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Research Involving Children

Balancing Potential Risks And Benefits In Pediatric Research

Procedures undertaken for research purposes are, by definition, designed to produce information to benefit future patients[1]. Although in some forms of research, participants may additionally hope to benefit from the research, in most cases they are not undertaken with the direct aim of benefitting the research participant while in some cases even exposing the participants to a substantial level of risk. On the other hand, children have the fundamental right to the protection and care that is necessary for their well-being. In all actions relating to children, whether taken by public authorities or private institutions, the child's best interests must be a primary consideration[2]. Thus, balancing risks and benefits of the particular research is the crucial requirement for the researchers and research ethics committees. The Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research as well as Clinical Trial Regulation defines two categories of permissible research involving children.

First, the research is permissible if it is expected to produce direct benefit for the minor taking part in the research outweighing the risks and burdens involved.

The essential precondition for the research that entails more than minimal risk to a child is that the research holds out the prospect of direct benefit for the child or may contribute to the child’s wellbeing. However, the risk benefit assessment in such research studies may be complicated as research is a complex activity consisting of multiple procedures and interventions, some of them being performed entirely for the research purposes and not for the benefit of the patient. For the further information on risk/benefit assessment please see the module “Core principles of research ethics”.

It is also worth mentioning that there is a legal imperative that no additional potential benefits of the research may be used to justify an increased level of risk or burden, i.e., no incentives or financial inducements may be given to the minor or his or her legally designated representative except for compensation for expenses and loss of earnings directly related to the participation in the clinical trial.

Second, the research that has no potential to produce the results of direct benefit to the health of a child is permissible if there are scientific grounds for expecting that participation in the research will produce some benefit for the population represented by the minor concerned and such a research study will pose only minimal risk to, and will impose minimal burden on, the minor concerned (such are, for example, observational studies, some pharmacokinetic studies, etc.)[3]. Benefit for the population includes increased knowledge on the condition, diagnosis, treatment or prevention relevant to the population represented by the minors concerned. The crucial requirement for the studies with no direct benefit for the study participant is that it may pose only minimal risk and minimal burden. Minimal risk is defined as that which, in terms of the nature and scale of the intervention(s), would result in an individual case at the most in a very slightly detrimental and temporary impact on the health of the person concerned[4] and minimal burden is defined as that for which the expected discomfort, which might be associated with the research, will be at most temporary and very slight for the individual. CTR adds that the risk should be minimal in comparison with the standard treatment of the minor's condition.

Even if the ethical review concludes that the level of risk and burden is minimal in comparison with the standard treatment, this does not necessarily mean that the trial is ethically acceptable. The foreseeable risks and burden should be justified and minimized[5] (EC recommendation, 2017).

Minimizing Risk

Most guidelines emphasize the need to minimize risks (both by preventing potential harms and minimizing their negative impacts should they occur) to make research ethically acceptable[6]. The investigators and the ethics committees should make every attempt to prevent pain, fear, and any other foreseeable harm (risk and burden) in the study and minimize it when unavoidable. This may be done by integrating research procedures and interventions with clinical care and diagnostic procedures whenever possible; research studies should be performed by trained investigators with pediatric experience in the appropriate research environment; appropriate methods should be used to accustom children to the research environment and to decrease potential anxiety and discomfort whenever possible. Protocols should include specific rules setting limits on the number of unsuccessful attempts at a procedure or the length of time for completion of a questionnaire. Research procedures such as simple blood draws, noninvasive urine collections, questionnaires, and interviews with healthy children when performed once are deemed to be consistent with the definition of minimal risk. However, the same procedure performed repetitively over a short period may stil  not  constitute minimal risk[7].

It is also required to have a pediatric expertise in the ethical review process, to assess and balance the benefits, risks and burden of research with minors.

Parental Consent And Minors´ Assent (Or Deliberate Objection)

By definition, children (minors) are unable to consent in the legal sense, therefore the specific, written informed consent must be obtained from the one or both parents/legally designated representative on the child’s behalf prior to enrolling the child in a research.

But minors should also be involved in the process of informed consent as much as possible in a way adapted to their age and mental maturity[8],[9]. The evaluation to what extent a minor can understand provided information should not be based solely on chronological age, but also on individual factors such as developmental stage, intellectual capacities, life/disease experience and their family situation[10]. To provide age-appropriate information assent forms should be used for children, using language and communication tools (visuals, cartoons, videos etc.) appropriate to the participants’ age and maturity[11].

There is a general principle that the explicit wish of a minor who is capable of forming an opinion and assessing given information to refuse participation or to withdraw from the clinical trial at any time, i.e. dissent, must be respected even if the parents have given consent[12]. However, other international documents (e.g. CIOMS guidelines) make an exception stating that the dissent may be overridden by the need of treatment that is not available outside the context of research, the research intervention has a clear prospect of clinical benefit, and the treating physician and the legally authorized representative consider the research intervention to be the best available medical option for the given child or adolescent[13],[14].

Under a dissent requirement, children are not required to understand the research and make their own prospective decisions. Instead, they simply react to how the research is affecting them and indicate any distress they experience[15]. That makes it different form the assent, which may be a legal requirement. For example, it is stated in the CTR that without prejudice to national law requiring that, in addition to the informed consent given by the legally designated representative, a minor who is capable of forming an opinion and assessing the information given to him or her, shall also assent in order to participate in a clinical trial. (CTR art. 29, para 8).

As children’s ability to understand and evaluate this information increases, so does the moral weight of their assent and dissent. As adolescents near the age of majority, their agreement to participate in research may be ethically (but not legally) equivalent to consent[16]. Provision of information is a continual process during a trial. Once an adolescent is no longer a minor, or when he or she is an “emancipated minor”, he or she should be asked to provide written informed consent as soon as practically reasonable, as for any adult capable of giving consent.

[1] Nuffield Council on Bioethics. Children and clinical research: ethical issues  (2015) http://nuffieldbioethics.org/project/children-research

[2] Charter of Fundamental Rights of the European Union (2012), Art. 24

[3] Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use Ethical considerations for clinical trials on medicinal products conducted with minors (2017)

[4] Explanatory Report to Additional Protocol to the Convention on Human Rights and Biomedicine on Biomedical research

[5] Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use Ethical considerations for clinical trials on medicinal products conducted with minors (2017)

[6] ibid

[7] Ezekiel J. Emanuel, Christine C. Grady, Robert A. Crouch, Reidar K. Lie, Franklin G. Miller, David D. Wendler. The Oxford Textbook of Clinical Research Ethics. Oxford University Press, 2008.

[8] Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

[9] Charter of Fundamental Rights of the European Union (2012).

[10] Ezekiel J. Emanuel, Christine C. Grady, Robert A. Crouch, Reidar K. Lie, Franklin G. Miller, David D. Wendler. The Oxford Textbook of Clinical Research Ethics. Oxford University Press, 2008.

[11] Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use Ethical considerations for clinical trials on medicinal products conducted with minors (2017)

[12] Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC

[13] Council for International Organizations of Medical Sciences (CIOMS). International Ethical Guidelines for Health-related Research Involving Humans. Guideline 17. Geneva, 2016. Fourth Edition.

[14] European Commission. European Textbook on Ethics in Research. European Luxembourg: Publications Office of the European Union, 2010.

[15] Ezekiel J. Emanuel, Christine C. Grady, Robert A. Crouch, Reidar K. Lie, Franklin G. Miller, David D. Wendler. The Oxford Textbook of Clinical Research Ethics. Oxford University Press, 2008.

[16] For the further ethical considerations regarding different age groups please see the EC recommendation, 2017.

Further resources:

European Commission. Horizon 2020 Online Manual. https://ec.europa.eu/research/participants/docs/h2020-funding-guide/cross-cutting-issues/ethics_en.htm

Human beings, page 6 in European Commission (2019) Horizon 2020 Programme. How to complete your ethics self-assessment-material guidance. European Commission. Directorate-General for Research & Innovation.

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  1. Charter of Fundamental Rights of the European Union (2012). http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:12012P/TXT&from=EN
  2. Council for International Organizations of Medical Sciences (CIOMS). International Ethical Guidelines for Health-related Research Involving Humans. Guideline 17. Geneva, 2016. Fourth Edition. https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf
  3. Nuffield Council on Bioethics. Children and clinical research: ethical issues (2015) http://nuffieldbioethics.org/project/children-research
  4. Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use Ethical considerations for clinical trials on medicinal products conducted with minors (2017) https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2017_09_18_ethical_consid_ct_with_minors.pdf
  5. Explanatory Report to Additional Protocol to the Convention on Human Rights and Biomedicine on Biomedical research: https://rm.coe.int/16800d3810.
  6. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf
  1. Horizon 2020 Online Manual. European Commission. https://ec.europa.eu/research/participants/docs/h2020-funding-guide/cross-cutting-issues/ethics_en.htm
  2. Human beings, page 6 in European Commission (2019) Horizon 2020 Programme. How to complete your ethics self-assessment-material guidance. European Commission. Directorate-General for Research & Innovation.
  3. TheNorwegian National Research Ethics Committees (etikkom.no) https://www.etikkom.no/en/library/topics/research-on-particular-groups/barn/
  4. European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) http://www.ema.europa.eu/ema/index.jsp?curl=pages/partners_and_networks/general/general_content_000303.jsp
  5. European Network of Excellence for Paediatric Clinical Research https://www.teddynetwork.net/ethics/

Learning Objectives

  • to discuss ethical issues raised by research involving children (minors)
  • to acknowledge normative framework for research on children (minors)
  • to explore additional safeguards aimed at protecting the interests and welfare of children taking part in research
  • to apply normative framework to analyze suggested cases

Introduction

In the context of research, a child (minor) is usually defined as an individual who is under the age of legal competence to give informed consent as determined under the applicable law of the jurisdiction in which the research will be conducted. Most international documents leave it to the national governments to determine the age of maturity[1],[2]. The EU Paediatric Regulation[3] and many European countries define the pediatric population as those under 18. However, in some countries, the rights and responsibilities of individuals from 16 to 18 might be expanded by the national law.

The major concern raised by research involving children relates to the inmaturity and related inability of children to give informed consent without appropriate support. That is the main feature of their vulnerability[4]. Moreover, their distinctive physiologies and emotional development may place children and adolescents at increased risk of being harmed in the conduct of research[5]. On the other hand, research on children is needed to develop new effective ways of treating childhood diseases, to enhance the health and well-being of children and to avoid practices in the treatment of childhood diseases that lack evidence-based justification.

Thus, the research involving children is justified, but only with the condition of additional safeguards to protect children’s rights and welfare in the research. There are several general requirements stated in the international legal documents and guidelines that are necessary to justify research involving minors. Such research is permissible only if it is directly related to a medical condition from which the minor concerned suffers and is intended to investigate treatments for a medical condition that only occurs in minors or it is necessary to conduct a clinical trial on minors to validate data obtained in the clinical trials on persons able to give informed consent[6]. Thus, it is recommended that research on minors should only be started after obtaining relevant data from research with animals and/or research with adults. Similarly, older children who can participate in the decision-making process should, when feasible, precede research with young children and infants[7]. There are, however, concerns that a ‘staggered’ medicine development approach, starting by the older and going sequentially to the younger age groups, may lead to delays in data availability and result in prolonged off-label use in younger age groups (especially neonates) and difficulties in conducting any trial in these groups once the medicine is on the market[8].

There are also specificities in risk and benefit assessment and informed consent issues that should be taken into account.

[1] Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC

[2] CIOMS. International Ethical Guidelines for Health-related Research Involving Humans (2016)

[3] Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use, OJ L 378, 27.12.2006, p. 1.

[4] For the further information on vulnerability issues please see the module “Research involving vulnerable groups”.

[5] CIOMS. International Ethical Guidelines for Health-related Research Involving Humans (2016)

[6] Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC

[7] Neil McIntosh, David Hull. Guidelines for the ethical conduct of medical research involving children. Archives of disease in childhood. 2000 Volume 82, issue 2 http://dx.doi.org/10.1136/adc.82.2.177

[8] Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use Ethical considerations for clinical trials on medicinal products conducted with minors (2017).

Further resources:

European Commission. Horizon 2020 Online Manual. https://ec.europa.eu/research/participants/docs/h2020-funding-guide/cross-cutting-issues/ethics_en.htm

Human beings, page 6 in European Commission (2019) Horizon 2020 Programme. How to complete your ethics self-assessment-material guidance. European Commission. Directorate-General for Research & Innovation.

 

Cases and Questions - Research Involving Children

Case 1

Dr. Mays is a doctor of ophthalmology interested in the medical potential of gene transfer to treat Leber’s congenital amaurosis (LCA). LCA is a degenerative retinal disorder. Patients have very poor vision at birth and can suffer a number of other effects from the condition. Dr. Mays is proposing a Phase I clinical trial using gene transfer to treat LCA. LCA is a particularly good candidate for gene transfer because of location and type of genetic defect involved as well as the fact that the condition is degenerative and there is no known effective therapy. 

Pre-clinical data suggest that the proposed transfer will likely be most–if not exclusively–effective in patients who have not yet experienced significant degeneration of the retina. Younger patients are the best candidates for the purpose of assessing efficacy. However, enrollment in the study would pose a significant risk, due to the novelty of the intervention. The study can be conducted on healthy adults, but they would very likely not benefit from the gene transfer, due to the advancement of retinal damage. 

Source: http://ethicsresearchcore.org/high-risk-genetic-therapy/ 

- What might be the main ethical issues in this case? In particular, would you justify the inclusion of children into this study?