At the Xavier Health Combination Products Summit in mid-September at Xavier University in Cincinnati, Ohio, FDA Office of Combination Products (OCP) Associate Director for Policy John Barlow “Barr” Weiner presented an overview of OCP’s current rulemaking and guidance priorities and discussed the status and agency rationale for each initiative, beginning with the long-awaited OCP guidance on postmarketing safety reporting that was just finalized in July.

Current OCP Policy Priorities

Postmarketing Safety Reporting (PMSR) Guidance and Implementation

Weiner characterized the “Postmarketing Safety Reporting (PMSR) for Combination Products” guidance as the “biggest issue” OCP has been dealing with.

“We have worked a lot with industry on this,” he explained.  “We are in the implementation phase.  The final rule came out in late 2016.” 

The 44-page guidance addresses how combination product makers can comply with the 2016 final rule.  The final PMSR guidance has been eagerly anticipated by the industry since concerns emerged with the draft version published in March 2018 with a compliance date of July 2019.

The compliance enforcement deadline for most products has now been pushed back from July of this year to July 31 of next year, and to January 31, 2021 for companies reporting using the Vaccine Adverse Event Reporting System (VAERS).  “We understand that there is more time needed to make sure industry can properly stand up the IT systems and control procedures to do it right and in an aligned way,” Weiner said. “We think that is important.”

“There is a lot of work for us to do internally as well.  So in addition to issuing a final guidance we have also been working on internal procedures and training to ensure that we are fully up and running and ready to go for what will presumably be a higher flow of certain types of reports once the rules are being fully enforced.” 

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Amending Request for Designation (RFD) Process

Next on the OCP official’s list is the final rule to amend Part 3 that deals with the classification and assignment of medical products.  The effort is specifically on the Request for Designation (RFD) process. This proposed rule aims to clarify the scope of the regulation, streamline and clarify the appeals process, align the regulations with more recent legislative and regulatory measures, update advisory content, and otherwise clarify the regulation.

“This is an effort to clean that rule up,” he explained.  “It has been around for a long time.” The RFD process in 21 CFR Part 3 section 3.7 was last amended in 2005.  “Statutory law has changed. Agency policy has evolved. We are trying to make it easier to understand how we do business so you can use our processes more effectively.”

New and Finalized Guidance Documents Are in Progress

Weiner provided brief updates on two guidance documents the agency has yet to release and more detailed discussion of two drafts it is working to finalize.

The first one he discussed is a guidance on premarket pathways.  A draft was published in February and OCP is working to incorporate feedback it received and finalize the guidance.  The guidance focuses on two main topics.

“One is a fairly high-level explanation of how we think things should be done in terms of how we approach and coordinate regulation of combination products principally in the premarket context, although it contains some broader principles as well,” Weiner said.

“There is not a lot that is new in that discussion.  But it is the first time it has been all put together in one place.  It will be a useful reference once it is final that will allow you to see how we really think about this area.  It provides a framework or directional tool that elaborates on how we go into more in-depth or specialized guidance and policies and activities.”

The other major section of the guidance details what pathways are available to industry for a combination product based on the kinds of questions the product raises.  Weiner characterized that section of the guidance as “a really useful tool” but “fairly high level.” He anticipates based on the feedback OCP has gotten from companies and from trade associations that it will continue to produce guidance on issue-specific, product-specific topics, “where we can get more into the weeds.”

The bridging guidance has been a priority for industry “for a while,” Weiner said.  He noted that while CDER is leading the effort, OCP is a very active participant working to help get the draft guidance out.  “I will not say much since it is a draft and it is not even out yet, but it will address how we are approaching the bridging question and what you can bridge when.” 

The draft guidance on human factors from 2016, “Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development” is being finalized, the OCP official said.  “We hope to have the final guidance done this year, but we will see. We have been working on it for a while, and I think it is pretty close.”

The pre-submission procedures draft guidance is a mandate from the 21st Century Cures Act, Weiner explained, and should be released this year.  The Act passed by Congress on December 13, 2016 is “designed to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently,” according to FDA.  It authorized $6.3 billion in funding, mostly for the National Institutes of Health, and includes a number of agency mandates.

One of the mandates gives FDA four years (until December 13, 2020) to issue guidance that lays out, among other things, a “structured process for managing pre-submission interactions with sponsors developing combination products and best practices for ensuring that the feedback in such pre-submission interactions represents the Agency’s best advice based on the information provided during such pre-submission interactions.”

Q&A Focuses on Human Factors and Compliance

During the Q&A after Weiner’s presentation, questions posed to him focused on clarification regarding various human factors guidance documents and agency enforcement actions in the combination products area.

Q:  One audience member said, “One of the priorities I saw listed was for the human factors final guidance.  At this point there are several draft guidance documents that are out. I was wondering if you could comment on your approach.  Is it to have a comprehensive human factors guidance, or are you going to finalize one or more of the existing guidance documents?”

A:  Weiner responded, “I was focusing more on the combination products human factors guidance, and the guidance for generic drug-device combination products.  But there are others, including one that CDER is working on, which is a separate activity and deals with different issues. I do not know where that one stands.  The one I do know about is the human factors guidance on combination products, which has been out in draft for a while.”

He explained that there is other work being done on human factors, including how the agency centers work together and coordinate their efforts, “which is one of the primary concerns industry has been raising during both the 21st Century Cures Act and PDUFA [Prescription Drug User Fee Act] public discussions.  We are working on making sure we have clear procedures for when consultations should occur, that we have the correct expertise to deal with the human factors questions, and that we take the same approach to the same types of questions across products.”

Q:  Another audience member asked Weiner to comment on any recent enforcement-related actions for 21 CFR Part 4, regarding both PMSR and CGMP.

A:  “To be clear,” Weiner emphasized, “on the PMSR side there should be no enforcement actions because we said we will not be enforcing it until July of next year. If anyone is getting enforcement actions for PMSR, give me a call.”

On the GMP side, Weiner said there have been a few warning letters, “but nothing I would call super exciting in terms of things that would be surprising.”

He mentioned two recent FDA warning letters to combination product manufacturers.  One was an issue with a company implementing its own SOPs, which is not specifically a combination product issue, it just happened at a firm that makes combination products.

The other one had to do with post-market issues, specifically product complaints, and the associated investigations.  “The message there is an important message for everybody to hear: this is a lifecycle issue. If you are seeing issues with your products post-market, it suggests there may be a reason to reevaluate the product design and take appropriate actions.”

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