NCHR Comments on FDA Ethical Considerations for Clinical Investigations of Medical Products Involving Children

December 27, 2022

We are pleased to have the opportunity to share our views with the Food and Drug Administration (FDA) on their Ethical Considerations for Clinical Investigations of Medical Products Involving Children Draft Guidance.

The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.

The draft guidance on ethical considerations for trials involving children is both welcome and necessary. Many new medical products that are used by children are never actually tested on them or approved for them prior to entering the market. Many children are either left with no treatment options or given products “off label” that have not been tested for safety, effectiveness, or dosage requirements in patients of their age, size, or weight.1 While the FDA has required drug-makers to conduct postmarket pediatric clinical trials on many of these medications, only about a third of studies required under the US Pediatric Research Equity Act have actually been completed.2 In addition, most new drug labels do not include information related to pediatric drug use. Only about 41% include any pediatric information on the label.2 Pediatric medical devices undergo even less scrutiny. Few are developed specifically for use in children, although pediatric patients have unique requirements related to their size as well as device indication and function. In most cases, data on safety and effectiveness for these off-label applications are lacking.3

NCHR addresses concerns and suggestions on how to improve this guidance to promote safety and efficacy in clinical investigations of medical products involving children:

  1. Regarding scientific necessity

The section addressing scientific necessity specifies that “for products that are being developed for use in adults and children, if effectiveness in adults can be extrapolated to children, then effectiveness studies in adults should be conducted to minimize the need to collect effectiveness data in children.” The use of extrapolation is detailed in the FDA guidance document Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices, which is referenced in this guidance. As a whole, it places priority on accelerating the rate of device development over ensuring the safety and efficacy of devices for children. In this draft guidance and other relevant documents, NCHR strongly urges the FDA to provide explicit restrictions on the use of extrapolation, reliance on (appropriate) biomarkers, and assumptions about the degree of similarity between the adult and the pediatric populations. Extreme caution should be exercised before relying on extrapolation from adult data to children. Adult data should not be encouraged as a substitute for pediatric data, but rather to supplement and support clinical investigations of children.

  1. Regarding the inclusion of diverse populations

We recommend the FDA amend their guidance to include a statement concerning the need for equitable selection of participants in clinical investigations involving children. Consideration must be given to the diversity of participants for whom an intervention is intended. Inclusion and representation in terms of race, ethnicity, gender, disability, social determinants of health, and language, is essential. It is essential that accommodations be provided as necessary, including translation and interpreter services. These considerations are important to ensure informed consent for children, their parents, guardians, and caregivers.

  1. Regarding clinical investigations of medical devices

This section states, “The available clinical data for the device (e.g., published studies and reports and actual use information) should be considered when designing the clinical trial to maximize the amount of information gained and minimize the number of subjects involved.” This raises unacceptable ethical issues. Shrinking sample size probably minimizes the potential harm to participants in the short term; however, when safety and efficacy are only determined in a small population, and multiple trials are not conducted (as is often that case in pediatric trials), safety issues may only be clearly identified when the product is available to larger numbers of children.  To protect the safety of children, the number of children in clinical trials should be gradually increased to ensure sufficient safety and efficacy data prior to clearance or approval.

  1. Regarding assent to participate in clinical investigations

According to the guidance draft, “children 7 years of age and older are often considered capable of assent.” Although capable of assent, such young children are likely to be strongly influenced by adults’ persuasive statements, whether from parents, guardians, or physicians. We therefore question that 7 is an appropriate age to provide meaningful assent. We instead urge that children ages 12 and above are generally able to understand a written form and should provide written assent in addition to oral assent. Since research decisions vary greatly in their complexity, IRBs must have the ability to tailor decisions about the age of assent to the circumstances of a particular research study.

  1. Definition of minimal risk and minor increase over minimal risk

We applaud the definition of minimal risk in this Draft Guidance, which provides a clear explanation of just how minimal that risk should be.  However, it is our understanding that there is confusion about the definition of “minor increase over minimal risk.”  Examples of what is or isn’t a “minor increase” is needed.

It is past time for the FDA to improve guidance around the participation of children in clinical trials. Inclusion of sufficient numbers of children under 18, across diverse populations, will promote safety and efficacy of medical products. As specified above, FDA should make it clear that it expects clinical data on sufficient numbers of children, rather than a reliance on extrapolation data or very small numbers of children, to ensure better quality data that is generalizable to most children relevant to the product being tested. We strongly urge the FDA to make our recommended revisions when finalizing their guidance.

Thank you for the opportunity to share our concerns.  We would be glad to provide additional information and can be reached at or at (202) 223-4000.

  1. National Center for Health Research. (2017). NCHR Comments on Manufacturer Communications on Use of Off-Label Medical Products.
  2. Hwang, T., Orenstein, L., Kesselheim, A., Bourgeois, F. (2019) Completion Rate and Reporting of Mandatory Pediatric Postmarketing Studies Under the US Pediatric Research Equity Act. JAMA Pediatr. 173(1):68–74. doi:10.1001/jamapediatrics.2018.3416
  3. Pathak, K., Narang, C., Hwang, T., Espinoza, J., Bourgeois, F. (2022). High-risk Therapeutic Devices Approved by the US Food and Drug Administration for Use in Children and Adolescents From 2016 to 2021. JAMA Pediatr. Published online November 07, 2022. doi:10.1001/jamapediatrics.2022.4131