The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document describing in detail the acceptance review for the requests submitted under the De Novo classification process. Due to its legal nature, the document does not introduce new regulatory requirements itself but provides additional clarifications and recommendations to be considered by medical device manufacturers intended to submit a De Novo request concerning a medical device they are responsible for. The authority also mentions that an alternative approach could be applied, provided such an approach complies with current regulatory requirements and has been agreed with the authority in advance.
As it was mentioned before, once a De Novo request is received, the Agency shall conduct an acceptance review to determine its completeness and admissibility for further substantive review. Such an assessment should be carried out within 15 calendar days from the date the appropriate request has been received by the Agency. In particular, at this stage, the lead reviewer should fill in the Acceptance Checklist containing the question to be checked first. As it is stated by the FDA, the way these questions are answered would determine the process to be performed. For instance, in case upon answering the questions the lead reviewer will determine that the appropriate review procedure should not be continued, the applicant should be duly notified by the respective procedure.
The document further provides a list of preliminary questions and describes each of them in detail. These questions are:
- Is the product a device (per section 201(h) of the FD&C Act) or a combination product (per 21 (CFR 3.2(e)) with a device constituent part subject to review in a De Novo request? Should it be identified that the product subject to review falls outside the scope of the definition of a medical device, the review should be stopped, and the applicant should be informed accordingly.
- Is the De Novo request with the appropriate Center? Should it be identified that the particular Center the De Novo request has been submitted to is not the one that should be responsible for a product in question, the review process should be stopped as well, and the appropriate notification should be provided to the applicant.
- If a Request for Designation (RFD) was submitted for the device or combination product with a device constituent part and assigned to your Center, identify the RFD# and confirm the following: (1) Is the device or combination product the same (e.g., design, formulation) as that presented in the RFD submission? (2) Are the indications for use for the device or combination product identified in the De Novo request the same as those identified in the RFD submission? The authority states that an RFD is closely connected to the medical device it is submitted for, hence, in case of changes to the device implemented after the RDF determination, the latter should not be applied.
- Is the De Novo request for a combination product that contains as a constituent part a drug that has the same active moiety as an approved drug with exclusivity as described in section 503(g)(5)(C)(ii)-(v) of the FD&C Act? According to the guidance, should it be identified that the product subject to review is a combination product containing medicine that has been already approved, the person responsible for review should contact the appropriate Center to decide on further steps to be taken.
- Is this device type eligible on its face for the De Novo classification? The authority additionally emphasizes the importance of determining the eligibility of a medical device in question for review under the De Novo pathway. For instance, should it be identified that there is a similar medical device already placed on the market, that could be referred to as a predicate, of the device of the same type has been approved under the PMA framework, this could create grounds for arguing the eligibility of a medical device for the De Novo classification. However, the scope of this question does not cover the cases when the ineligibility could be determined only in the course of the following substantive review. Should the Agency find the device subject to review as ineligible, the decision to refuse should be made. At the same time, the authority mentions that in a case similar requests would be submitted by different medical device manufacturers, this would not automatically result in refusing any of the requests.
- Is the requester subject to the Application Integrity Policy (AIP)? Should it be identified that the applicant is included in the AIP list, the person responsible for review should contact the appropriate Center to decide on further actions.
Acceptance Review Checklist in Detail
Apart from the key questions described hereinabove, the document also highlights other important aspects to be taken into consideration by medical device manufacturers intended to submit a De Novo request. These aspects include, inter alia, the following ones:
- A De Novo request should contain all the elements necessary for the FDA to proceed with the substantive review.
- When proceeding with the Acceptance Checklist, the responsible person should answer “Yes”, “No”, “Not applicable”, or provide a more detailed response if it is necessary due to the nature of the question itself.
- The Acceptance Checklist was initially designed to cover the widest scope of devices possible. Hence, in the case of a particular medical device, some of the questions should be determined as “Not applicable”.
- The Agency explicitly states that when ticking the boxes in the Acceptance Checklist, the responsible person would just assess the completeness of the application, but not the completeness of the particular documents submitted, while the completeness of the documents themselves should be assessed in the course of the substantive review to be carried out once the acceptance review is completed successfully.
- When some of the questions are answered “No”, the Agency will provide the appropriate clarifications to the applicant to describe the documents needed, and the information they should contain.
Additionally, the guidance addresses such issues as:
- Combination product administrative items,
- De Novo requesters of combination products that do not contain as a constituent part an approved drug (and the ones that contain as well);
- Is there an open or pending premarket submission or reclassification petition for the same device with the same indications for use?
- De Novo request is for a single device type;
- Prior submission(s) relevant to the De Novo request under review.
In summary, the present FDA guidance covers the most important points related to the acceptance review to be carried out under the De Novo classification framework. The document describes in detail the questions included in the Acceptance Checklist the authority will use to examine a new De Novo request.
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