of informa on on possible current and future uses of the biological material and of the data to be generated from the research. Other speci cs are as follows –

. a) Period of storage of the sample/data

. b) If the material would be or is likely to be used for secondary purposes

. c) If material is to be shared with others, this should be clearly men oned

. d) Risk of discovery of biologically sensi ve informa on and provision to safeguard con den ality

. e) Right to prevent use of her/his biological sample (DNA, cell-line, etc. and related data at any me during or a er the conduct of the research

. f) Bene t sharing, if research on biological material and/or data may lead to commercialisa on.

6. Publica on plan, if any, including photographs and pedigree charts.
A copy of the par cipant/ informa on sheet should be given to the par cipant for her/ his record. Content on the informed consent form should be brief and wri en in simple local language highligh ng that it is given of free will or voluntarily a er understanding the implica ons of bene ts and risks that the par cipant could withdraw without loss of rou ne care bene ts. Assurance is given that con den ality would be maintained and all the inves ga ons/interven ons would be carried out only a er consent is obtained.
Consent process for illiterate parents /LARs
When a par cipant is willing to par cipate but not willing to sign or give thumb impression or cannot do so, then verbal/oral consent may be taken on approval of the EC, in the presence of

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National Ethical Guidelines for Biomedical Research involving Children
an impar al witness who should sign and date the document. This can be documented through audio or video recording of the par cipant, the PI and the impar al witness, all of whom should be captured in the frame. However, verbal consent should be an excep on for speci c reasons carried out with the approval of EC and not to be followed rou nely.
In non-regulatory, observa onal studies, some mes literate or illiterate, parents /LARs may verbally agree to par cipate but refuse to give their thumb impression. In such cases, again, the documenta on of the consent process needs to be done by a literate impar al witness.
In some cases, fresh or re-consent may need to be taken, such as when:
1. New informa on becomes available which would necessitate amendment/devia on ofprotocol (excluding any new safety related informa on which can harm the par cipant if not immediately implemented by the inves gator);

2. A research par cipant regains consciousness from an unconscious state or becomes mentally competent to understand the study (procedures to address such a possibility should be spelt out in the informed consent form);

3. Long term follow-up or study extension is planned at a later stage;

4. There is change in treatment modality, procedures, site visits;

5. A ains 18 years of age, or the legally acceptable representa ve has changed;

6. There is possibility of disclosure of iden ty through data presenta on or photographs (which should be camou aged adequately) in an upcoming publica on; or

7. Future research may be carried out on stored biological samples if not anonymized

3.1.2 Waiver of consent
Voluntary informed consent is always a requirement for every research proposal. However, this can be waived if it is jus ed that the research involves not more than minimal risk or when the par cipant and the researcher do not come into contact or when it is necessitated in emergency situa ons. If such studies have protec ons in place for both privacy and con den ality, and do not violate the rights of the par cipants then ECs may waive the requirement for informed consent in the following instances:
i. When it is imprac cal to conduct research since con den ality of personally iden able informa on has to be maintained throughout research as may be required by the sensi vity of the research objec ve, for example, study on disease burden of HIV/AIDS

ii. Research is carried out on publicly available informa on, documents, records, works, performances, reviews, quality assurance studies, archival materials or third-party interviews, service programmes for public bene t, having a bearing on public health programmes, and consumer acceptance studies

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National Ethical Guidelines for Biomedical Research involving Children
iii. Research on anonymized biological samples, le over samples a er clinical inves ga on/ research, cell lines or cell free deriva ves like viral isolates, DNA or RNA from recognizedins tu ons or quali ed inves gators, samples or data from repositories or registries, etc. provided permission for future research on these samples has been taken in the previousconsent form. For further details on research using stored samples, please refer to the sec on11.0 Biological materials, Biobanking and Datasets for further details of the Na onal EthicalGuidelines for Biomedical and Health Research Involving Human Par cipants, 2017 ICMR.

iv. In emergency situa ons when no surrogate consent can be taken. Examples include research in neonatal resuscita on, life threatening emergencies, etc. In such situa ons, the parents/ care givers / LAR may not be in a situa on to give consent. However, once the child has been stabilized, a deferred/delayed consent must be taken. In case the parents refuse the deferred consent, the child should not be included in the research, and no further research related procedures /data collec on must be done from the pa ent. Also, the data previously collected prior to the consent process should not be used without the authorised adult’s permission.

v. Retrospec ve studies, where the par cipants are de-iden ed or cannot be contacted.

The protocols in all the above studies need to be submi ed to the EC, and the decision for waiver of consent will lie with the EC.
3.1.3. Concerns regarding informed consent
1. The process of obtaining consent and assent should not be a mere formality, limited to ge ng the par cipants’ signatures on the forms. Instead this should be a process, wherein the onus is on the inves gator to ensure that the parents and children (as far as their developmental level and maturity permits) understand what is going on in the research. This process should also include opportuni es for the parents and children to ask ques ons. The consent process is not a one- me process but should be an ongoing interac on between the researcher and the par cipant, to help resolve the queries which may arise in the par cipant’s mind during the course of the study.

2. The language of the pa ents/par cipant informa on sheet (PIS) should be simple and easily understood by the parents. Many mes, in order to protect themselves from any future li ga on, inves gators ll PIS with technical terms (medical and legal) which the parents nd di cult to understand. While transla ng to a local language di cult technical words must be avoided, and simple daily-use words that the par cipant is able to understand should be used.

3. When checking that parents understand all the aspects of research par cipa on, a par cular concern is whether they understand that they will be par cipa ng in research and that the purpose of research di ers from the purpose of normal clinical care. The purpose of research is to generate knowledge, usually for the bene t of pa ents or individuals in the future. The

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National Ethical Guidelines for Biomedical Research involving Children
misbelief that the purpose of research is treatment is termed as therapeu c misconcep on.
3.2 Children’s assent
Assent is de ned as a child’s a rma ve agreement to par cipate in research. A mere failure of the child to object should not be interpreted as assent. The assent process should take into account the children’s developmental level and capability of understanding. Cultural and social factors also play an important role. Children vary considerably in the ability to understand abstract concepts depending on their age and maturity. The assent form chosen should be appropriate for the child’s age and reading ability. Children with chronic illness may have been challenged to develop increased capacity to make independent judgments based on previous experiences. The other important issue here is the child’s general level of independence and autonomy.
Content of the assent form has to be in accordance with the developmental level and understanding capacity of the child. For example, a child aged 8 years should be told what exactly she/he is going to undergo, although they may not understand the concept of research Younger children are be er able to grasp the more prac cal aspects of research (e.g., what they are expected to do or what will happen) than they are to understand the abstract concepts such as randomiza on. For a 15-year-old, however, the assent process should be similar to the informed consent process. If the study is of a long dura on study, the researchers may have to repeat the assent process with more informa on, as the child grows older.
3.2.1 Age and method of obtaining assent
For children between 7 (84 months and above) and 11 years of age, oral assent must be obtained in the presence of parent/LAR. For children between 12 and 18 years of age, wri en assent must be obtained. If a child becomes 13 years old during the course of the study, then wri en assent must be obtained in addi on to parent/LAR consent. This is a joint decision-making process between the child and the concerned adult. In cases of verbal assent, the parent /LAR’s counter- signature must be obtained con rming that the child’s verbal assent has been taken. Re-assent must be taken in all the same situa ons as re-consent as men oned above. For children less than 7 years of age, parental consent is su cient. As assent is part of the informed consent process, the regula ons as per the CDSCO guidelines for regulatory clinical trials apply for assent as well.
3.2.2 Waiver of assent
Waiver of assent may be provided by the ethics commi ees in the following situa ons:
. 1) If the research has the poten al of directly bene ng the child and this bene t is available only in the research context. In such situa ons, the child’s dissent may be overruled.

. 2) Waiver of assent may also be considered if the research involves children with mental retarda on and other developmental disabili es, where the children may not have the developmental level and intellectual capability of giving assent.

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National Ethical Guidelines for Biomedical Research involving Children
4) Assent may also be waived under the same condi ons in which adult’s informed consent maybe waived.
Dissent or refusal of a child to par cipate must always be respected. Explana on must be given to ensure that to the child understands that she/he may withdraw her/his assent at any me during the study.
3.3.3 Content of assent form
The type and amount of informa on given needs to be simpli ed as per the child’s cogni ve and developmental level. The informa on should be simple, and age-appropriate. The basic informa on that needs to be provided includes:
1. What the study is about and how it might help
We want to see whether a new medicine will or won’t help children like you who have skin rashes”
“We want to understand why children get tummy aches, like you do”

2. What will happen and when
“You will have to come to the hospital in the morning with an empty stomach. We will insert a needle and take a teaspoonful of blood”

3. What discomfort there might be and what will be done to minimize it
“It will hurt as much as a pin prick, but the pain will last only 5 minutes. The area may look red for some me”

4. Who will answer the child’s ques ons during the study If you have any ques ons at any me, you can ask Dr X.”

5. Whether an op on to say “no” exists
“You can say “no” if you don’t wish to take part in the study. No one will be angry with you.” “If you say “yes” and then change your mind later, it will be ne. No one will scold you”.

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National Ethical Guidelines for Biomedical Research involving Children

Table 2 : Consent of parent/LAR
1
Ethics commi ee (EC) should determine if consent of one or both parents would be required before a child could be enrolled.
2
Generally, consent from one parent/LAR may be considered su cient for research involving no more than minimal risk or low risk.
3
Consent from both parents may have to be obtained when the research involves more than minimal risk or high risk to the child.
4
Only one parent’s consent is acceptable, if the other parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child irrespec ve of the risk involved.
5
Whenever relevant, the protocol should include a parent/LAR informa on sheet that contains informa on about speci c aspects relevant to children such as e ects on growth and development, psychological well-being and school a endance, in addi on to all the components described in the par cipant informa on sheet.
6
When the research involves sensi ve issues related to neglect and abuse of a child, the EC may waive the requirement of obtaining parental/LAR consent and prescribe an appropriate mechanism to safeguard the interest of the child.
7
Cogni vely impaired children or children with developmental disorders form one of the most vulnerable popula ons. In fact, their parents are also vulnerable and there is a high likelihood of therapeu c misconcep on. The poten al bene ts and risks must be explained carefully to parents so that they understand the proposed research.

4.1 Ethics commi ee (EC )
The current Na onal Ethical Guidelines for Biomedical and Health Research Involving Human Par cipants, ICMR, provide clear guidelines for the requirement of EC for ins tutes conduc ng biomedical and health research. Ethics Commi ees when providing opinion in a study in involving children should have member/s, with paediatric exper se1. The expert or experts may be permanent members of the EC, or invited as subject experts to provide advice and consulted on an ad hoc basis.
1Paediatric exper se -– “Exper se could be considered based on the educa on and experience on various aspects of child development, ethics, psychological and social aspects. It would include physicians with paediatric quali ca on; apediatric ethicists; quali ed paediatric nurses or psychologists, among others. In addi on to quali ca ons, it is recommended that the experts have at least some years of experience in child care/ health / research / advocacy. If the requisite experience cannot be found in one individual, two or more experts could be selected to provide the composite exper se needed. The exper se of invited experts should be documented and recorded by the ethics commi ee in its proceedings/minutes.”
SECTION 4: Safeguard Systems

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National Ethical Guidelines for Biomedical Research involving Children
All experts reviewing the research proposal should be independent of the sponsor, the inves gator and the research proposed. Experts should be available during the review of the ini al protocol as well as any subsequent signi cant changes. The basic framework for review of research proposals by ECs’ remains the same as for research in adults. (Table 1)
Table 3: Considera ons by ECs while evalua ng research proposals

Scien c validity
Has the scien c evalua on of the proposal been completed before the ethics review? *
Risks
[EC considers only addi onal interven ons which are done as a part of research]
What is the level of risk?
Have the risks been minimized?
Are risks reasonable in rela on to an cipated bene ts?
What are the poten al bene ts to par cipants?
What is the importance of the knowledge likely to be gained from the study?
Do the bene ts jus fy the risks?
Safety
Are there adequate provisions to monitor the data and ensure par cipant safety
Autonomy
Is proper consent, assent procedures and documenta on being followed? Is selec on of par cipants equitable?
Are any vulnerable groups being enrolled?
Is there addi onal protec on for vulnerable groups?
Con den ality
Are adequate measures taken to ensure privacy of par cipants and maintain con den ality of data?
Voluntariness
What is the in uence of payments, if any?
Are payments reasonable or can act as inducements?
Are the selec on, amount, and ming of payments appropriate?
Are there addi onal safeguards for any vulnerable group prone to inducement?
*Examples include the following- thesis protocols reviewed by department faculty/commi ee, formal review by scien c expert commi ees/ peer group, etc.
4.2 Experience of inves gator and research se ng
For the protec on of children involved in research, the inves gator’s competence and ethical conduct are the most important safeguards. The experience of inves gators should be reviewed by the EC. The EC should seek the details of inves gator’s publica on and research experience along with the research proposal. The research team should have inves gator(s) with exper se in sciences (health/social/ behavioural, etc.) related to childhood. If the inves gator is less experienced, then EC should ascertain appropriate mentorship, or oversight by a senior researcher/ oversight commi ee.
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National Ethical Guidelines for Biomedical Research involving Children
It is desirable that research in children be conducted in a child-friendly environment. This, however, is not applicable to community-based research. It is further desirable that individuals involved in interac ng with children during the study be trained and experienced in dealing with children.
4.3 Data and Safety Monitoring Board (DSMB)
The need for a DSMB may be determined as an addi onal safeguard by the EC depending on the an cipated risks to the children involved in the research. Data and Safety Monitoring Board evalua ng research performed in children should have members with appropriate exper se in reviewing clinical studies in children.
When studies have a signi cant safety concern, the establishment of a DSMB can enhance the safety of study par cipants. An independent review of research data may be essen al to ensure the ongoing safety of study par cipants. Those involved in the study design and conduct of a study may be biased in reviewing the data. Hence, there is a need for a group of expert advisors to ensure that such concerns would be addressed in an unbiased way.
Data and Safety Monitoring Boards are tradi onally established for large, mul centric, randomized, studies that evaluate interven ons intended to prolong life or decrease an adverse health outcome. Though desirable, DSMBs add complexity to a study and need addi onal resources.
Factors to consider while establishing a DSMB for a par cular study;
· The study endpoints are such that a highly favourable or unfavourable result, or even a nding of fu lity, during an interim review might make the con nua on of the study unethical.

· The indicators for safety concern due to the interven on (for example, an invasive procedure, or poten ally toxic drug).

· The study is being performed in a poten ally vulnerable popula on such as neonates or other vulnerable individuals.

· The study involves a popula on at heightened risk of death or other serious adverse health outcomes.

· The study includes a large number of individuals, is of long dura on, or is mul -centric.
In studies with one or more of the above characteris cs, the addi onal oversight provided by a
DSMB can further protect the study par cipants.
If the study is likely to be completed in a short span, the DSMB may not be e ec ve. In such situa ons, mechanisms should be in place a priori to expedite DSMB reviews and inputs. Alterna vely, the study could build in periods of pauses to allow the DSMB to review interim data before any further enrolment of par cipants.
A DSMB can also enhance the scien c validity of a study by reviewing accumula ng data of the study (for example, overall event rates) and suggest modi ca ons in the protocol such as change in the inclusion criteria, the study endpoints, or the size of the study.

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Finally, any independent DSMB evalua ng studies performed in children should have members with appropriate exper se in the evalua on of clinical studies in children.
4.4 Data protec on and con den ality
Children are unlikely to challenge records about themselves. Therefore, there the inves gator and the EC have an addi onal responsibility to protect data of children and ensure con den ality. ECs should review the issue of data protec on and con den ality in all research protocols. All records must be archived for a period of at least 3 years a er the comple on/termina on of the study. Documents related to regulatory clinical trials must be archived for 5 years a er the comple on /termina on of the study or as per regula ons. Preserving the data for a longer dura on is suggested, keeping in mind the poten al need for a long-term review of data. This primarily pertains to long term safety data of interven ons.
When studies are performed in schools, parents or another individual may desire to know the responses of a child. This situa on arises when studies include adolescents and address issues of sexuality, illicit drug use or violence. It should be made explicitly clear in the protocol, in the parent/LAR/PIS, and the consent and assent form, that informa on collected will not be disclosed to anyone.
4.5 Bio-banking of samples:
Please refer to the current Na onal Ethical Guidelines for Biomedical and Health Research Involving Human Par cipants ICMR for details.
4.6 Interna onal collabora on and data sharing
Please refer to the current Na onal Ethical Guidelines for Biomedical and Health Research Involving Human Par cipants (ICMR) for details. The Interna onal Health Division at ICMR is the secretariat for Health Ministry’s Screening Commi ee (HMSC) and facilitates technical and administra ve review of the collabora ve proposals for placement before this Commi ee as a mandatory requirement.
SECTION 5: Compensa on
5.1 Compensa on for par cipa on
Parents and children should not be asked to bear the expenses of research par cipa on. It is advised that ECs allow reimbursement of reasonable expenses incurred by child or caregivers to par cipate in research (for example, travel, wage loss). Children involved in research may also receive free medical services. The ECs’ have to ensure that payments do not act as inducements. Payments should not in uence parents’ or children’s decisions on research par cipa on, especially if such par cipa on is not in the child’s best interest. For example, providing a li le payment at the comple on of the study may encourage compliance, but making a large payment on comple ng

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the study could act as an inducement for con nued par cipa on. Such issues become even more per nent in research in low resource se ngs. When a LAR is consen ng on behalf of the child, no remunera on should be o ered. The only excep on being a refund of out-of-pocket expenses.
Protocols should clearly men on the details about the type, level, and ming of payments to par cipants. The details should also be included in the informed consent form. EC ’s should approve the type, level, and ming of payments made by researchers. Full details of payments to be given to parents/LAR and other bene ts of par cipa on (such as, free medical care) should be explicitly men oned in the parent/par cipant informa on sheet.
When children are enrolled in drug trials that come within the ambit of DCGI, all rules/guidelines of regulatory trials apply.
5.2 Compensa on for Accidental Injury
Children are en tled to nancial compensa on and/or other assistance for any temporary or permanent impairment or disability resul ng from par cipa on in research. In the case of death, their parents are en tled to compensa on.
Please refer to the current Na onal Ethical Guidelines for Biomedical and Health Research Involving Human Par cipants (ICMR) for more details on compensa on.
SECTION 6: Special situa on
6.1 Research in neonates
Neonates represent the most vulnerable group within the paediatric popula on. Study protocols in this popula on should take into account this, and the poten al long-term e ects of interven ons, including developmental e ects. ECs’ reviewing any research proposed in neonates should have an advisory member with exper se in neonatal research/care.
ECs’ should carefully scru nize all research proposed in neonates for poten al risks. Risks if any should be carefully weighed against possible bene ts in this fragile popula on. ECs’ should ensure a proper scien c review of the protocol by a competent person/s to remove any risks resul ng from poor methodology. Neonates should be researched when the ndings of the study will have poten al implica ons for neonatal healthcare. All measures to reduce risks should be undertaken. When possible, older children should be studied before conduc ng studies in younger children and infants. Within neonates, those who are cri cally ill should be considered for research even more carefully. Parents or caretakers of these babies face stresses that may interfere with their ability to make an informed decision on behalf of their baby. Strategies such as con nuous consent can to some extent reduce such problems. The consent of one parent is required for studies in neonates with research exposing them to no or minimal risk or in studies that o er the prospect of direct bene t to the par cipant. However, for studies that do not o er the prospect of direct

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bene t or are high risk, consent from both parents is required. The excep on being when only one parent has legal responsibility for the care and custody of the child, one parent is deceased, unknown, incompetent, or not reasonably available. In such cases, it is the duty of the inves gators to provide adequate jus ca on.
If one of the parents is a minor, then consent should not be taken from her/him. If both parents are minors, then enrolment of such a baby should be avoided as far as possible. To enrol such neonates for research, the inves gators should provide adequate jus ca on to the EC. A legally acceptable representa ve should provide an informed consent in such situa ons.
6.2 Research in HIV-posi ve children
Research in HIV-posi ve children involves some special situa ons that need to be considered by the EC. Issues of con den ality and anonymity assume great signi cance in these children. For children enrolled in long term studies, and who lose a surviving parent or guardian during the study period, re-consen ng needs to be done for con nued par cipa on. This consent can be given by another custodian appointed by the family.
6.3 Vaccine studies in children
Please refer to the sec on on vaccine studies in the current Na onal Ethical Guidelines for Biomedical and Health Research Involving Human Par cipants (ICMR)
6.4 Ethical issues in gene c research
Please refer to the sec on on gene c research in the current Na onal Ethical Guidelines for Biomedical and Health Research Involving Human Par cipants (ICMR)
One important aspect of gene c research pertains to stored samples in which pa ent iden ty is iden able. In such situa ons, periodic re-consent is needed once the child a ains the age of assent or consent.
6.5 Research involving children in an emergency situa on
Research involving children in emergency situa ons should be carried out only when it is scien cally jus ed and cannot be carried out outside this se ng. All principles of ethical research need to be followed and ECs’ need to carefully scru nize and approve all research proposed in emergency situa ons. There are no excep ons for obtaining consent in research done in emergency situa ons. However, it may not be possible to take formal consent in some emergency or cri cal care research se ngs (for example, research on drugs used in resuscita on). In such situa ons, deferred consent is suggested (see sec on 3.1.2). In deferred consent the process is split to give minimum informa on verbally, followed by full details and formal consent later. Therefore, in extremely sick children where immediate informed consent is not possible the process of deferred consent, as described above, can be followed. The me-frame within which formal consent would be obtained should be reviewed and approved by the ECs. If the

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National Ethical Guidelines for Biomedical Research involving Children
parent is not available or unable to give consent, another individual can give consent as a legal representa ve. This could be the doctor primarily responsible for the person’s treatment (if not involved in the research) or, a person nominated by the healthcare provider. Forma on of a DSMB should be strongly considered for research studies in emergency se ngs in which the informed consent requirement is waived or is not possible.
6.6 School-based research
Any research that is to be conducted in a school se ng must be submi ed and reviewed in accordance with the na onal guidelines by an EC. The researchers should submit the protocol to school authori es and obtain wri en approval to conduct research. A copy of the approval given by the school should be submi ed to the EC. Researchers should comply with a school’s policies and procedures for all proposed research. All the guidelines for consent and assent apply to school based research as well (see sec on 2). If jus ed, the EC may decide to waive individual consent, depending on the context and the type of research (for example, collec ng data already with school authori es like number of disabled children, number availing mid-day meal services, etc.).
6.7 Internet /Telephone-based research in children
All research planned in children including Internet-based/tele research needs to be submi ed to the EC. Following the guidelines provided by ICMR, the EC may choose to exempt some Internet- based research from the review (such as working on data that is in the public domain). Even if the research is exempt from a full EC review, researchers are required to keep an auditable record of the data a er the comple on of research. All records must be archived for a period of at least 3 years a er the comple on/termina on of the study. Documents related to regulatory clinical trials must be archived for 5 years a er the comple on/termina on of the study or as per regula ons.
The EC may allow for Internet-based consent and tele-consent (recordings to be stored) depending on the type and nature of research. All the guidelines for consent and assent apply to Internet-based/ tele research as well (see sec on 2). Special precau ons may be needed to ensure con den ality and safe storage of data in this kind of research. ECs and researchers need to ensure that data con den ality and privacy of par cipants needs to be maintained as per the current Na onal Ethical Guidelines for Biomedical and Health Research Involving Human Par cipants (ICMR).
6.8 Community-based Research in Children
Community-based epidemiological research encompasses two forms of research; observa onal and experimental. Ethics in epidemiological studies is mul dimensional covering clinical medicine, public health, and the socio-cultural milieu of the popula on. The general principles and guidelines of epidemiological research or community-based studies are detailed in the current Na onal Ethical Guidelines for Biomedical and Health Research Involving Human Par cipants (ICMR).
Research done in popula ons based in the community as opposed to hospital-based popula on is required in the following scenarios:

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National Ethical Guidelines for Biomedical Research involving Children
. a) When epidemiological studies have a tacit need to be based in a popula on;

. b) The research ques ons are such that the study can only be conducted in the community

. c) Data from e ec veness studies (real world studies) are impera ve for providing evidence- based data for policy-makers, so that an informed decision can be made; or

. d) Iden ca on and enrolment of par cipants is from the community directly and not from pa ents a ending an outdoor clinic/hospital.

The guiding ethical principles do not change at all except that they are harder to put in place. Also, in addi on to ensuring the rights and safety of the par cipa ng popula on, the rights and safety of the community as a whole needs to be kept in mind. These studies are more challenging to opera onalize, and the study team needs to build systems (pa ent management, transporta on for home visits, transporta on systems for delivery of specimens to the laboratory, etc.) that already exist or are not needed in studies conducted in hospitals.
These studies are done a er engaging the community leaders, the health workers and other organiza ons working in the area. The important issues are to gain the trust of the community through open and transparent communica on and address promptly any queries or issues that are raised at any me during the study implementa on.
6.9 Research involving adolescents (12-18 years)
Adolescents di er both from children and adults. The di erences are not limited to psychological, social and behavioural aspects, but also in drug kine cs and therapeu c responses. Research involving adolescents can guide interven ons and inform public policy in this area. Violence, sexually transmi ed diseases (including HIV), high-risk behaviours, unintended pregnancy, alcohol and drug use, are serious challenges to the health of the youth. Any researcher a emp ng research in this popula on should be conversant with the unique aspects of adolescent’s cogni ve, psychological and social development.
Studies suggest that adolescents have the ability to provide an informed consent. It is suggested that by mid-to-late adolescence, their capacity to make decisions about research par cipa on are similar to that of adults. However, this capability is dependent on both cogni on and previous life experiences. Their capacity for independent decision making is reduced if they have not made decisions in the real-world situa ons. On the other hand, adolescents who have had chronic illnesses may develop this capacity earlier. Inclusion of adolescents in the informed consent process increases their sense of self-control, improves their decision-making capacity and possibly improves compliance too.
In community-based studies in adolescents, involvement of youth advisory commi ees can be an e ec ve way of incorpora ng youth into the planning research. Youth members of these commi ees should ideally mirror the diversity of the study popula on in terms of ethnicity,

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National Ethical Guidelines for Biomedical Research involving Children
caste, socioeconomic status, educa onal background and residence. Youth advisory commi ees can be helpful in exploring ethical issues and advising on other aspects study planning and implementa on.
Any research that is to be conducted in adolescents must be submi ed and reviewed by an EC in agreement with the current na onal guidelines. While conduc ng sexual health research in adolescent’s researchers need to pay utmost a en on to issues of con den ality and anonymity. EC’s should ensure that research protocols are prepared to keep in mind the local beliefs and socio-cultural sensi vi es. EC’s may consider waiver of parental consent in certain studies where parental permission may interfere with the validity of study results. Examples include the collec on of data as the use of contracep on and psychotropic drug. Such waivers only apply to research of low risk (e.g., con den al or anonymous surveys). In all such situa ons, EC must take the nal decision regarding waiver of the requirement of parental consent. Addi onally, an informed assent should be obtained from the adolescent in such types of research. In all other forms of research in adolescents, the principles of assent and consent have to be followed. (see Sec on 2 for further details).

7.1 Glossary
Assent
A child’s agreement to par cipate. Failure to object should not be interpreted as assent.
Child
A person under the age of 18 years
Consent
The voluntary agreement of an adult, based on adequate knowledge and understanding of relevant informa on, to par cipate in research.
Harm
That which nega vely a ects the interests or welfare of an individual. (for example, physical harm, discomfort, anxiety, pain, and psychological disturbance or social disadvantage).
High risk
All research procedures which have a risk over and above the low risk are classi ed as high risk. These include procedures such as lumbar puncture, lung or liver biopsy, intravenous seda on for diagnos c procedures, etc.
SECTION 7: Annexures
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National Ethical Guidelines for Biomedical Research involving Children
Legally acceptable/authorised representa ve
An individual or judicial or other body authorized under applicable law to give consent on behalf of a prospec ve par cipant to par cipate in research or to undergo a diagnos c, therapeu c, or preven ve procedure as per research protocol.
Low risk
Low risk is de ned as a slight increase in the poten al for harms or discomfort beyond or more than minimal risk (as de ned in rela on to the normal experiences of average, healthy, normal children). These include procedures that might cause no more than brief pain or tenderness, small bruises or scars, or very slight, temporary distress (for example, a blood test, oral seda on for diagnos c procedures. etc.).
Minimal risk
Minimal risk is de ned as one which may be an cipated as harm or discomfort not greater than those ordinarily encountered in daily life or during the performance of rou ne physical or psychological examina ons or tests. This includes procedures such as ques oning, observing, and measuring children, provided that procedures are carried out in a sensi ve way, respec ng the child’s autonomy, and that consent has been given by appropriate persons. Procedures with minimal risk include history taking, physical examina on, chest X-ray, obtaining bodily uids without invasive interven on, (for example, taking saliva or urine samples, etc.). It is expected that the harm caused by the minimum risk level research would be very slight and temporary.
Therapeu c misconcep on
The belief that the purpose of research is treatment.
7.2: Web Resources
Clinical Trials Registry-India. Available from: h p://ctri.nic.in/Clinicaltrials/login.php
Central Drugs Standard Control Organiza on. Available from: h p://www.cdsco.nic.in/forms/ Default.aspx
Indian Council of Medical Research. Available from: h p://icmr.nic.in/index.html
Department of Science and Technology. Available from: h p://www.dst.gov.in/index.htm Department of Biotechnology. Available from: h p://db ndia.nic.in/index.asp WHO-Interna onal Clinical Trials Registry Pla orm. Available from: h p://www.who.int/ictrp/en/ US Na onal Ins tutes of Health Clinical Trials Registry. Available from: h ps://clinicaltrials.gov/
FDA. Guidelines on good clinical prac ce. Available from: h p://www.fda.gov/downloads/Drugs/ Guidances/ucm073122.pdf.

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National Ethical Guidelines for Biomedical Research involving Children
Compensa on for Accidental Injury, 29
Compensa on for par cipa on, 28
Con den ality, 19,20,21,26,28,30,21,33
Consent, 10,12,16,19,20,21,22,23,24,25,26,29, 30,31,32,33,34
Consent Form, 19,20,21,29
Consent process, 20,21,22,23,32 Consumer acceptance studies, 21 Content of assent forms, 23,24
D
DSMB, 27,28,31
Data protec on, 28
Data sharing, 28
DCGI, 14,29
Declara on of Helsinki, 10
Deferred consent, 22,30
Department of Health Research, 6,9 Determinants of risk, 17
Developing countries, 11 Developmentally appropriate, 12 Devices, 13
Disabled children, 31
Drug and Cosme cs, 14
Drugs, 11,12,13,14,15,30,34
Drugs and Cosme cs Act, 13
E
E cacy, 13,15
Emergencies, 22
Emergency, 21,22,30,31
Ethical concerns, 12
Ethics, 9,10,12,13,14,17,18,23,25,26,31

Index
A
Adolescents, 28,32,33
Adverse e ects, 11,13
Anatomy, 15
Animal studies, 10
Anonymized, 21,22
Assent, 19,22,23,24,26,28,30,31,33 Autonomy, 10, 12, 19, 23, 26,34
B
Bene cence, 10
Bene t, 10,11,12,14,15,16,18,19,20,22,23,25,2 6,29,30
Bio-banking, 28
Biological, 13,20,21,22
Biomedical, 10,11,12,13,15,22,25,28,29,30,31 Birth asphyxia, 11
Blood sample, 17,18
C
CDSCO, 14, 23
Child, 11
Child rights, 13
Child-friendly environment, 15, 27
Children’s assent, 23
Classi ca on of Risks, 16
Clinical care, 10,11,23
Clinical research, 11,22
Clinical trial, 13,14,23,28,31,34
Coercion, 10
Community Based Research, 27,31 Compensa on, 20,28,29
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National Ethical Guidelines for Biomedical Research involving Children

Ethics Commi ee, 13,14,17,18,23,25 European union guidelines, 13 Experience, 15,16,17,23,25,26,32,34 Experience of inves gator, 26 Exper se, 15,25,26,27,28,29
F
Fixed dose combina on, 14 Formula ons, 12,18
G
Gene c research, 30 Government of India, 2,9,13,14 H
Harms, 20,34
Health, 10,11,12,13,21,22,25,26,27,28,29,30,3 1,32,33,34
Helsinki, 10
High risk, 12,16,17,25,30,32,33
HIV posi ve children, 30
HIV/AIDS, 21
Hyaline membrane disease, 11
Hypertension, 11
I
Illiterate parents, 20
Indian Council of Medical Research, 12,13,34
Infan le spasms, 11
Informed consent, 12,19,20,21,22,23,24,29,30, 31,32
Interna onal collabora on, 28
Internet /Telephone based research, 31 Inves gators, 19,22,26,30
J
Jus ce, 10
K
Kawasaki disease, 11
L
LAR, 19,20,21,22,23,25,28,29
Legally acceptable representa ve, 21,30,34 Legislature, 13
Licensing Authority, 13,14
Li ga on,, 22
Low risk, 16,17,18,25,33,34
M
Marketed, 14
Maturity, 17,22,23
Medical Research Council, 13
Metabolism, 11
Minimal Risk, 16,17,18,21,25,29,34 Mul -centric studies, 12
N
Na onal Commission, 13
Na onal guidelines, 31,33
Neonatal healthcare, 29
Neonatal hyperbilirubinemia, 11
Nephro c syndrome, 11
New drug, 13,14
Newborns, 13
Non-male cence, 10
O
Observa onal studies, 21
P
Pain, distress, and fear, 17
Par cipant informa on sheet, 20,22,25,29 Pathophysiology, 12
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National Ethical Guidelines for Biomedical Research involving Children

Paediatric ethicists, 25 Paediatric exper se, 25 Paediatric nurses, 25 Paediatrician, 15,18,41 Pharmacokine c, 11,13,15,18 Poor methodology, 29
Poor socio-economic status, 11
Powered, 12
Premature, 15
Procedures,10,12,15,16,17,18,20,21,22,26,31, 33,34
Psychologists, 25
Psychology, 15,39
Public health programs, 21
Q
Quality assurance studies, 21
R
Re-consent, 21,23,30
Regulatory, 13,14,21,23,28,29,31
Regulatory guidelines, 14
Rela ve versus absolute interpreta on of risk, 17
Repositories, 22 Research in neonates, 29 Resource-poor, 11 Review of literature, 15 Reye’s syndrome, 11 Rheumatoid arthri s, 11
Risk, 15
Route of administra on, 14
S
Safety, ,13,15,18,21,26,27,28,32
Sampling, 15,18
Schedule-Y, 14
School-based research, 31
Service programs, 21
Special needs, 15
Sponsor, 26
Sta s cally, 12
Study designs, 12
Surfactant, 15
Syrups, 12
T
Tes ng, 15
Therapeu c misconcep on, 11,23,25,34,39 Toxicity, 11
V
Vaccine studies, 30
Voluntariness, 26 Vulnerable,10,11,25,26,27,29
W
Waiver of assent, 23
Waiver of consent, 21
Witness., 21
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National Ethical Guidelines for Biomedical Research involving Children
Bibliography
Allmark P, Spedding M. Clinical trials in neonates: ethical issues. Seminars in Fetal & Neonatal Medicine [Internet]. 2007;12(4);318–323. 2007. Available from: h p://doi.org/10.1016/j.siny.2007.01.023
Appelbaum PS, Roth LH, Lidz C. The therapeu c misconcep on: informed consent in psychiatric research. Interna onal Journal of Law and Psychiatry. 1982;5(3–4):319–329.
Bannister E, Benoit C, Leadbeater B, Jansson M, Marshall A, Riecken T (Eds.). (Ethical Issues in Community- Based Research with Children and Youth. Toronto: University of Toronto Press, Scholarly Publishing Division; 2006.
Clinical trials. European Commission [Internet]. n.d. (cited 2014 November 26). Available from: h p:// ec.europa.eu/health/human-use/clinical-trials/index_en.htm
Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? American Journal of Ophthalmology. 2000;283:2701–2711.
Ethical Considera ons for Research on Housing-Related Health Hazards Involving Children.[Internet]. n.d. (cited 2014 November 26). Available from: h p://www.nap.edu/openbook.php?record_id=11450
Fleming TR, Hennekens CH, Pfe er MA, DeMets DL. Enhancing trial integrity by protec ng the independence of data monitoring commi ees in clinical trials. Journal of Biopharmaceu cal Sta s cs [Internet]. 2014;24(5):968–975. Available from: h p://doi.org/10.1080/10543406.2014.925719
Flicker S, Guta A. Ethical approaches to adolescent par cipa on in sexual health research. The Journal of Adolescent Health: O cial Publica on of the Society for Adolescent Medicine [Internet]. 2008;42(1):3–10. Available from: h p://doi.org/10.1016/j.jadohealth.2007.07.017
Government Gaze e No. 492nd edi on;28944. Republic of South Africa; 2006.
Guidelines for interna onal collabora on [Internet]. n.d. (cited 2014 December 2). ICMR. Available from: h p://www.icmr.nic.in/guide.htm
Harper GW, Carver LJ. “Out-of-the-mainstream” youth as partners in collabora ve research: exploring the bene ts and challenges. In: Health Educa on & Behavior: The O cial Publica on of the Society for Public Health Educa on. 1999;26(2):250–265.
Hawe P, Noort M, King L, Jordens C. Mul plying health gains: the cri cal role of capacity-building within health promo on programs. Health Policy. Amsterdam, Netherlands. 1997;39(1):29–42.
Hess CN, Roe MT, Gibson CM, Temple RJ, Pencina MJ, Zarin DA et al. Independent data monitoring commi ees: Preparing a path for the future. American Heart Journal [Internet]. 2014;168(2):135–141. Available from: h p://doi.org/10.1016/j.ahj.2014.05.003
Ethical guidelines for biomedical research on human par cipants. ICMR. 2006 (cited 2014 November 26).
Jarre RL, Sullivan PJ, Watkins ND. Developing social capital through par cipa on in organized youth programs: Qualita ve insights from three programs. Journal of Community Psychology [Internet]. 2005;33(1):41–55. Available from: h p://doi.org/10.1002/jcop.20038
Leikin SL. An ethical issue in biomedical research: the involvement of minors in informed and third party consent. Clinical Research. 1983;31(1):34–40.

38
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Lin JY, Lu Y. Establishing a data monitoring commi ee for clinical trials. Shanghai Archives of Psychiatry [Internet]. 2014;26(1):54–56. Available from: h p://doi.org/10.3969/j.issn.1002-0829.2014.01.009
Lindeke LL, Hauck MR, Tanner M. Prac cal issues in obtaining child assent for research. Journal of Pediatric Nursing [Internet]. 2000;15(2):99–104. Available from: h p://doi.org/10.1053/jn.2000.5447
Macaulay AC, Delormier T, McComber AM, Cross EJ, Potvin LP, Paradis G, Desrosiers S. Par cipatory research with na ve community of Kahnawake creates innova ve Code of Research Ethics. Canadian Journal of Public Health/ Revue Canadienne De Santé Publique. 1998;89(2):105–108.
Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, FEAST Trial Group. Mortality a er uid bolus in African children with severe infec on. The New England Journal of Medicine [Internet]. 2011;364(26):2483–2495. Available from: h p://doi.org/10.1056/NEJMoa1101549
Minkler M, Wallerstein N. Community-based Par cipatory Research for Health. San Francisco: Jossey-Bass. 2003.
MRC Ethics Guide; Medical research involving children [Internet]. n.d. (cited 2014 January 13). Available from: h p://www.cardi .ac.uk/optom/ resources/ Medical%20research%20involving%20children.pdf
Na onal Ethical Guidelines for Biomedical and Health Research in Human Par cipants, 2017, ICMR.
Palermo AG, McGranaghan R, Travers R. Developing and Sustaining Community-Based Par cipatory Research Partnerships: A Skill Building Curriculum [Internet]. n.d. (cited 2014 November 26). Available from: h p:// depts.washington.edu/ccph/cbpr/index.php
Shaddy RE, Denne SC, The Commi ee on Drugs and Commi ee on Pediatric Research. Clinical report: guidelines for the ethical conduct of studies to evaluate drugs in pediatric popula ons. Pediatrics [Internet]. 2010;125(4):850–860. Available from: h p://doi.org/10.1542/peds.2010-0082
Strode AE, Slack CM. Using the concept of “parental responsibili es and rights” to iden fy adults able to provide proxy consent to child research in South Africa. South African Journal of Bioethics and Law. 2011;4(2):69.
The Ethical Conduct of Clinical Research Involving Children[Internet]. Washington DC: Na onal Academies Press. 2004. Available from: h p://www.nap.edu/catalog/10958
The Protec on of Pupil Rights Amendment (PPRA), which is part of the No Child Le Behind Act of 2001(Public Law 107-110) US Law. 2001.
Victor PM. Community-based Par cipatory Research: Community Respondent Feedback (The 1st Interna onal Conference on Inner City Health). Toronto. 2002.
Weithorn LA. Children’s capaci es to decide about par cipa on in research. IRB. 1983;5(2):1–5.
Wendler D. Minimal risk in pediatric research as a func on of age. Archives of Pediatrics & Adolescent Medicine [Internet]. 2009;163(2):115–118. Available from: h p://doi.org/10.1001/archpediatrics.2008.524
WHO. Frequently Asked Ques ons. n.d. (cited 2014 November 26). Available from: h p://www.who.int/ ictrp/faq/en/#faq5

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Members of the Expert Commi ee on Dra ing and Reviewing of guidelines

Co-Chairs:
Dr. H.P.S. Sachdev, New Delhi, Chairperson (Project Review Group on Child Health) Dr. S. Swaminathan, Secretary DHR and DG ICMR
Dr. V. M. Katoch, Former Secretary DHR and DG ICMR
Neonatologist:
Dr. Vinod K. Paul, New Delhi
Dr. Armida Fernandez, Mumbai Dr. Swarna R. Bha , Bangalore Dr. Atanu K. Jana, Kolkata
Dr. Arvind Saili, New Delhi
Dr. Ashok K. Du a, New Delhi Dr. Sourabh Du a, Chandigarh Dr. Ashok K. Deorari, New Delhi Dr. Ramesh Aggarwal, New Delhi Dr. M. Jeeva Shankar, New Delhi
Paediatrician:
Dr. Anand Pandit, Pune
Dr. Sunit K. Singhi, Chandigarh
Dr. Vijay Yewle, Mumbai,
Dr. Siddarth Ramji, New Delhi
Dr. Rashmi Kumar, Lucknow
Dr. Shally Awasthi, Lucknow
Dr. Narendra K. Arora, New Delhi
Dr. O.M. Bhakoo, Chandigarh
Dr. Anupam Sachdev, New Delhi
Dr. Late Panna Choudhury, New Delhi Dr. Suvasini Sharma, New Delhi
Dr. Naveen Sankhyan, Chandigarh
Obst. & Gynae.
Dr. Kiran Guleria, New Delhi
Dr. Lakhvir K. Dhaliwal, Chandigarh
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National Ethical Guidelines for Biomedical Research involving Children
Public Health:
Dr. Abhay Bang, Gadchiroli
Dr. Nita Bhandari, New Delhi Dr. Viswajeet Kumar, Lucknow
Civil Society representa ve:
Ms. Sarojini N., New Delhi
Ethics experts:
Dr. Vasantha Muthuswamy, Coimbatore Dr. Urmila Tha e, Mumbai
Dr. Renu Saxena, New Delhi
Dr. Kusum Verma, New Delhi
Dr. Roli Mathur, Bengaluru
Legal Expert:
Dr. B.T. Kaul, New Delhi
Mr. Alishan Naqvee, New Delhi
Representa ve from IAP Legal Cell
Dr. Sa sh Tewari, Amrava , Maharashtra
Central Drugs Standard Control Organiza on (CDSCO)
Ms. A. Visala, New Delhi
Industry :
Ms. Suneela Tha e, Quin les/Indian Society for Clinical Research, Mumbai Wri en comments from:
Gina Calarco, Quin les, Kansas City, USA
Azadar Khan, Sun Pharmaceu cals Industries Limited, Vadodara
Snehal Chalke, P zer India, P zer Limited, Mumbai
List of Core Advisory Commi ee for Dra ing Guidelines
Dr. Kusum Verma, New Delhi
Dr. Vasantha Muthuswamy, Coimbatore Dr. Renu Saxena, New Delhi
Dr. Peush Sahni, New Delhi
Dr. Dr. Jayashree Murlidharan, Chandigarh Dr. Vinod K. Paul, New Delhi

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National Ethical Guidelines for Biomedical Research involving Children
Dr. Ashok Deorari, New Delhi
Dr. Ramesh Agarwal, New Delhi Dr. Jeeva Sankar, New Delhi
Dr. Nita Bhandari, New Delhi
Dr. Sharmila Majumder, New Delhi Dr. Madhulika Kabra, New Delhi Dr. Roli Mathur, New Delhi
Dr. Reeta Rasaily, New Delhi
Ini al Dra prepared by:
Dr. Suvasini Sharma, New Delhi Dr. Naveen Sankhyan, Chandigarh
Ethics Advisory Group
Dr. Vasantha Muthuswamy, Coimbatore Dr. Nandini K Kumar, Chennai
Dr. NK Arora, New Delhi
Dr. Urmila Tha e, Mumbai
Dr. Vijay Kumar, New Delhi Dr. Roli Mathur, Bengaluru
ICMR:
Dr. Radhey S. Sharma, New Delhi Dr. Vijay Kumar, New Delhi
Dr. Chandrasekhar, New Delhi Dr. Malabika Roy, New Delhi
Dr. Reeta Rasaily, New Delhi Dr. Roli Mathur, Bengaluru Dr. Anju Sinha, New Delhi

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