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7.3.4 Research Involving Children

Thérèse St-Laurent-Gagnon MD, FRCP(C), PhD

Educational objectives:

  1. Reflect on the assessment of risks among children
  2. Reflect on the assessment of benefits among children
  3. Reflect on the involvement of children in research consent

First case

This study was discussed in March 2004 during the Clinical Center Ethics Grand Rounds (http://www.bioethics.nih.gov/courses/ethgr/orourkemar04.pdf ).

The study examined children with attention deficit hyperactivity disorder (ADHD). ADHD is the most common behavioural disorder in children (5-10% of children overall). Symptoms include impulsiveness, inattention and inappropriate behaviours. The cause of ADHD is unknown, although a genetic component has been identified. Psychostimulants (for example, dextroamphetamine, or methylphenidate) are the standard medications for treatment.

Methodology:

Scientific objective of the research: verify whether children with ADHD experience a different response to stimulants in the central nervous system compared to children without ADHD.

Subjects: children ages 9 to 18, including: 14 children with ADHD and 14 healthy control subjects, as well as 24 monozygotic twins discordant for ADHD and 24 dizygotic twins discordant for ADHD.

Experimental procedures: all of the subjects will undergo data collection, a physical exam, and a neuropsychological assessment. They will all have blood drawn for genetic analyses and functional magnetic resonance imaging. Some children from both the control group and the ADHD group will receive either a single dose of dextroamphetamine (10 mg orally) or a placebo in a randomized, double-blind manner.

Second case

This study examined the relationship between the metabolism of serotonin in the central nervous system and aggressive behaviour in children with behavioural disorders associated with attention deficit and hyperactivity (ADHD). This study was adapted from a study published in The British Journal of Psychiatry 2007; 190: 410-414.

Subjects: children ages 7 to 11 presenting ADHD and aggressive or oppositional defiant behaviours.

Experimental procedures: clinical assessment, a low-monoamine diet for three days, an eight-hour fast (12:00 a.m. to 8:00 a.m.), and then a day at the experimental laboratory for a fenfluramine challenge.

Description of the fenfluramine challenge: An intravenous catheter was inserted. A baseline blood sample was taken between 9:00 a.m. and 10:00 a.m. A 1-mg/kg dose of fenfluramine was ingested orally. Blood samples to assess the levels of prolactin, fenfluramine and norfenfluramine in plasma were taken at 60, 120, 180, 240 and 300 minutes after the fenfluramine was ingested orally.

Q1. How do you assess the benefits and harms of this type of study? Do you make a distinction for children who are healthy?

The research benefits may be physical, intellectual, psychological, social, spiritual, etc. Some normative texts differentiate between "therapeutic" research and "non-therapeutic" research. According to Section 21 of the Civil Code of Quebec, therapeutic research [should] have the potential to produce a benefit to the individual child's health. Non-therapeutic research [should] have the potential to produce results for a group of people having similar characteristics to the child participating in the research (age, disease or handicap). What will the actual benefits of the research be for the individual child? Will the research benefits be more long-term; for example, in children diagnosed with the disease in the future?

The research harms can be physical, intellectual, psychological, social, spiritual, etc. In general, physical harm is easier to assess than psychological harm. However, this case involves just a single dose of medication. The short-term effects seem rather benign. However, will there be any long-term effects? It is harder to predict the risks to the child at a psychological level: confronting his or her behavioural disorder as in this case, or the fact of being "labelled".

Risk assessment in pediatric research is complex. Most normative texts base risk acceptance in research involving children on the concept of minimal risk1. There is no consensus on what constitutes minimal risk. Thus, some authors consider a blood sample to be minimal risk while others consider it to be greater than minimal risk. Canadian and Quebec standards support a relative assessment of the risks. Therefore, in Canada and Quebec, research risks are assessed in relation to the risks that the individual child encounters "in those aspects of his or her everyday life that relate to the research" (Tri-Council, 1998). Based on this contextual principle, we would therefore agree that, in theory at least, the sick child would have to undergo more tests than the healthy child when he or she is participating in research.

However, disagreement exists in the literature about how to define minimal risk: i.e. in a "relative" way in relation to the minimal risk encountered by this individual child during the course of treatment, or in an "absolute" way in relation to the minimal risk encountered by a child in good health. Recently, the Institute of Medicine in the United States (IOM, 2004), recommended an absolute assessment of the minimal risk, i.e. "interpret minimal risk in relation to the normal experiences of average, healthy, normal children"2. Assessment of the research-related harms also takes into account the fact that the procedures are necessary for the treatment of the disease being studied (therapeutic risk) or exceed the patient's clinical needs and are used solely for research purposes (non-therapeutic risk). Assessment of the actual or potential risks in relation to the anticipated benefits lies at the root of the principle of beneficence and non-maleficence within the pediatric research framework. Even if the anticipated benefits are significant, the absence of harm to the self or others predominates in the case of children.

Assessment of the research project by a research ethics committee is another way to ensure a balance between the benefits and harms related to the research. In Quebec, projects involving a minor person (under 18 years old) must be submitted to research ethics committees that have pediatric expertise and are approved by the designated governmental bodies3.

Q2. In your opinion, what involvement should the child have in the decision-making (assent)? (Do you make a distinction between children 8, 10, or 12 years old?)

The age of majority varies from province to province4. In some provinces, such as Quebec, research consent must be signed by the research subject's parents until he or she attains the age of majority. In other provinces, the child's maturity and the risks associated with the research are taken into account and assessment is carried out on an individual basis (e.g. Ontario and Nova Scotia). The researcher must verify the standards in his or her province with the research ethics committee. Overall, Canadian and Quebec normativity leave scope for the child in research-related decisions in the form of assent5. However, the clear and informed consent of the authorized third party is given a prominent role (CCQ, 1991; Health Canada, 1997; Tri-Council, 1998). Moreover, the regulations that suggest the child's involvement do not specify age. The standards are based on the children's ability to understand, but they do not specify the information that the child must understand. Canada and Quebec give greater importance to the child's objection.

In the literature, four categories of children were identified for assent: (1) children with no language comprehension, such as neonates, (2) children with some language comprehension but no decisional capacity, (3) children with good language comprehension and developing decisional capacity, and (4) children with good language comprehension and decisional capacity (Baylis F et al., 1999; Simpson C, 2003). The authors agree that the first two categories of children cannot give assent. Even if most of the authors believe that the children in the fourth category should give their assent for research, there is disagreement regarding the third category (Baylis F et al, 1999; Simpson C, 2003).

At present, it is therefore difficult to define—both in the normativity and literature—the exact meaning of the child's assent and what type of information is required for it to be valid. Even if the proposed age categories seem to offer an interesting framework, we can wonder whether the disagreements that persist could diminish their utility for researchers and research ethics committees in assisting them in forming their decisions with regard to the involvement of children in research decisions: assent-refusal.

The child is a developing human being and his or her capacity for self-determination varies according to age and maturity. The principle of respect for the child takes into account the child's increasing autonomy and suggests that, in addition to parental authorization, the child give his or her assent according to his or her level of comprehension.

Recommended reading

Normative texts:

  • AAP (1995). Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations (RE9503). Pediatrics, 95 (2),286-294
  • AAP (1995). Informed Consent, Parental Permission, and Assent in Pediatric Practice (RE95190). Pediatrics, 95, 314-317
  • CNBRH et SCP. (1993). Réflexions sur la recherche auprès des enfants, Ottawa IOM. (2004). Chapitre 4. Defining, interpreting, and applying concepts of risk and benefit in clinical research involving children. In The ethical conduct of clinical research involving children (pp. 113-145): Institute of Medicine.
  • Trois conseils. (1998). énoncé de politique. éthique de la recherche avec des �tres humains.

Articles:

  • Baylis F, Downie J, Denny NP. (1999). Children and decision making in health research. Health Law Review, 8(2), 3-9
  • Flory JD, Newcorn JH, Miller C, Harty S, Halperin JM, � Serotonergic function in children with attention-devicit hyperactivity disorder �m The British Journal of Psychiatry 2007; 190: 410-414.
  • Freedman B, Fuks A, & Weijer C, (1993). In loco parentis, minimal risk as an ethical threshold for research upon children. Hastings Center Report, 23(2),13-19
  • Weijer C.(2002) L'analyse des risques et des avantages éventuels dans la recherche. NCEHR Communiqué, 9(2)

Websites consulted:

References

  1. The standard of minimal risk is commonly defined as follows: if potential subjects can reasonably be expected to regard the probability and magnitude of possible harms implied by participation in the research to be no greater than those encountered by the subject in those aspects of his or her everyday life that relate to the research, then the research can be regarded as within the range of minimal risk.” (C.1, p.1.5, Tri-Council Policy Statement, 1998)
  2. Interpret minimal risk in relation to the normal experiences of average, healthy, normal children, see Recommendation 4.1 of The Ethical Conduct of Clinical Research Involving Children, p.126 (IOM, 2004).
  3. These research committees are "designated" by the Minister of Health and Social Services pursuant to Section 21 of the Civil Code of Quebec and their operating procedures are published in the Gazette officielle du Québec.
  4. The age of majority is 18 in Quebec, Saskatchewan, Prince Edward Island, Ontario, Alberta and Manitoba. It is 19 in other provinces, the Northwest Territories, Nunavut and the Yukon.
  5. Assent is the voluntary acceptance of the action or suggestion of another, but without a full understanding of it [translation] (NCBHR, 1993; vii)