Recent developments in the protection of pediatric research subjects
Article Outline
- Inclusion of children and the minimal risk standard
- Innovative approaches to pediatric studies
- The role of data and safety monitoring boards in pediatric studies
- Challenges to informed consent with pediatric subjects
- Conclusions
- References
- Copyright
Investigators seeking to expand the evidence base for pediatric practice often struggle to balance the protection of children with the need to include them as participants in clinical research protocols.1 Failure to deal effectively with this challenge can hamper research, put children at unnecessary risk, or sacrifice public trust in the research enterprise. The ethical, legal, and social consequences of such failures were recently reviewed in an Institute of Medicine Report.2 That report also made a series of specific recommendations for optimizing safety of pediatric research participants. The consequences of failure to protect the safety of children involved in research are illustrated by the controversial legal action surrounding a clinical study designed to identify an economical method of partial lead paint abatement,3, 4 which pointed out the ethical imperative of minimizing risk to children when there is no counterbalancing benefit to them.
Inclusion of children and the minimal risk standard
To balance the need to include children in research with the ethical imperative to protect children, federal authorities will allow institutional review boards (IRBs) to include children in studies that offer no benefit only if the risks of participation are minimal. Children may participate in research trials that incur a minor increase over minimal risk if there is reasonable expectation of future benefit to those with the same condition; inclusion of children in studies with more than a minor increase over minimal risk can only be justified by the prospect of direct benefit. The concept of direct benefit has recently been challenged. In a large portion of cases, the likelihood of direct benefit is quite small for any individual child in a trial of an intervention intended to confer direct benefit. Clearly, pediatric subjects in a placebo arm will receive no benefit, and those in the interventional arm are not guaranteed of benefit.
Minimal risk is intended to mean risks comparable to the activities of daily life or those occurring during routine physical or psychological examinations or tests. Until recently, there was very little quantification of that minimal risk standard. The possibility that some children may have higher daily life risk because of their conditions or environmental circumstances cannot be considered; the standard is for normal, average, healthy children living in safe environments. A recent study by Wendler et al5 reported that the risks of physical and psychological harm can vary widely in daily lives of a population sample of healthy children, depending on a number of specific factors including sports participation. They argued that one might consider a risk level at the low end of this range to be minimal. In any case, the variable level of such risks begs the question of whether there should be a single acceptable risk level, as opposed to a risk level relative to the daily living risk posed to the particular population being studied. Furthermore, quantifying risks for interventional studies is usually highly conjectural, although common medical procedures involved were categorized in the Institute of Medicine report.2
Innovative approaches to pediatric studies
Many new procedures have been developed in an attempt to more fully protect pediatric participants in clinical research (Table; available at www.jpeds.com). These newer policies and procedures do not serve to supplant the primary role of investigators, and the role of IRBs, which is to minimize risks to subjects through assuring: sound study design; reasonable balancing of risks and benefits; equitable subject selection; recruitment and retention; adequate and appropriate informed consent; trained and qualified researchers; and ethical review involving community members.
Table. New procedures to improve protection of pediatric research participants
| Procedure | Goal |
|---|---|
| Pediatric data and safety monitoring committee | Assist in evaluating risk assessment of study procedures and assist in interim analysis of data with regard to safety and efficacy |
| Assent process | Facilitate growing autonomy of children involved as research subjects |
| Decision monitoring | Verify “informed” nature of consent, particularly with regard to therapeutic misconception |
A growing number of funding agencies and institutions are recommending the use of data and safety monitoring boards (DSMBs) to supplement the supervision provided by IRBs; this is particularly relevant to the inclusion of children in research studies. While DSMBs may be provided for some studies by an external sponsor or funding agency, some academic institutions, including the University of Florida, have developed internal DSMBs to ensure coverage of all pediatric protocols. Given the costs associated with the establishment of DSMBs, it seems unlikely that this approach will be generally applied to observational research in addition to interventional studies. The internal DSMB may serve as a resource for small studies, particularly those led by junior investigators who do not have access to an external DSMB or the funding to constitute a DSMB of their own. There may be added value from a consistent group of pediatric DSMB members who have complementary expertise and experience with research risk and data assessment. Also, the informed consent process is especially challenging in the pediatric population, particularly in studies of new therapies for serious conditions that affect children.6, 7 Finally, there are even greater concerns in studies that involve genetic testing and gene therapy. Alternatively, many centers support a pediatric IRB, which can serve many of these same purposes.
The role of data and safety monitoring boards in pediatric studies
The purpose of a DSMB is to safeguard the interests of study participants, assess the safety and efficacy of the interventions during the study, and monitor the overall conduct of the clinical study. Optimally, DSMBs can ensure the scientific integrity of the study8 and can be “critical to the ethics, efficiency, integrity and credibility of clinical trials and the conclusions of such trials.”9 Each DSMB is formally established according to a charter that describes how it will function.
The decision to use a DSMB is based on a number of factors, including the risk to subjects, the complexity of the trial design, and the number of sites.10 A DSMB is especially important for studies enrolling children because Board members can mitigate risk in this vulnerable population. Pediatric DSMBs consist of clinicians experienced in the treatment of the disease under study and statisticians who are skilled in research methods. Other participants may include clinical researchers, ethicists, and members of a disease-specific group. DSMB members must be financially and professionally independent from the study.
The National Institutes of Health (NIH) requires a DSMB when there is potential risk to subjects and generally for Phase III studies.10 There are also guidelines for Phase I and II studies, and each institute and center has guidelines available on the web.11 The National Center for Research Resources established a Research Subject Advocate position to assist in deciding when DSMBs are required and how best to monitor studies conducted in a General (or Pediatric) Clinical Research Center.12 Nonetheless, there are no standard guidelines for how to establish a DSMB, and NIH guidelines affect only NIH studies.
Some foundations and pharmaceutical companies may also establish DSMBs or similar committees called Data Monitoring Committees when they support trials that pose significant risk. Although sponsors usually pay for the costs of organizing and supporting a DSMB, another (newer) approach is to create a standing “internal” Data and Safety Monitoring Board for studies. Examples include DSMBs for pediatric hospitals, pediatric departments, or for pediatric studies in Clinical Research Centers. This type of DSMB is supported by institutional funds and consists of local pediatric experts and statisticians who recuse themselves if a conflict of interest exists. Ultimately, the use of DSMBs leads to improved public trust in clinical research.12
Challenges to informed consent with pediatric subjects
One of the overarching principles in the ethical conduct of clinical research is full disclosure of the potential risks and benefits to individuals who volunteer to participate. For many reasons, children and adolescents cannot participate in this process of giving their informed consent in the same manner as adults. Depending on their age, children may lack the cognitive maturity, emotional maturity, or legal standing to fully participate. This ethical limitation is only partially addressed by the role of parents and guardians as surrogate decision makers.
Specific mechanisms can augment the role of parents as surrogate decision makers. One of these is the “assent” process in which children receive age-appropriate information about study procedures, risks, and benefits of proposed research. Materials used in the assent process are typically reviewed and subject to approval by IRBs as part of the informed consent documents. If the study includes children from a wide range of ages, it is often necessary to include different assent documents and procedures, each appropriate to a specific age group. What remains more controversial is the level of active assent required from pediatric subjects of various ages as compared with the lack of active dissent.
Another approach is the use of decision monitoring. Decision monitoring is a process whereby the adequacy of informed consent is validated by an interview done by a third party after the informed consent, and assent, where applicable, has been obtained. The decision monitor’s role can fit within the broader structure of being a research subject advocate and ideally should be administratively and financially independent of the investigative team. The decision monitor’s interview assesses the volunteer’s and the parents’ knowledge of the study procedures, risks, and potential benefits. This technique has been felt to be particularly useful in avoiding “therapeutic misconception,” the false expectation that clinical benefit will be derived from a study agent that is in early stages of safety testing in human beings. This is especially true if the consent is being sought by the subject’s treating physician or a member of the physician’s health care team. However, it remains to be determined whether therapeutic misconception can be prevented by any specific aspect of the consent or monitoring process.
Conclusions
Regulatory oversight of clinical trials in children is intended to enhance the safety and overall positive impact of those trials on children’s health, particularly in the context of testing the safety and efficacy of new drugs, biologic agents, and devices that are to be used in children. The review processes noted above should also be able to define research practices that are clearly unacceptable or dangerous. The recognition of children as a vulnerable population leads to a unique approach to risk-benefit assessment, external monitoring, and informed consent. Weaknesses in this research protection framework have been highlighted in recent cases. Conversely, the well-intentioned effort to strengthen research protections for children could have a stifling effect on pediatric research. This dilemma can be positively addressed through the use of innovative techniques to protect children involved in research.
References available at www.jpeds.com.
References
- . The impact of the Food and Drug Administration Modernization Act on the recruitment of children for research . Ethical Hum Sci Serv . 2003;5:83–108
- . Children CoCRI. The Ethical Conduct of Clinical Research Involving Children . Washington, DC: Institute of Medicine; 2004;
- . West’s Atl Report . 2001;782:807–862
- . Maryland court ruling sets precedent on research involving minors . GHA Today . 2001;45(9):3; 8
- . Quantifying the federal minimal risk standard (implications for pediatric research without a prospect of direct benefit) . JAMA . 2005;294:826–832
- . What do researchers say? What do subjects hear? Not what they would like to hear. What do subjects need? More information . Prot Hum Subj . 2005;12:10–11
- . Informed consent in pediatric clinical trials . Curr Opin Pediatr . 2005;17:20–24
- . In: Gallin J editors. Principles and practice of clinical research . Burlington, MA: Elsevier; 2002;
- . Data Monitoring Committees in Clinical Trials (Preface ix) . Hoboken, NJ: Wiley; 2003;
- National Institutes of Health. NIH Policy for Data and Safety Monitoring. June 10, 1998. Available at: http://grants.nih.gov/grants/guide/notice-files/not98-084.html.
- National Institutes of Health. Further Guidance On Data And Safety Monitoring For Phase I AND Phase II Trials. June 5, 2000. Available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html
- Vaitukaitis JL. Clinical Research and Public Trust. NCRR Reporter Fall 2004. Available at: http://www.ncrr.nih.gov/newspub/Fall04rpt/director.asp. Accessed May 23, 2006.
PII: S0022-3476(06)00359-3
doi:10.1016/j.jpeds.2006.04.033
© 2006 Mosby, Inc. All rights reserved.
