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New FDA Draft Guidance Clarifies Postapproval Modifications Process for Combo Products

Posted 22 January 2013 | By

A new draft guidance published by the US Food and Drug Administration (FDA) intended for its staff provides a framework for postmarket modification submissions for combination products originally approved under a new drug application (NDA), biologics licensing application (BLA) or a premarket approval application (PMA).

Though combination products may include any combination of pharmaceutical, medical device or biological products, they are generally regulated as a single product submission under one form-either an NDA, BLA or PMA (for new or novel products)-and understood to have a primary mode of action (PMOA) that determines which center regulates it. That submission must contain all information necessary to support an approval decision from any center involved in its review.

FDA's regulations and various guidance documents provide a thorough framework describing the standards that must be met by companies submitting applications for combination products, but they are considerably less descriptive regarding how to submit for a change to a constituent part of an approved combination product, FDA conceded.

A Tricky Problem: Which Form to Use?

Despite a combination product being essentially one product, it is still reviewed as being two or more technically separate constituent parts, each retaining its own regulatory identity as a drug, device or biologic. Accordingly, if any changes are made to one constituent part that would require a postmarket submission were it its own product, the entire submission requires the same postmarket submission.

But therein lies the problem, says FDA.

Consider a company with a drug-eluting stent that is regulated as a pharmaceutical product because its PMOA is the drug, requiring an NDA. Consider for the sake of argument that the stent is novel enough on its own to require a PMA. If that company were to make changes to the stent itself-a medical device-would it submit the changes as a PMA, or as an NDA?

Existing guidance and regulations provided little in the way of guidance for companies grappling with this issue, and FDA said its new guidance is aimed at clarifying this conundrum.

A Clear Framework

The draft guidance establishes a four-part process for determining which type of submission to provide for a postmarket change.

First, companies should identify the type of application used to gain initial approval for the combination product. Second, they should identify the type of application that would ordinarily have been submitted to FDA for the modification for the constituent part if it were a stand-alone product.

If these submission types are the same, the sponsor should submit that application type to the appropriate regulatory center.

If the submission types are different, a new set of criteria applies-one extensively laid out in a series of tables in the guidance.

The guidance generally advises sponsors to adhere to the type of submission originally made to its respective centers. If, for example, a drug-device combination product approved under an NDA had changes made to its medical device constituent part such that it would ordinarily require a PMA submission, the sponsor should submit to FDA an NDA. Similarly, a drug-device combination product approved under a PMA would require submission of an PMA if changes made to the constituent drug part would ordinarily have required an NDA.

Supplements, such as panel-track, 180-day, prior approval (efficacy/manufacturing) or real-time supplements, follow a similar logic, FDA wrote.

Communications and Caveats

Though the guidance covers and defines many of the changes that could be made, it also calls on sponsors to communicate with FDA to determine the appropriate submission forms, particularly if a product is one that exhibits "added complexity."

"FDA encourages applicants to anticipate the type of postapproval changes that they wish to make and to develop protocols to help establish comparability of the modifications in methodology or products to the original approved combination product," the agency wrote. "Further, FDA encourages industry to discuss with FDA the type of information that may be necessary to address the change to the constituent part, including whether and how this change may affect the other constituent part(s) and the combination product as a whole; and any alternative approaches for submission types the applicant may propose."

These communications should generally be made in the form of a meeting, it added.

The guidance does not address changes made through other application types, such as a 510(k) premarket notification, an abbreviated new drug application, a 351(k) biologics licensing application for biosimilar products or over-the-counter (OTC) products cleared through a monograph process. It is unclear whether these changes would be addressed in a follow-on, separate guidance.

Read the full draft guidance: Guidance for Industry and FDA Staff: Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA

Read the Federal Register notice: Draft Guidance for Industry and Food and Drug Administration Staff; Submissions for Postapproval Modifications to a Combination Product Approved Under Certain Marketing Applications; Availability

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