The new article describes in detail the principle of necessity and the way it should be applied. The article also covers the aspects related to risk categories for interventions or procedures without a prospect of direct benefit.
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 the ethical considerations for clinical investigations of medical products involving children. The document is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be followed to ensure compliance thereto. However, provisions of the guidance are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations. The authority also explicitly states that an alternative approach could be applied, provided such an approach is in line with the applicable legislation and has been agreed with the authority in advance.
Principle of Scientific Necessity
According to the guidance, the principle of scientific necessity is encompassed in two regulatory requirements: the equitable selection of subjects (21 CFR 56.111(a)(3)) and the minimization of risk (21 CFR 56.111(a)(1)). As explained by the FDA, institutional review boards (IRBs) should take into consideration the scientific necessity of conducting a clinical investigation in children. The authority also mentions that it will be reasonable to assess the scientific necessity before assessing the risks associated with a study. The authority additionally emphasizes that children should not be enrolled in a clinical investigation unless their participation is necessary to answer an important scientific and/or public health question directly relevant to the health and welfare of children. According to this principle, in case the product in question is initially intended to be used for both children and adults, the study sponsor should conduct a clinical investigation with only adults involved, provided the results of such investigation could later be extrapolated to children. Such an approach allows for minimizing the need to collect effective data on children.
As further explained by the FDA, when assessing the selection of study participants (subjects), the aspects to be considered should include the purpose of the study, as well as the setting. Furthermore, it is stated that IRBs should be informed of the unique challenges of research. Concerning risk minimization, it is important to ensure that any procedures conducted in the course of a clinical investigation are in line with the study design and do not result in study participants being exposed to unnecessary risk. For instance, it is recommended to use the procedures necessary as a part of clinical care.
Should it be determined that the involvement of children is necessary to collect sufficient information, a study should be designed in a way to make sure all the necessary data will be collected properly. According to the guidance, key elements of well-designed clinical investigations include the selection of appropriate control groups and study endpoints relevant to the pediatric population; while studies that are not well-designed expose children to unnecessary risk and are unlikely to yield informative study results, and as a result may be considered unethical. The authority also mentions that in case the study is intended to assess the effectiveness of a medicinal product, randomized placebo-controlled trials could be required.
Risk Categories for Interventions or Procedures without Prospect of Direct Benefit
Another important aspect addressed in the guidance relates to risk categorization. In particular, the document describes the applicable risk categories for interventions or procedures without the prospect of direct benefit. According to the guidance, any intervention or procedure, including the administration of an investigational drug or use of an investigational medical device, undertaken as part of a clinical investigation in children may be associated with risk. As set forth by the applicable regulation, there are two categories of risk to be applied, namely:
- Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Thus, minimal risk is equivalent to the one experienced daily. However, the authority additionally emphasizes the importance of taking into consideration such categories as age, since this could significantly impact the interpretation of risk and its acceptability, as for different ages the normal risk could be different as well. Apart from this, factors to be considered include the duration of exposure to the risk, the characteristics of the risk, and the reversibility of harm. When assessing the above in terms of an investigational medical device, a study sponsor should take into consideration specific factors associated with the design of the device in question and its intended use.
- A minor increase over minimal risk stands for a slight increase over any minimal risk that poses no significant threat to the child’s overall health or well-being. The above means that any harm that could be potentially caused to study participants should be reversible. In this respect, it is important to take into consideration such factors as the setting where the study is to be conducted, and also the level of experience of an investigator who will perform the procedures as per the clinical study protocol.
In summary, the present FDA guidance describes the approach to be applied when determining the need for children to be involved in a clinical study, based on whether it is reasonably necessary to collect the data needed, and also highlights the key points to be considered concerning risk categorization. The document describes in detail the two applicable risk categories and outlines the main factors to be taken into consideration when determining the proper category.
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