The article provides an overview of the regulatory requirements related to handling post-approval studies. 

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 procedures for handling post-approval studies imposed by the PMA order. The document is intended to provide additional clarifications regarding the existing regulatory requirements, as well as recommendations to be taken into consideration in order to ensure compliance thereto. At the same time, provisions of the guidance are non-binding in their nature, nor are intended to introduce new rules or impose new obligations, but rather to assist the parties involved. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the respective legislation and agreed with the authority in advance.  


Regulatory Background 

As explained by the authority, the process of review of a premarket approval application (PMA) consists of multiple steps during which the authority will assess whether the medical device in question meets the applicable regulatory requirements for safety and effectiveness. In certain cases, the authority may request post-approval studies (PAS) to be conducted, and this could be a condition for approval. According to the guidance, a PAS is usually a clinical or non-clinical study, as specified in the PMA approval order, as is typically intended to gather specific data to address questions about the postmarket performance of or experience with an approved medical device. The present guidance also refers to another guidance document issued by the authority – Balancing Premarket and Postmarket Data Collection for Devices Subject to Premarket Approval – which states that FDA may consider it acceptable to collect certain data in the postmarket setting, rather than premarket under certain circumstances when FDA has uncertainty regarding certain benefits or risks of the device, but the degree of uncertainty is acceptable in the context of the overall benefit-risk profile of the device at the time of premarket approval. 

Thus, the present guidance is intended to assist medical device manufacturers and other parties interested in placing medical devices on the US market in fulfilling the requirements related to PAS in the context of the PMA approval process. For this purpose, the document provides:

  • Additional information regarding the procedures,
  • Recommendations to be taken into consideration with respect to the format and content of the appropriate submission,
  • Recommendations intended to simplify and accelerate the application review process in the part related to PAS,
  • Recommendations to be taken into consideration with respect to studies themselves, 
  • Details about PAS status categories, and 
  • Updated timeframes the authority applies when reviewing submissions related to PAS. 

However, as it was mentioned before, provisions of the present guidance are non-binding and are intended merely to assist with the interpretation of the underlying regulations and following the requirements prescribed therein. 

According to the document, an internal tracking system for the PAS Program has been established by the authority earlier in 2006. Later the authority has also taken additional steps in order to improve transparency and related procedures in general. For instance, a separate webpage was created for the Post-Approval Studies Program Database. The said database contains the most important details about each study including general information, general and detailed PAS protocol parameters, interim or final data summary, the sponsor’s progress or “study status,” and reporting information. Furthermore, the authority may issue additional updates to be communicated to study sponsors and other parties involved. 

As summarized by the authority, the PAS program initiatives are intended to assist in ensuring that:

  • Sponsor conducts PAS that use valid scientific methodologies in the study design;
  • Least burdensome approaches, including use of relevant and reliable real-world data (RWD), are followed when designing and conducting a PAS, as appropriate;
  • Sponsors provide PAS results at intervals specified in the approval order;
  • FDA provides timely notification to sponsors regarding their PAS status; and 
  • FDA posts PAS information publicly and, in situations where the legal criteria are met, undertakes regulatory actions such as withdrawal proceedings by section 515(e) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360e(e)) and 21 CFR 814.46. 

Post-Approval Study Requirements in PMA Approval Orders

The guidance further describes in detail the way post-approval study requirements should be included in PMA approval orders in case of conditional approval. According to the document, such an order should outline the key information about the requirement imposed by the authority, including the reasons behind it, the number of patients to be involved, as well as the reports the authority expects to receive. In particular, for each study to be conducted by a party responsible for a medical device, the authority will specify the main details, including the study design and objectives, the target population, as well as the length of follow-up, and the data analysis plan. Furthermore, the authority may also provide the timelines to be followed, including the study and reporting timelines. 

The FDA also encourages study sponsors and other parties involved to get in touch and collaborate in situations when post-market approval studies are required as an approval condition. The scope of such collaboration should cover all the important matters related to the study, including its objectives and timelines. 

Based on experience with studies of this type, the authority recommends the following enrolment milestones to be calculated from the study protocol approval date:

  • First subject enrolled within 6 months;
  • 20% of subjects enrolled within 12 months;
  • 50% of subjects enrolled within 18 months; and 
  • 100% of subjects enrolled within 24 months. 

As it is stated by the FDA, the use of the above milestones will contribute to the successful completion of a study.

In summary, the present FDA guidance describes in detail the requirements to be applied for post-approval studies that are requested as a condition for approval of a premarket application. The document outlines the scope of information about the study to be included in the respective PMA approval order and also highlights the key points to be considered by medical device manufacturers, study sponsors, and other parties involved. 



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