FDA Finalizes Premarket Pathway Guidance for Combination Products | Hogan Lovells

Recently, the Office of Combination Products (OCP) of the United States Food and Drug Administration (FDA) published final direction “Principles of Premarket Pathways for Combination Products,” which provides current high-level FDA thinking on ways to market combination products. reflecting the orientation project published in February 2019, the final guidance provides further emphasis and clarification, including the same five detailed circumstances when these pathways apply.

Final guidelines are being released as the FDA seeks to implement the 21st Century Cure Act (Cures Act) as the agency wishes to uphold its commitment to transparency, efficiency and regulatory consistency to facilitate the development of safe and effective combination products. The guidelines outline CDER, CBER, and CDRH premarket submissions and their respective submission processes for combination products associated with each specific exam center and pathway.

As in the draft, the final guidance addresses the following:

  • definition of combined products under 21 CFR 3.2(e)
  • jurisdictional allocation of combination products to agency centers
  • the approval pathways available for device-based, drug-based, and biologic-based combination products, and considerations for determining those pathways
  • safety and efficacy data and information that sponsors must offer, depending on the pathway

Other key questions from the draft reappear in the final guidance:

  • “A single application is generally appropriate for a combination product”, but “may not be appropriate in limited cases”. With that in mind, the FDA is seeking comments on when two applications — one to the primary jurisdictional agency center and one to the non-primary center — should be submitted.
  • FDA’s OCP directs centers to coordinate applications for combination product approval, “including ensuring that agency components and personnel coordinate appropriately during pre-marketing review. commercialization of these products, and that the thinking of the agency is aligned in conducting these reviews”. This may suggest an internal FDA view that centers have not been fully aligned in reviewing submissions, and it may indicate greater OCP involvement, both to encourage strong involvement throughout the agency and to arbitrate the resulting conflicts.
  • The FDA specifically addresses an issue that may have been misunderstood and inconsistently applied, stating that “the data and information necessary to answer questions of safety and efficacy related to the non-lead constituent part of a combination product may differ from the data and information needed to obtain marketing authorization for this item as a stand-alone product that is not part of a combination product.

However, in the final guidelines, the FDA added the following additional elements:

  • The FDA specifically states that while sponsors may propose the classification and/or assignment they believe should apply for a pre-RFD, and must do so for an RFD, the OCP makes the final decision based on the components. relevant to the agency.
  • “Cross-labeled combination products for which separate marketing authorization is sought for the components (e.g., a New Drug Application (NDA) for the drug and a Premarket Notification (510(k)) for the device) may raise separate considerations.Prior to the filing of separate marketing authorization applications, all interactions with the FDA must go through the primary center for these combination products, regardless of the comments requested.
  • The guidelines ensure that in conjunction with OCP, if necessary, meetings between FDA and sponsors are attended by review staff at each center, as appropriate in light of the topics and purpose of the review. meeting, and that counseling centers complete their reviews in a timely manner.
  • The guidelines emphasize the importance of combination products being identified on the appropriate form or document: FDA Form 1571, INVESTIGATIONAL NEW DRUG APPLICATION; FDA Form 356h, APPLICATION FOR MARKETING A NEW DRUG OR NEW OR ABRIDGED BIOLOGICAL PRODUCT FOR HUMAN USE; or in the cover letter of a pre-investigational new drug application (IND), investigational device exemption (IDE) application, Q submission, 510(k) submission, a premarketing approval (PMA) request and/or a request for classification submitted under section 513(f)(2) of the FD&C Act (De Novo request).
  • Current FDA thinking is that a single application would generally be appropriate for a combination product, to streamline regulatory interactions with the agency and avoid unnecessary duplication that can occur with multiple applications.
  • For De Novos, understanding the biologic product or drug components, including the limitations of such understanding, should be considered when determining the suitability of the De Novo pathway for these combination products directed by a device.

In general, the final guidelines are consistent with existing practice regarding central jurisdiction and escalation processes for combined products. In the Appendix of Examples, for example, the FDA reiterates the existing approach when a 510(k) is not an available route to market, but the agency does not suggest a mechanism for determining the appropriate route in these circumstances, leaving significant leeway to the FDA. discretion.

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