The new article highlights the key points related to the study objectives and subject selection in the context of pivotal clinical investigations. 

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 design considerations for pivotal clinical investigations for medical devices. The document describes in detail the principles for the choice of clinical study design and also outlines the most important aspects to be considered. It is important to mention that provisions of the guidance are non-binding, nor are intended to introduce new rules or impose new obligations, but to provide additional clarifications for the applicable regulations, as well as recommendations to be followed by the parties involved to ensure compliance thereto. The authority additionally emphasizes that an alternative approach could be applied, provided such an approach is in line with existing legislation and has been agreed with the authority in advance. 


Study Objectives 

According to the guidance, the study objectives provide the scientific rationale for why the study is being performed, as well as support for the intended use of the device, including any desired labeling claims. As further explained by the FDA, any claims made for the device, its functions, safety, and performance should be duly backed by the testing results. In case a pivotal clinical investigation is conducted to test a scientific hypothesis, these objectives should also contain statements regarding the alternative hypotheses related to any of the claims made by the manufacturer. At the same time, if the study is intended to assess the actual performance of a medical device in question, the claims made concerning the performance of the product should be supported by the estimates.

Subject Selection: Key Points 

Another important aspect addressed in the guidance is an approach to be applied when selecting study participants (subjects) to be involved in a pivotal clinical study. By the applicable legislation, namely, 21 CFR 860.7(f)(1)(ii), there are specific requirements a selection method used should meet. In particular, the plan of a study or its protocol should include a method of selection of the subjects that: 

  1. Provides adequate assurance that the subjects are suitable for the intended purposes of the study, provides diagnostic criteria of the condition to be treated or diagnosed, provides confirmatory laboratory tests where appropriate, and, in the case of a device to prevent disease or condition, provides evidence of susceptibility and exposure to the condition against which prophylaxis is desired. 

As further explained by the FDA, the study selection should be adequate in terms of representing the population the device in question is intended to be used for following the respective enrolment criteria and non-clinical testing conducted before initiating a pivotal clinical investigation. In this respect, the authority also mentions that the studies for which the participants are not representative of the target audience could have issues with the accuracy and reliability of the results. To avoid such situations and prevent bias, the protocol should specifically define eligibility criteria that match the key characteristics of the intended target population. When conducting an investigation, a responsible party should make sure that all individuals involved meet the said criteria, i.e., inclusion/exclusion criteria. Furthermore, the individuals involved should be represented in terms of demographics. If one of the groups would not duly be presented, this could affect the decision the authority will make on whether the information provided is sufficient. The authority also encourages the parties responsible for clinical investigations to include a summary of discussions regarding the scope of study subjects to be involved together with the protocols and training materials used by investigators. The same approach should be applied to clinical studies conducted abroad, in case the data collected during such studies is used to support the application for marketing approval in the US. It is also important to mention that in the case the study design provides the involvement of vulnerable groups (e.g., pregnant women or children), the authority may ask to discuss the related matters in advance, before the commencement of a study. 

When planning a study, its sponsor should take into consideration all the information that could be useful and can improve its conduct. This includes the most important factors, such as disease severity or age of study participants. 


Selection Methods

According to the document, a clinical study protocol may include one of the following methods to be used to select study participants: 

  • Random selection is when all subjects have a known (usually the same) chance of being selected for the clinical study.
  • Consecutive selection (selecting every subject in the order they present at the site) or systematic selection (selecting every tenth subject) among the ones who meet the general inclusion/exclusion criteria. The said methods ensure an unbiased approach towards the selection of study participants, which is important to ensure the accuracy and reliability of the study results. 
  • Convenience selection stands for a method where subjects are selected because of their convenient accessibility to the researcher. The authority additionally emphasizes that in situations when such a method is used, the results cannot be generalized to the target population. 

In summary, the present FDA guidance outlines the main criteria to be taken into consideration for the methods used to select study participants. For instance, the authority explains the way the selection methods should be applied depending on the target population indicated by the medical device manufacturer. The document also describes the key concepts related to the study objectives. 



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