The popularity of drug-device combination products has been soaring. These products — which comprise combinations of drugs, biologics and devices — had sales reaching $22 billion in 2014, and the market is expected to grow to $31 billion by 2019.1
However, growth in this sector is threatened by a lack of alignment within the FDA, which is slow to approve drug-device combination products. For those considering developing a combination product, I thought it helpful to provide an FDA primer to help people navigate the approval process and understand where the challenges are.
Medical device products range from drug-coated stents and prefilled syringes, to antibodies combined with drugs for targeted cancer therapy, and products that mimic or replace organs, such as an artificial pancreas.
Combination products pose unique challenges because they may involve new, complex technologies and because their review at the FDA usually involves the expertise of more than one FDA center. With regard to medical devices, how the product can be used is as important as the product itself.
These products are reviewed by the medical product center at the FDA that is responsible for the constituent part providing the product’s primary mode of action. Manufacturers of combination products have to submit applications through more than one center for regulatory approval, a confusing and delay-prone process. Also, differences in communication, policies, practices, systems, and application types can be challenging when the centers work together.
The FDA’s Office of Combination Products (OCP) oversees and coordinates this activity. OCP was created over 10 years ago with a mandate to ensure timely and consistent premarket and postmarket regulation of combination products. While OCP is charged to be the mediator and has been successful in getting the centers to talk, it has no authority to direct an outcome. When disagreements arise, OCP has no mechanism to facilitate or resolve them.
With little alignment in the FDA when it comes to the approval of combination products, there are countless examples of combination products taking five years or more to receive approval.
When looked at through the devices lens, a combination product has to meet a drug standard, which often requires large clinical studies and is not what people in the medical device industry are accustomed to. When looked at through the drug lens, it would be inappropriate to lower the standard just because there is a device delivery system.
Development of combination products often involves expanded preclinical study programs, including human factor testing to determine if patients use a device delivery system appropriately. The questions addressed by human factor studies overlap with those addressed by medication error assessments, an area of user-product interaction evaluation commonly applied to drugs.
The FDA has recommended that manufacturers and clinical researchers design human factor studies to put products through real-life circumstances with close monitoring and integration with patients. According to the FDA, studies of combination products should be conducted as part of the product design controls process, and before commencing major clinical trials. One step forward is a recent draft guidance that explains human factor studies recommended for combination products.2
With no internal alignment in the FDA around how centers can work together, it’s not surprising that there is also confusion about how to appropriate user fees, which should be used to ensure that the FDA reviews a combination product in a reasonable amount of time. With combination products, the user fee isn’t apportioned to the respective product review centers — drugs and devices. Therefore, they tend to fall to the bottom of the prioritization heap.
Another significant challenge is that manufacturing controls and quality systems vary considerably for drug and device companies, as do product labeling and postmarketing requirements. Also, it is unclear how the revision of medical device regulations by the EU authorities will impact the development and authorization of combination products.
The question is how drug and medical device companies can best operate within the regulatory framework today and in the future to deliver innovative solutions to patients in a reasonable timeframe. Until there is more alignment within the FDA, companies will need to build both drug and device expertise across regulatory, quality, clinical, and the supply chain to work with two reviewing centers simultaneously and synthesize two sets of regulatory requirements.
(1) “Global Markets for Drug-Device Combinations,” BCC Research, January 2015.
(2) Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development, FDA.
This is an excerpt from Pharm-ers Almanac 2016: The Butterfly Effect. Read the full report here:
About the Author:Judith Meritz, J.D. is a Strategic Advisor in YourEncore’s Medical Devices and Diagnostics Practice and was previously the Associate General Counsel at Covidien/Medtronic. Ms. Meritz specializes in compliance counseling for FDA and other international regulatory authority matters for medtech companies.