Fixing the FDA’s broken combination products policies

One of the most fertile areas of medical innovation today is the combination of devices and drugs. These products, also known as combination products, are comprised of two or more regulated components, i.e., drug and/or device and/or biologic, and don’t fit nicely into existing regulatory pathways, yet comprise roughly one-third of all products in development today. Some well-known examples of a combination products include surgical meshes with antibiotic coatings, patches for drug delivery, drug-eluting stents, and light-activated treatments and diagnostics. The current regulatory process for combined products is inefficient with ambiguous paths to approval dictating the review plan. To truly drive innovation for combination products, we need to put the review plan before the regulatory path.

{mosads}The assignment of combination products to the appropriate agency for regulatory review as either a device, drug or biologic currently depends on a determination of the primary mode of action by which the product achieves its overall intended therapeutic effect. The goals of drug/device regulations are laudable — to (1) simplify and expedite the review of combination products that qualify as devices; and (2) to reduce the number of combination products that would be regulated as drugs to include only those that rely on chemical action to achieve their primary intended purposes.

In practice, however, this interpretation is not being carried out by the Food and Drug Administration (FDA) and standards that differ from the statute are being applied, pushing reviews of combination products having a chemical action “even in part” or “that meaningfully contributes” to the primary intended purpose (e.g., in the case of Diphoterine Skin Wash, or DSW, by Prevor) to the FDA drugs center, as opposed to the devices center, as intended in the law. Neither of these interpretations are contained in the law, and that is why the courts on two occasions have remanded the DSW case back to the FDA to classify the product appropriately. This adds to the cost, time and uncertainty in the development of these innovative products, thereby stifling their advancement.

The case of DSW is just one of many examples that illustrates why we need to put the review plan before the regulatory path when it comes to combination products instead of vice versa. Not only do the FDA’s actions violate the letter and spirit of the law, but they also make no logical sense. Current combination product procedures necessitate that companies engage the FDA early in the development process and well before they are able to ascertain whether their products have a significant chemical action. The agency insists on regulating combination products that do not have data on contributions of the drug component to the mode of action as drugs, thereby defeating the purpose and intent of the regulations. Moreover, the FDA routinely requires companies to prove the negative case (that a product does not achieve its primary mode of action through a chemical reaction) in order to assign the review to the devices center, which is extremely difficult and often not feasible.

Devices are regulated by risk classification — Class I, II or III — with pre-approval requirements commensurate with risk. Drugs and biologics are reviewed according to a single framework: all drugs require a New Drug Application (NDA) and all biologics require a Premarket Approval (PMA). Since the device regulations offer more regulatory flexibility and the ability to match the regulatory path with the risk profile of the product, the FDA’s position also defies common sense from an operational perspective. It would make sense to preferentially assign most combination products to the device framework (with input from drugs and biologics) than the reverse. But that is not what has been happening. This hurts medical innovation, which is why (along with the reasons stated above) the FDA combination products policies recently received a Medical Impact Index (MI3) score of zero (range -10 to +10) for their impact on medical innovation by the Initiative for Patient Centered Innovation (iPCI) of Fairleigh Dickinson University’s Rothman Institute of Innovation and Entrepreneurship (of which I serve as executive director).

We are not alone in recognizing that the FDA’s combination products policies are broken. Sen. Johnny Isakson (R-Ga.) recently introduced the Combination Product Regulatory Fairness Act of 2015, which takes into account prior findings of safety and effectiveness of components of a combination product and assigns a leader center within the FDA to address whether a product is reviewed as a drug, device or biologic, based off the primary intended purpose for the product. This approach is ideal because it would allow sponsors to submit and work out an agreement with the FDA on a Combination Product Review Plan that details a clear and defined regulatory path to approval, addressing necessary clinical studies, timelines and an evaluation of incremental risks posed by the combination product.

The Combination Product Regulatory Fairness Act of 2015 is a step in the right direction. It aims to create an innovation-friendly process by which the review plan (calibrated to the safety and effectiveness issues raised by the product) would dictate the regulatory path, rather than the abstract assignment of the path dictating the review plan. This would likely align the process with the original intent of the combination products legislation and advance medical innovation.

Gulfo is the executive director of the Rothman Institute of Innovation and Entrepreneurship at Fairleigh Dickinson University and author of Innovation Breakdown: How the FDA and Wall Street Cripple Medical Advances (Post Hill Press). He has more than 25 years of experience in the biopharmaceutical and medical-device industries and is the former CEO of Mela Sciences. Follow him on Twitter @josephgulfo.