The article provides the details regarding the review process and the key points to be considered in this respect.
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 and inspection of premarket approval (PMA) applications in terms of manufacturing information and operations. The document provides additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be taken into consideration to ensure compliance thereto. At the same time, provisions of the guidance are non-binding, 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 authority in advance.
In particular, the scope of the guidance covers, inter alia, the aspects related to the review process.
Review Process: Key Points
As explained by the FDA, the premarket review process begins when the applicant submits six copies of a fileable PMA or three copies of a fillable PMA supplement to the CDRRH Document Mail Center (DMC) in ODE. Once the application is received, the appropriate body will review the details related to the manufacturing of the product in question and request an inspection, should such an inspection be reasonably needed to collect additional information. The authority also mentions that according to the existing regulatory framework, an applicant is allowed to indicate several manufacturing facilities located both in the US and abroad. Once the inspection has been completed, the reviewing body will also analyze the information collected in the course of such an inspection and make recommendations concerning the status of the quality system (QS) for the facility subject to review.
Thus, the purpose of the present guidance document is to provide additional details regarding the way the authority will review the submission, including the applicable timeframes. The authority also mentions that in case of deficiencies identified, additional review cycles may be required, and this will make the overall process more lengthy. Apart from this, the document provides a detailed flowchart describing all the steps of the review process.
Procedures Undertaken by the FDA
First of all, the authority describes the specific steps it will take once the PMA application is received. According to the guidance, the authority completes the following steps:
- Logs in and tracks the submission;
- Assigns due dates for the CDRH offices based on the date of receipt, e.g., 180 days after receipt;
- Alerts the ODE Program Operations Staff (POS) of the incoming PMA;
- Sends one complete copy of the PMA to OC Field Operations Branch (OC/FOB) within 7 calendar days for a receipt;
- Files one copy in the DMC;
- Further processes the application administratively, prepares a transmittal cover sheet, and forwards the document to the appropriate ODE review division or OIVD.
The FDA further describes in detail the steps to be taken by OC/FOB once the copy of the application is received and also specifies the review timelines based on the type of application, which is the following:
- For Non-Expedited Traditional PMA – 30 calendar days;
- For Expedited Traditional PMA – 20 calendar days;
- Non-Expedited Modular PMA – 30 calendar days when submitted with the final module; up to 90 days if submitted before the final module;
- Expedited Modular – 20 calendar days when submitted with the final module; up to 90 days if submitted before the final module;
- 180-Day Supplement – 30 calendar days;
- Amendment – 20 or 30 calendar days depending on the type of PMA amended.
Finalizing the Review: Conclusions
The authority also describes the steps to be taken upon conclusion of the review. According to the guidance, once the review of the manufacturing information included in the PMA application has been completed, the reviewing body may take one of the two decisions:
- Confirm that the manufacturing section is acceptable; or
- If there are deficiencies identified – notify the applicant accordingly by issuing the appropriate deficiency letter, and also requesting additional details to be provided to the matters highlighted in the said letter.
The body will also determine whether an inspection is to be conducted to collect additional information.
Should it be identified that some of the vitally important details are missing, the manufacturing information section of the PMA application will be deemed incomplete. In such a case, as was mentioned before, a deficiency letter will be issued to the applicant, outlining the information to be provided. As further explained by the FDA, some minor issues could be fixed on the go. However, for certain requests, additional time could be required to prepare a response and provide it to the FDA. It is also important to mention that submission of a response to a deficiency letter will begin a new 20, 30, or up to 90-day manufacturing section review time frame depending on the type of application.
Should it be decided that the manufacturing section is complete (no deficiencies or all the deficiencies identified have been duly addressed on spot), the reviewing body will also assess the documentation related to the initial inspection conducted by a local body. In certain cases, an additional domestic/foreign inspection could be assigned.
The authority additionally emphasizes that the applicant the PMA should be ready for inspection at any point in time. However, the respective body of the regulating authority will contact the applicant and notify them about the upcoming inspection in advance. In response, the applicant should confirm the readiness for inspection. It is also important to mention that in case of major deficiencies identified, an already scheduled inspection could be canceled.
In summary, the present FDA guidance highlights the key points related to the PMA application review in terms of manufacturing information. The authority explains the way the respective section will be reviewed, and also outlines the regulatory actions and decisions that can take place in the course of the review process.
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