Questions about the future regulation of combination products came to a head in 2015, and it's likely that significant changes will be put on the table in 2016.

From FDA, companies can expect a comprehensive proposal for a new approval pathway focused on combination products by the end of next year that could dovetail with efforts to reauthorize the device and drug user fee programs in 2017. Deputy Commissioner (and Commissioner-nominee) Robert Califf committed to as much at a recent congressional hearing. (See Also see "Califf Supports Combo Products Pathway At Confirmation Hearing" - Medtech Insight, 17 November, 2015..)

But even before such comprehensive reforms are put forward, incremental changes are already in the works. FDA is updating its processes to improve information-sharing and collaboration between centers, and will issue guidance documents with the hope of streamlining premarket combination product reviews, as well as postmarket compliance efforts.

"Dr. [Stephen] Ostroff and Dr. [Robert] Califf have been clear that this is a priority area and we hope to provide you with more detail about forthcoming projects in this first quarter of 2016," Thinh Nguyen, director of FDA's Office of Combination Products, told "The Gray Sheet."

Ongoing FDA reforms "will assure inter-center consults are sought when needed, that review staff know whom to consult, and that timing for completion of consults is appropriate to enable the lead center to meet its user-fee performance goals," FDA's Thinh Nguyen says.

Postmarket Particulars: cGMPS, Safety Reporting

FDA issued a draft guidance at the start of 2015 on the application of current good manufacturing practices (cGMPs) to combination products; it is intended as a companion to a 2013 final rule on the topic. (See Also see "Combo Products GMP Guidance Fills In Gaps On Drug-Delivery Device Compliance" - Medtech Insight, 27 January, 2015..) Both the rule and the draft describe an approach for combo products to comply with FDA quality standards if a company implements either drug cGMPs or the device Quality System Regulation, plus select sections of the other standard.

While companies say the overall approach laid out in the regulation is appropriate, much more explanation is needed from FDA to help manufacturers comply for specific combo products. The draft guidance did not go far enough in providing the needed clarity, many firms say. Specifically, companies are requesting more details on how to apply stability testing and reserve sample requirements to different types of products. Companies also want more help with the proper approach to device design controls and cross-labeled products. (See [A#01150511016].)

The agency says it has reviewed the comments and is preparing a final guidance. "The industry requested that FDA develop guidance to explain the requirements and agency expectations further," John Weiner, associate director for policy at the Office of Combination Products, said in an interview. "FDA is reaching out to the combination products industry to understand and address their questions and concerns about compliance with cGMP requirements."

Thus far the agency has met with the Combination Products Coalition and AdvaMed's Combination Products Committee to collect feedback on the issue. The agency is also working with individual companies to answer product- and facility-specific questions.

Also in the postmarket realm, FDA says it's stepping up efforts to finalize its proposed rule for adverse event reporting for combination products, which has been pending for more than six years. (See Also see "FDA Unveils Adverse Event Reporting Rules For Combination Products" - Medtech Insight, 5 October, 2009..)

"FDA receives questions regularly on these reporting duties, and the Combination Products Coalition, as well as individual members of the combination products industry, have told the agency that they support finalizing the rule so that they can ‎make decisions on how to establish and update their reporting IT and systems," Nguyen said.

Putting The Pieces Together

On the premarket review side, FDA officials acknowledge that there are gaps and inefficiencies in how the different product centers collaborate and share information during combo-product reviews, Nguyen noted. Califf made this point too in an exclusive podcast interview with "The Gray Sheet" in June. (See Also see "Podcast: FDA's Califf Talks About Combo Product Reform, Commish Prospects" - Medtech Insight, 17 June, 2015..)

The matter was underscored in an FDA internal assessment of its inter-center consultation process released in October that spotlighted shortcomings in the agency's IT systems, procedures and resource-allocation methods. (See [A#01151019020].)

FDA is now in the process of implementing the report's recommendations, Nguyen affirmed. As part of that, the agency is updating its procedures for inter-center consults to replace current processes that are more than a decade old.

"They will assure inter-center consults are sought when needed, that review staff know whom to consult, and that timing for completion of consults is appropriate to enable the lead center to meet its user fee performance goals," Nguyen said. "IT adjustments are also being made to enable timely inter-center access to databases‎ needed for combination products reviews, and efficient coordination and oversight for these activities."

The reforms come as FDA struggles to handle the rapid rise in inter-center consults. A particularly large number of information requests come to the device center from the drug center, asking about human-factors issues raised by drug-delivery technologies. (See Also see "Human Factors Questions Drive Rise In FDA Inter-Center Consults" - Medtech Insight, 7 May, 2015..)

FDA is trying to address common confusions in that particular area by prioritizing development of a draft guidance document this year on human factors design for combination products, Nguyen said.

"FDA continues to believe that a new pathway for device-led combination products could help to address challenges that currently face manufacturers and FDA," OCP's John Weiner says.

A New Pathway?

But all of this does not get to the broader questions of whether the established device and drug approval processes provide the necessary flexibility for the review of next-generation combination products or whether a new statutory pathway is needed.

About 10 years after FDA established the "primary mode of action" rule that underpins current combination products regulation, there is growing consensus from industry and within the agency that a significant update to the program is needed.

Both Califf and Center for Devices and Radiological Health Director Jeffrey Shuren have publicly touted prospects for a new pathway, potentially with new user fees to support it. Shuren has said that the number of combination-product consultations within the agency is especially burdensome for the device center and that the drug and device pathways don't align very smoothly to support a streamlined combination-product review. (See Also see "Combo Product Reforms Are A Priority For Next User Fee Round, FDA Officials Say" - Medtech Insight, 24 June, 2015..)

"FDA continues to believe that a new pathway for device-led combination products could help to address challenges that currently face manufacturers and FDA," OCP's Weiner also told "The Gray Sheet."

"On the one hand, manufacturers for some types of combination products may be concerned that the PMA pathway is overly burdensome given the nature of the products they seek to market. On the other hand, the 510(k) pathway presents challenges for combination products because it is designed to assess the substantial equivalence of devices, not the safety or effectiveness of drugs."

Exactly what a new pathway would look like remains to be seen. And there is also the question of the agency's standard for determining whether a product in fact has a device or drug primary mode of action. Companies have increasingly complained that FDA too often leans toward sending products down the primary drug review route, with its more burdensome standards. At least one bill introduced in the Senate in 2015 seeks to push more combo products into device-led reviews. (See Also see "Senate Bill Aimed At Streamlining Combo Product Regulation" - Medtech Insight, 20 July, 2015..) That issue will certainly be part of the discussion as combination-product reform efforts escalate in 2016 and as user fee reauthorization moves to conclusion in 2017.

2016 Will Be A Big Year For Combo Product Reform, FDA Says

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