FDA says its proposed adverse event reporting requirements for combination products will help manufacturers navigate the intricate array of reporting requirements for deaths and injuries.

Released Sept. 30, the ¹ proposed rule also will streamline reporting to avoid duplication, FDA says.

The long-awaited proposal follows the Sept. 22 release of draft regulations on good manufacturing practices for combination products (² Also see "Proposed Rule Defines Good Manufacturing Practices For Combo Products" - Medtech Insight, 28 September, 2009.). The adverse event reporting rule builds on an FDA concept paper on the subject issued four years ago.

Combination products can include device/drug, device/biologic or drug/biologic products, or products that contain all three component types.

Existing post-market safety reporting requirements for devices, drugs and biologics are "substantially similar" to each other, FDA says in the proposal.

For example, each set of regs requires manufacturers or importers to report deaths and serious adverse events, provide periodic and follow-up reports, and signal certain types of safety events that require expedited reporting.

However, each set of regs also contains certain unique requirements and reporting timeframes. As a result, combination product makers have been struggling to navigate the intersection of up to three sets of regulations.

The proposed rule would streamline the process by requiring a company to follow the safety reporting rules associated with the marketing application under which its combination product was cleared or approved - 510(k), PMA, NDA, or BLA - plus five specific additional requirements, when applicable.

These five requirements are unique to the various product categories: five-day reports for devices, 30-day malfunction reports for devices, 15-day alerts for drugs and biologics, three-day field alert reports for drugs, and expedited blood fatality reports for biologics/blood products.

A drug/device product that is approved via a device application, then, must meet the Medical Device Reporting (MDR) requirements under 21 CFR part 803, plus the 15-day alert and three-day field alert provisions.

Five-day reports are required for MDRs that demand remedial action to prevent an unreasonable risk of substantial harm. And 30-day reports are required for certain device malfunctions that could cause death or serious injury if the event recurred.

Since 2007, 30-day reports have been required only for Class III devices and Class II devices that are permanently implanted, life-supporting or life-sustaining.

On the other hand, 15-day alerts are required for serious and unexpected drug adverse events; three-day field alerts are required for certain other drug-related problems such as bacterial contamination; and expedited blood fatality reports are required for fatal blood collection or transfusion complications.

The lead FDA center charged with reviewing the product will also review the post-market reports, consulting with the other centers as needed.

FDA Wants To Avoid Duplicate Reports

FDA clarifies that it wants to avoid duplicate reports. If a combination product maker is operating under the MDR regulations, for example, and submits a 15-day alert report for a serious, unexpected adverse drug experience, the firm does not have to submit a 30-day MDR report for the same event. The 15-day alert satisfies the 30-day report requirement.

If only one company is responsible for post-market safety reporting, it should consider the product as a whole and submit reportable events for all the constituent parts.

If multiple companies hold applications for the different components of the product, each must follow the reporting requirements for the regulatory scheme of that component.

However, each reporter must notify any other reporters or FDA of safety information it receives within five days so the others may investigate potentially reportable events for themselves.

In these situations, certain events may be reported to the agency twice, FDA acknowledges.

Recordkeeping requirements hold for each unique set of regulations. Drug- or biologic-related reportable event records must be kept for 10 years, and device-related reportable events must be retained for either two years or the expected life of the combination product, whichever is longer.

The proposed rule applies to mandatory safety reports only. User facilities and distributors would not be subject to the rule, though importers would be.

Manufacturers and importers would have 180 days after final rule publication to comply with the new requirements. The rule will affect post-market safety reports submitted on or after the rule's effective date.

Combo Product Makers Spot Holes In Proposed Reg

Combination product makers have a few initial concerns with the proposed rule, particularly about the suggested reporting system for multiple manufacturers or application types involved in a single finished combination product.

The need for one manufacturer of a constituent part to report an adverse event to either FDA or the other manufacturer of the companion part is a new requirement, says Brad Thompson, head of the Combination Products Coalition trade group.

The rule says when there are multiple applications held by multiple firms, each company must follow the rules associated with whatever submission they filed, he explained.

But questions arise. For example, would a 510(k) holder that sells its device to a drug company, which then files an NDA that includes the device component, still be responsible for filing adverse event reports for the device component downstream?

Thompson said the Coalition plans to look at the work streams behind various types of filings to identify complexities and challenges under the proposed rule.

The five-day timeframe for notifying other manufacturers or application holders of safety information seems "relatively short," for example. "That could be very challenging to accomplish."

Comments on the proposed rule are due Dec. 30.

- Jessica Bylander ( ³ j.bylander@elsevier.com )

FDA Unveils Adverse Event Reporting Rules For Combination Products

More from Archive

More from Medtech Insight