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 with children involved. By virtue of the guidance, the authority highlights specific aspects to be considered due to the involvement of children as a vulnerable group of study participants. The authority outlines the main principles to be followed, and also explains the approach to be applied to ensure compliance with the applicable regulatory requirements. At the same time, the document is non-binding, nor is intended to introduce new rules or impose new obligations, but rather to provide additional clarifications regarding the existing regulatory framework, as well as recommendations to be followed by medical device manufacturers, study sponsors, and other parties involved.
The scope of the document covers, inter alia, the key points related to the design considerations for clinical investigations. Under the general rule, clinical investigations involving children should be designed to maximize the amount of information gained and minimize the number of subjects involved. As it was mentioned in previous articles, clinical trials involving children should be carried out in case there is no other reliable solution to collect clinical data necessary to assess the safety and effectiveness of a medical device intended to be used for the pediatric population. The authority additionally emphasizes that in case there are options to collect the clinical evidence necessary without involving children, such options should be used, unless this impacts the reliability and accuracy of clinical data when used in the context of assessing the risks and benefits associated with the device. As explained by the FDA, a party responsible for a medical device should conduct a rigorous assessment of risks before commencing a study. These aspects are also described in the guidance, together with the matters related to the way parental consent should be obtained.
Design Considerations: Main Points
The authority acknowledges that the actual risk associated with an investigation depends on the subgroup of study participants involved. The key factors to be taken into consideration when deciding on the design of a clinical investigation and assessing the risks associated thereto should include, inter alia, the following ones:
- Age and degree of physiological maturity of the child;
- Nature and natural history of the clinical condition to be treated;
- Current severity of the condition to be treated in the child;
- Presence of other complicating clinical conditions;
- Safety and effectiveness of the drug or device that may have been demonstrated in older subjects, or that is expected based on other clinical or nonclinical investigations; and
- Likely duration of drug or device use and its impact on the growth and development of the child, including behavioral and psychosocial effects.
The document further describes in detail specific considerations for clinical trials related to medicines (drugs) and medical devices and also outlines their differences and similarities.
Clinical Investigations of Drugs
First of all, the authority states that the intervention to be conducted in the course of a clinical investigation involving children should offer a prospect of direct benefit. In this respect, a study sponsor should assess the impact and therapeutic effect of a dose of a drug to be used. In certain cases, clinical data related deriving from the use of a product for adult patients could be used, provided the results of such use are applicable in the context of specifics of the pediatric population. For instance, such data could be used to determine the initial dosing, as well as to conduct a preliminary assessment of the therapeutic effect the product in question has. In this respect, the authority mentions that extending a dose for a product from another patient population (or a different indication) to the new pediatric population should be based on a sound scientific assessment, particularly addressing how the exposure response for effectiveness and safety in the other population was used to predict the exposure-response relationship in the pediatric population of interest. In certain cases, animal models could also be used to collect additional data supporting the further assessment of the product. However, the authority additionally emphasizes that the use of any sources of data should be duly justified from a scientific standpoint.
The duration of a drug-related clinical trial involving children should be sufficient for the child being a study subject to benefit from a therapeutic effect caused by the product in question. However, in the case of a single-dose study, a prospect of direct benefit is not usually offered due to the quite short period of the trial. At the same time, multiple-dose studies usually do offer the prospect of direct benefit, nevertheless, a study sponsor should ensure the duration of a study is sufficient for the clinical benefit to be achieved.
Clinical Investigations of Medical Devices
The document further describes the approach to be applied concerning clinical investigations involving children when conducted concerning medical devices and also highlights the main differences in comparison to the ones related to drugs. In particular, the authority mentions that compared to drugs, devices present different challenges due to the range of technology they incorporate and their varying applications. When deciding on the design of a clinical investigation, a sponsor should take into account all the information available at the point. In case the indications apply to both adults and children, a study could be designed in a way covering both these patient groups. The whole investigation process should be conducted in a way that adequately addresses the data collection for each of the groups, however, the data collected could be extrapolated from one age group to another when such an approach is reasonable based on the nature of the data and other key factors.
In summary, the present FDA guidance highlights the main considerations for clinical studies involving children. The document describes in detail the approach to be applied by study sponsors when developing a study design to ensure the clinical data collected is sufficient to assess the safety and effectiveness of the product in question while also ensuring the clinical benefit for the study subjects involved.
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