The article provides a general overview of the approach to be applied with respect to the review clock in the context of applications for marketing approval. The document also describes the main regulatory actions to be taken by the authority based on the application review, being an approval letter (order) and an approvable letter. The authority explains the difference between the two aforementioned actions and clarifies the way they will impact the review clock.

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 FDA review clock in the context of premarket approval (PMA) applications for medical devices intended to be marketed and used in the US. In particular, the document describes in detail the effect of actions committed by the authority and applicants on the review clock, as well as the respective goals. The document provides an overview of the applicable regulatory requirements, and also additional clarifications and recommendations to be considered by medical device manufacturers and other parties involved in order 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 the existing regulatory framework and has been agreed with the authority in advance. 

Regulatory Background

First of all, the authority mentions that in accordance with the provisions of the Federal Food, Drug, and Cosmetic (FD&C) Act as amended by the Medical Device User Fee Amendments 2022 (MDUFA V), the authority is entitled to collect fees for certain regulatory activities including, inter alia, reviewing premarket approval applications (PMAs). As it is mentioned in the guidance, the funds received in such a way will be used to improve the review regulatory procedures in general and make them more efficient.

According to the document, its scope covers:

  • The different FDA actions that may be taken on premarket approval applications (PMAs);
  • The effect each action has on goals under MDUFA IV (for PMAs received in FY 2018 – 2022);
  • The effect each action has on goals under MDUFA V (for PMAs received in FY 2023 – 2027);
  • The different industry actions that may be taken on PMAs. 


FDA Actions

The authority starts by describing its own actions and the way they will impact the review clock. Depending on the results of its review, the authority may take one of the following actions and issue:

  • An approval order;
  • An approvable letter;
  • A major deficiency letter;
  • A not approvable letter; and
  • Denial order.

The authority also mentions that in the case of real-time supplements, a major deficiency letter is not applicable. All other actions are considered to be “MDUFA decisions” and, consequently, should be measured against the respective MDUFA IV/V goals.

Approval Order 

Should the application submitted by the applicant be approved by the authority, the latter will issue an approval order (letter) notifying the interested party accordingly. Based on this letter, an applicant will be allowed to commence the distribution of a medical device in question and make it available on the US market. The authority will take such a decision provided the below conditions are met:

  • The reasons for denial as set forth under the current regulatory framework are not applicable;
  • It was clearly demonstrated that the medical device subject to review complies with any and all regulatory requirements in terms of safety and effectiveness when used for its intended purpose;
  • Facilities involved in the manufacturing process, as well as all the methods and controls used, are compliant with the Quality System Regulation. 

According to the guidance, an approval letter is a final action that shuts off the review clock since it is taken upon completion of the review. 


Approvable Letter 

In case of minor deficiencies are identified, preventing the authority from issuing an approval letter, an approvable letter will be issued to notify the applicant accordingly and communicate about the needs to:

  • Resolve minor deficiencies identified by the authority in the course of its review;
  • Completion of the appropriate inspection to be conducted by the authority in order to verify compliance with the Quality System (QS) regulation (in such a case, the status of the device in question will be “approvable pending GMP inspection”. 


Once an approvable letter has been issued, the review clock will be stopped, while the application will be placed on hold. The clock will resume once the authority will receive a complete response to the said letter. Under the general rule, the authority will issue its decision within 60 calendar days from the date a complete response was provided by the applicant. 

A similar approach applies in the case of an approvable pending GMP inspection letter. In such a case, an approval letter will be issued once the authority determines that the manufacturing facilities, as well as the manufacturing methods and controls employed by the manufacturer, are compliant with the QS regulation. 

In summary, the present FDA guidance describes the legal background for the review clock in the context of the premarket approval framework and also highlights the key points to be considered by the parties submitting the respective applications. The authority also provides additional clarifications regarding specific actions it may take based on the results of the application review depending on its outcomes. 



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