FDA's proposed adverse event reporting requirements for combination products should be rewritten to simplify the way events are reported when multiple manufacturers are involved, firms say.

The ¹ proposed rule, released last Oct. 1, lays out a streamlined process for reporting adverse events for products made up of multiple FDA-regulated categories - and therefore subject to multiple, overlapping regulations (² Also see "FDA Unveils Adverse Event Reporting Rules For Combination Products" - Medtech Insight, 5 October, 2009.).

The rule addresses how firms "reconcile and ensure compliance with all those different requirements without having to do multiple, full-blown separate regimes for the different constituent parts," John Weiner, associate director for policy at FDA's Office of Combination Products, said during a Jan. 21 webcast on the proposed rule.

The event was hosted by the Regulatory Affairs Professionals Society (RAPS) and the Combination Products Coalition (CPC), an industry group of about 15 manufacturers.

For the most part, combo product makers say the "streamlined" approach outlined in the proposed rule is an improvement over the status quo.

Before, "there was quite a bit of variability," said lawyer and CPC Director Bradley Thompson. "Some were clearly overreporting, some were perhaps underreporting, and some were hitting it about right."

But there are still key questions to be addressed in the final rule, or in companion guidance.

Some firms are even calling for a broader overhaul of the combination product reporting requirements, better tailored to this unique set of products.

FDA's Streamlined Approach

Under the proposed rule, firms would adhere to one set of safety reporting rules in full, and tack on certain specified reporting elements for the other regulated parts of their product.

This is similar to the thinking behind the Sept. 23 proposed rule for combination manufacturing practices (³ Also see "Company Questions Remain Unanswered In FDA's Combo Products GMP Rule" - Medtech Insight, 25 January, 2010.).

So, a company making a drug/device combination product approved as a device would file Medical Device Reporting adverse event reports, as well as the 15-day alert and three-day field alert reports for drugs, as needed.

But according to biotech firm Genentech, the requirements are "unnecessarily complicated" and "could lead to unwanted multiple and inappropriate reporting."

Genentech and others are particularly concerned about requirements when multiple companies hold applications for the various parts of the product.

Multiple Reporters Could Mean Multiple Headaches

Under the proposed rule, each application holder must follow the reporting rules for that regulated component, but industry reps say only the application holder of the finished combination product should file.

"It's enough [if] the drug company files a complete report over all the aspects - not just the drug elements but the device elements," the CPC's Thompson said at the RAPS event. "[That] seems like it should be enough, rather than bringing a supplier into the situation."

In addition, FDA says each application holder must submit, within five days, safety information it receives related to the other constituent parts to either FDA or the company that makes that part.

That company would then investigate the report to determine whether to officially alert FDA.

CPC says this option could overwhelm FDA with unvetted safety information.

"Complaints and other information about an adverse event normally should go to the company first," Thompson said. "The company then reviews it, investigates it, is able to put that information in context ... to determine whether or not this potentially reportable event is in fact a reportable event."

Otherwise, direct reports to FDA about another firm's product, without appropriate investigation, "will lead to a lot of miscommunication and a lot of misinformation."

CPC says the final rule should be rewritten to explain that these five-day safety information reports should be made directly to FDA "as a fallback and only a fallback."

Firms also say it is not clear what types of events would trigger the five-day safety information reporting requirement. CPC questions whether the requirement applies to potentially relevant or just definitely reportable events.

"In all other adverse event reporting regulations, there's whole sections that describe what that [reportable] information is," Thompson said. "For a completely new reporting obligation, this one is a bit underdeveloped."

In addition, five days may be too short a timeframe to turn around those reports, the group said.

A Brand-New Paradigm For Combo Products?

Longer term, FDA should consider development of a wholly new hybrid scheme for combination product reporting, combination product makers say.

"The distinctions between drugs, devices and biologics are diminishing," Thompson explained. "There's a growing trend toward simply therapeutic products, and they might have more and more elements of multiple technologies."

FDA should "recognize the combination nature of the final product and not continue to attempt to separate the constituent parts from a regulatory perspective," Genentech added in its Nov. 23 ⁴ comments.

While it would be "premature" to recast the regulations now, CPC's Thompson said, "we're hoping that the agency's long-term plan, as combination products continue to grow and become more significant, will simplify and unify the reporting structures."

"Our hope is that this [post-market safety reporting rule] is just an intermediate step toward ultimately a unified framework for adverse event reporting for medical products."

FDA Weighs Companion Guidance Options

n the meantime, companion guidance to accompany the final rule is key, Thompson said, as the regulation cannot answer all of industry's questions.

Without guidance, companies will be hesitant to change their processes "for fear of having to do it multiple times," he said.

FDA's Weiner says the agency has not "gelled its thinking" on companion guidance, but is considering the options.

"We could try to address some issues, of course, in the preamble [to the rule,] but preambles are kind of static," he conceded.

Weiner agreed "it would be good to get a guidance out as quickly as we can," and then revise as needed.

But FDA also does not want to send "unhelpful signals ... until we're dead sure of what is going to happen," he said.

FDA has an internal working group for combo product post-market safety reporting that could answer industry questions in the meantime, and perhaps craft the companion guidance, Weiner noted.

Comments on the proposed rule were due Jan. 29.

- Jessica Bylander ( ⁵ j.bylander@elsevier.com )

Combo Product Firms Want Simpler Adverse Event Reporting Structure

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