The new article highlights the main points related to the assessment of applicable risk, as well as the concept of direct benefit for study participants. 

The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to clinical investigations of medical products involving children. The document provides additional clarifications regarding the existing regulatory requirements, as well as recommendations to be considered by manufacturers and study sponsors to achieve and sustain compliance thereto. At the same time, provisions of the guidance are non-binding, nor are intended to introduce new rules or impose new obligations. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the corresponding legislation and has been agreed with the authority in advance. 

The guidance highlights the key points resulting from the specific nature of clinical studies with children involved as study participants (subjects). Under the general rule, children should not be enrolled as study subjects, unless there is no other way to assess the safety and effectiveness of a medical device intended to be used for children. When describing the approach to be applied, the authority pays special attention to the aspects related to the risks and the way it should be determined whether the risk is acceptable or not. 


Prospect of Direct Benefit 

The authority acknowledges that the confirmed effectiveness of a medical device, when used for adults, does not mean that the device will be effective when used for children. Thus, concerning confirmation of effectiveness, the authority applies the concept of the prospect of direct benefit, which refers to the potential benefit to the individual child from exposure to the research intervention or procedure in the clinical investigation in question. The above definition is outlined in regulation 21 CFR 50.52. As further explained by the FDA, the prospect of direct benefit should result from the research intervention or procedure being studied (e.g., the investigational drug or medical device) and not from ancillary interventions or procedures, such as physical exams done as part of the trial. In other words, it is important to ensure that the risk associated with the intervention is justified due to the anticipated benefit. Moreover, it is also important to ensure that the said risk is justified in terms of alternatives available. According to the guidance, when evaluating if an intervention or procedure offers a prospect of direct benefit, the IRB [Institutional Review Board] should consider whether the evidence establishing proof of concept about a potential beneficial effect is sufficient and whether the proposed dose (particularly for drugs) and duration of exposure to the intervention of procedure are adequate to offer a potential clinical benefit to the individual child. The authority further explains that in case of an investigation related to a medical device, it is important to ensure that the characteristics of the device in question are compatible with the age of a child. 

According to the document, the evidence necessary to determine the prospect of direct benefit could be based on single or multiple sources of information. For instance, clinical data deriving from the use of a product in question for adults could also be used to demonstrate its safety for conditions that apply to both adults and children. In certain cases, the data from animal studies could also be used – for instance, in case some conditions apply only to children (hence, adult data could not be used).

Risk Assessment 

The authority further describes the approach to be applied to the assessment of risk for interventions or procedures with a prospect of direct benefit. As it was mentioned before, the applicable regulations require ensuring that the risk associated with the procedures to be undertaken in the course of a study is justified in terms of the potential benefit for study subjects. The scope of assessment should cover all the clinical data available, including the data deriving from studies with healthy adults, adults with the same conditions, etc. At the same time, in certain cases, the data available before the commencement of a clinical study could be limited to nonclinical studies, namely:

  • Nonclinical studies to evaluate maximum tolerated doses or device performance and safety;
  • Juvenile animal studies to support the pediatric age groups being studied, and/or 
  • Nonclinical studies of sufficient duration to support treatment for chronic conditions. 


Component Analysis 

Another important aspect addressed in the guidance relates to the component analysis. In this respect, the authority mentions that the study protocol usually covers multiple procedures, some of which offer the prospect of direct benefit, while some don’t. Thus, in case a procedure is to be performed for investigational purposes only, the risks associated thereto should be subject to a separate assessment to determine whether it offers the prospect of direct benefit to the child. Should it be identified that the procedure in question does not offer it, the risks associated thereto should be mitigated to the lowest extent possible, which should be a minor increase over minimal risk. 

In case a study sponsor fails to complete a risk assessment as described hereinabove, the actual risk might exceed the said level. In such a case, the study protocol would not be approved by an institutional review board. However, such a study could still be conducted, provided the below conditions are met:

  • The IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a problem affecting the health or welfare of children; and
  • The Commissioner, after consultation with a panel of experts in pertinent disciplines (e.g., science, medicine, education, ethics, law) and following opportunity for public review and comment, determines that either:
    • The research satisfies 21 CFR 50.51, 50.52, or 50.53; or
    • The conditions described in 21 CFR 50.54 are met. 

In summary, the present FDA guidance describes the concept of the prospect of direct benefit and explains the way it should be applied in the context of clinical investigations with children involved. The document also addresses the matters related to the risk assessment and key points to be considered in this respect. 



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