The new article highlights the aspects related to the actions taken by the applicant and their impact on the review clock and timelines.

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 review clock in the context of Premarket Approval applications (PMAs). In particular, the guidance describes in detail the way various actions performed by both the authority and the applicant will impact the review clock and calculation of the timeframes. 

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 taken into consideration by the 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 legislation and has been agreed with the authority in advance. 

The scope of the guidance covers, inter alia, the actions taken by the interested party applying for marketing approval under the PMA framework, and describes the impact these actions will have over the FDA review clock. According to the guidance, such actions may include the submission of an unsolicited major amendment, submission of a solicited major amendment, submission of a minor amendment, or withdrawal of the application – the latter could be performed either by letter or by not responding to an FDA request. The document addresses each of the abovementioned actions in detail and explains the effect they will have. 

The authority also mentions that in accordance with the respective regulatory requirements, an electronic copy is required for any submission under the PMA framework. 

Unsolicited Major Amendment 

First of all, the guidance provides additional clarifications regarding an unsolicited major amendment, defined as a submission of substantial new data by the applicant, on an applicant’s own initiative, to be added to a pending original or panel-track supplement PMA submission. As further explained by the authority, such a submission could be filed by the applicant in situations when: 

  • There is new test data becoming available to the applicant, or such data appears to be omitted when submitting the initial application, while the data is important in terms of the safety or performance of the device in question;
  • The data obtained by the applicant differs significantly from what was previously available;
  • New validation data obtained by the applicant. 

At the same time, the authority additionally emphasizes that this type of submission should not be used to add new medical device models or components thereof.

Under the general rule, such a submission extends the timeframes for the authority to take a regulatory decision with respect to the medical device subject to review. According to the document, the particular stage of the review process should be taken into account when assessing the impact of an unsolicited major amendment, namely:

  • If submitted before the Substantive Interaction, the appropriate number of days is to be added;
  • If submitted after the Substantive Interaction, the FDA decision goal date is extended by the number of days equal to 75% of the difference between the filing date and the date of receipt of the amendment, i.e., 75% of the FDA days elapsed as of the receipt of the amendment.


Solicited Major Amendment 

Another type of submission described in the guidance is a solicited major amendment which stands for the formal submission of information by the applicant, at the request of the FDA (i.e., in response to a major deficiency or not the approvable letter). As prescribed by the applicable regulations, an applicant will have to submit a solicited major amendment in case of:

  • The authority requesting additional information with respect to the product in question by issuing a major deficiency letter; or 
  • The authority issuing a not approvable letter based on the deficiencies identified in the course of its review. 

According to the guidance, once a solicited major amendment is submitted, the review clock will resume, provided the response is complete and duly addresses all the matters raised by the authority. 

Unsolicited Minor Amendment 

Should the applicant decide to provide clarification with respect to the data submitted previously, or find it appropriate to submit additional information which is minor in its nature, an unsolicited minor amendment should be submitted. In accordance with the existing regulatory requirements, this type of submission will not impact the review clock. 


Response to Interactive Review Request 

According to the guidance, all responses to Interactive Review requests should be submitted via email; however, in circumstances where that is not possible (e.g., due to electronic file size limitations), a response to an interactive review request that is submitted formally will have no effect on the review clock. It is further stated that such a response should be submitted only once. 


Application Withdrawal 

As set forth by the applicable regulations, an applicant is entitled to withdraw an application submitted at any time provided the final decision has not been taken by the authority. This action will result in a review clock being stopped once the appropriate communication is received by the authority since the action is considered final. 

Furthermore, it is important to mention that FDA considers an original PMA or PMA supplement to have been voluntarily withdrawn if an applicant fails to respond to an approvable, major deficiency, or not approvable letter within a total of 360 calendar days. 

In summary, the present guidance describes in detail various actions an applicant may take with respect to the application submitted, and the effect they will have over the review clock. The authority explains the regulatory status of each such action and highlights the key points to be considered. 



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