FDA's Combo Products Report Good First Step, Lawyers Say

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By Michael D. Williamson

Oct. 16 — A Food and Drug Administration report “very correctly identifies” a number of areas where the FDA could improve its combination product review process, an attorney told Bloomberg BNA Oct. 16.

Bradley Merrill Thompson, a Washington-based attorney with Epstein Becker & Green, P.C., said while he's pleased the FDA released the report, “there are other steps the agency could take to strengthen combination product review.”

The FDA issued its report Oct. 14 on the combination product review process. The report includes several recommendations from an agency study team.

Combination products are made up of combinations of a drug, device and/or biological product. They don't fit into the traditional categories of drugs, devices or biological products and “are a growing and important category of therapeutic and diagnostic products under FDA’s regulatory authority,” Robert Califf, the FDA’s deputy commissioner for medical products and tobacco, and Jill Hartzler Warner, the agency's associate commissioner for special medical programs, wrote in an Oct. 15 blog post about the report.

“Products in this category range from familiar products such as prefilled syringes and surgical kits to novel and innovative products, which target and enhance therapies,” Califf and Warner said, adding, “Examples of groundbreaking combination products include antibodies combined with drugs for targeted cancer therapy and products that mimic or replace organs, such as an artificial pancreas.”

President Barack Obama nominated Califf to be the FDA's commissioner in September. Califf's nomination is subject to Senate confirmation.

Product Reviews 

Combination products pose unique challenges for the agency because they may involve new, complex technologies and their review often involves the expertise of more than one of the FDA's centers, according to the officials' blog post.

The FDA has certain centers for different types of products. For example, a drugmaker wanting to get a medication approved would submit its product to the FDA's Center for Drug Evaluation and Research (CDER) for review. A device maker, however, would submit its product to the Center for Devices and Radiological Health (CDRH) for review.

Califf and Warner said that while review of combination products “falls to a cross-center team of experts, it is led by the medical product Center responsible for the constituent part that provides the product’s primary mode of action, which, in the case of a syringe prefilled with a drug, for example,” would be CDER. However, the FDA's “Office of Combination Products (OCP), within the Office of Special Medical Programs, oversees and coordinates FDA’s regulation of combination products,” they wrote.

The FDA recently conducted a focus group study with reviewers from the agency's different centers based on input from industry to assess how it's doing, the agency officials' blog said. “The report confirmed that differences in communication, policies, practices, systems and application types can be challenging when the Centers work together on a review of a combination product.”


To overcome the issues industry faces when submitting a combination product for review, the report recommended the following:

• establish clear guidance for the review of common combination product types;

• allow reviewers involved in intercenter review of combination products to access other centers’ digital systems;

• update the “Intercenter Consultative/Collaborative Review Process Standard Operating Procedures and Policies (SOPP) Manual and Intercenter Consult Request form” and make them easily accessible on the OCP website;

• create and maintain a combination product-specific organizational chart and contact directory, and ensure the information is up-to-date to reflect personnel changes; and

• establish a mechanism for estimating time spent on intercenter consults so resources can be allocated appropriately to organizational units to assure adequate review performance.


In the document, Califf said he endorsed the report and its recommendations. He directed the medial product centers, the Office of Special Medical Programs and the OCP to continue work on implementing the report's recommendations, the document said.


Thompson, who is also the general counsel for the Combination Product Coalition (CPC), an industry group, said “we are delighted that FDA is pursuing this so earnestly.”

“At the same time, we do think there are other steps the agency could take to strengthen combination product review, beyond those noted in the report,” Thompson told Bloomberg BNA in an e-mail.

Thompson said one example of an idea is developing a consensus combination product review plan with input from both the reviewing centers as well as the product sponsor. “Such a plan may help with the organization of the review in all of its complexity, and indeed facilitate the communication objective that FDA notes,” according to Thompson.

In addition, Thompson called on the FDA to update the intercenter agreements on combination products and flesh out the OCP’s roles and responsibilities in the review process. The OCP should “take on a more proactive role in not just resolving disputes through informal mediation but in monitoring the combination product review process,” he said.

The FDA also should update the combination product sections of its website with additional information so that sponsors can better assess when to, or whether to, engage the OCP in specific submissions or on other matters, Thompson said. For example, he said, it isn't “clear to sponsors and company team executives what influence or benefits OCP could” bring to certain meetings “on combination product issues, or what role it plays, or could play, in internal FDA discussions concerning the approval of submissions when there are differing CDRH and CDER opinions.”

None of Thompson's suggestions should “detract from the fact that FDA has taken a hugely positive step here,” he told Bloomberg BNA.

Califf's Involvement 

Another attorney, William A. Garvin, with Buchanan Ingersoll & Rooney P.C. in Washington, told Bloomberg BNA in an Oct. 16 e-mail that the report is a “good start for FDA to address the issues that have been occurring with the review of combination products.”

The real question is whether the FDA will be able to implement its proposed steps and whether the leadership can foster more cooperation among the centers to ensure a smoother review process, Garvin said.

“Hopefully, the fact that Dr. Califf is involved with announcing these actions will ensure that if he becomes Commissioner, he will continue to make resolution of the combination products review issue a high priority,” Garvin told Bloomberg BNA.

To contact the reporter on this story: Michael D. Williamson in Washington at mwilliamson@bna.com

To contact the editor responsible for this story: Brian Broderick at bbroderick@bna.com

The report is at http://www.fda.gov/downloads/CombinationProducts/GuidanceRegulatoryInformation/UCM467128.pdf.

Califf and Warner's blog is at http://src.bna.com/CE.


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