The new article highlights the aspects related to the cases when the authority takes negative decisions with respect to the application submitted, the applicant decides to withdraw the application itself, as well as the key performance goals.

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 and goals in the context of premarket approval applications (PMAs). In particular, the document describes in detail the impact different actions of both the authority and the applicant would have on the review clock. 

It is important to mention that FDA guidance documents are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations, but rather to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be followed by medical device manufacturers and other parties involved in order to ensure compliance thereto. 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. 

Not Approvable Letter 

First of all, the document describes not approvable letter and the consequences of it being issued by the authority. According to the guidance, by issuing a not approvable letter, the authority informs the applicant that it has completed its review and … do not believe that the application can be approved because of significant deficiencies which would be described in detail in the letter itself. In particular, the authority will provide clarifications regarding each of the points why the application cannot be approved, and also outline the measures to be taken by the applicant to make the submission acceptable. 

It is also important to mention that before issuing a not approvable letter, the authority will start with issuing a major deficiency letter, providing an applicant with an opportunity to address the key concerns the authority has. Should the applicant fail to respond properly to the said latter, or should the attempts to resolve the respective deficiencies in the course of interactive review fail, a not approvable letter will be issued by the authority. 

According to the guidance, once a not approvable letter is issued by the authority, the review clock should be stopped, and the application should be placed on hold. Upon receipt of a complete response provided by the applicant, the authority will resume the review clock with the timeframes to be calculated from the very beginning. As it is mentioned in the guidance, the authority intends to review such a response within 180 calendar days from the date it was received from the authority (even though this should not be construed as a performance goal). 


Denial Order 

Should the authority determine that the application should be denied, the appropriate letter will be issued and provided to the applicant. According to the guidance, the denial order will identify all deficiencies in the application, including each applicable ground for denial under section 515(d)(2) of the FD&C Act and, where practical, will identify measures required to place the application in approvable form (21 CFR 814.45). It is also stated that such an order will also include a notice of an opportunity to request review under section 515(d)(4) of the FD&C Act. In accordance with the current regulatory framework, the authority may decide to deny an application due to any of the reasons set forth under the applicable legislation. 

Once a denial order has been issued, the review clock will be shut off. However, as explained by the authority, in most cases it will be already stopped by a previous action performed by the authority (e.g., issuing a not approvable letter). At the same time, in certain cases, the authority is entitled to proceed directly with the denial order, which is considered a final action. 

Acknowledgment of Voluntary Withdrawal 

In accordance with the current legislation, an applicant may withdraw the application it has submitted under the PMA framework. Furthermore, under the PMA regulation, FDA considers an original PMA or PMA supplement to have been voluntarily withdrawn if an applicant fails to respond to an approvable, major deficiency, not approvable, or not filing letter within 180 calendar days (21 CFR 814.44(g)). As mentioned in the guidance, the authority intends to provide one 180-day extension, which will be granted automatically without any actions to be taken by the applicant. Thus, the overall response timeframe will constitute 360 calendar days. Once the said period expires, the authority will issue a letter acknowledging the voluntary withdrawal of the PMA or PMA supplement. Consequently, any submission provided by the applicant upon expiration of the said period will constitute a resubmission, so the general rules for new submissions would apply accordingly, including the review fee payable by the applicant. 


PMA Performance Goals for MDUFA IV

The document also outlines the key performance goals set forth under MDUFA IV in the context of the PMA framework. Some of them were initially introduced by MDUFA III and are retained in the later version, while the others are new, namely:

  • For submissions that require Advisory Committee input, FDA will issue a MDUFA decision within 60 calendar days from the Advisory Committee recommendation, as resources permit, but not to the detriment of meeting the quantitative review timelines and statutory obligations; and
  • For submissions that receive a MDUFA decision of Approvable, FDA will issue a decision within 60 calendar days of the sponsor’s response to the approvable letter, as resources permit, but not to the detriment of meeting the quantitative review timelines and statutory obligations. 


In summary, the present FDA guidance describes in detail the actions the authority may take with respect to the application submitted under the PMA framework in the context of their impact on the review clock. The document also outlines the main performance goals set forth under MDUFA IV. 




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