The article provides an overview of the regulatory policy for pivotal clinical investigations in terms of design considerations. 

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 is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered by medical device manufacturers, study sponsors, and other parties involved to ensure compliance thereto. At the same time, provisions of the guidance are non-binding in their legal nature, 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 existing legislation and has been agreed with the author in advance. 


Regulatory Background 

The guidance addresses the matters related to clinical studies conducted to collect clinical evidence further used to substantiate the claims made by medical device manufacturers in the context of applications for marketing approval. At the same time, the authority additionally emphasizes that the present document does not provide exhaustive guidance on the way the party responsible for a clinical study should determine the approach to be applied, but rather describes different study design principles relevant to the development of medical device clinical studies that can be used to fulfill pre-market clinical data requirements. 

Under the general rule, the clinical development process for medical devices could be divided into three main stages that are closely related to each other, so a rigorous evaluation conducted on one of the stages could accelerate and simplify the further review process. According to the guidance, the very first stage is an exploratory clinical stage during which the limitations and advantages of the medical device are evaluated; this stage includes first-in-human studies and feasibility studies. At the next, pivotal stage, attention should be paid to the information related to the safety and effectiveness of a medical device in question when used for its intended purpose. At this stage, one or a few pivotal studies could be conducted. The final, post-market stage covers certain additional studies carried out to address specific issues related to the safety of a medical device or its effectiveness in the long-term perspective. The scope of the present document covers the aspects related to pivotal clinical investigations (second stage), while the matters related to other stages are falling outside the scope of the present guidance. 

According to the guidance, a medical device pivotal study is a definitive study in which evidence is gathered to support the safety and effectiveness evaluation of the medical device for its intended use; while evidence from one or more pivotal clinical studies generally serves as the primary basis for the determination of reasonable assurance of safety and effectiveness of the medical device of a pre-market approval application (PMA) and FDA’s overall benefit-risk determination. The authority also mentions that if necessary, several studies could be carried out in the context of a pre-market approval application to address multiple scientific questions. 

By the virtue of the present guidance, the authority intends to provide recommendations to be taken into consideration for the design of clinical investigations carried out to support premarket approval applications. At the same time, the key principles described in the guidance could also be applied to other types of submissions, e.g., pre-market notification (510(k)) and De Novo requests – a special type of submissions used in case of novel medical devices having no analogies already placed on the market. As explained by the FDA, this guidance describes principles for the design of pre-market clinical studies that are pivotal in establishing the safety and effectiveness of a medical device and covers the most important aspects related to pivotal clinical studies, together with the way their results could impact the regulatory decision-making process. The said principles should be considered to ensure that any matters that are important in terms of medical device safety and effectiveness are duly addressed. 

Types of Studies 

The document further describes the main types of studies covered by its scope. For guidance, all medical devices are divided into two main categories: 

  • Therapeutic and aesthetic devices; and 
  • Diagnostic devices. 

The recommendations provided in the guidance could be applied to products related to both aforementioned categories. On a side note, the authority also encourages the parties responsible for clinical studies to get in touch with FDA and request case-specific recommendations and guidelines. 

It is important to mention that the scope of the guidance also covers the matters related to the device part of combination products, while the matters related to drug and biological parts are falling outside the scope of the present guidance. 

It is further stated that recommendations provided in the guidance should be taken into consideration in connection with the ones provided in other guidance documents issued by the FDA, the document is also not intended to replace any of the existing guidance documents related to similar matters. 

The authority also outlines the types of studies falling outside the scope of the guidance. According to the document they include, inter alia, the following ones:

  • Non-clinical studies; 
  • Studies intended to support Humanitarian Device Exemption (HDE) applications;
  • Pre-market feasibility clinical studies, or other pre-market clinical studies that are not part of the pivotal stage;
  • Studies to establish the clinical validity of companion diagnostic devices;
  • Post-market clinical studies;
  • Studies of products regulated by CBER that require an Investigation New Drug application and Biologics License Application, such as donor screening tests, are not included in the scope of the guidance. 

In summary, the present guidance describes the approach to be applied for the design of pivotal clinical studies carried out to collect additional information necessary to substantiate PMA submissions. By the virtue of the guidance, the authority provides recommendations to be taken into consideration for certain types of clinical studies. 



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