Combination products – medical products that do not fit into the traditional categories of drugs, devices, or biological products – are a growing and important category of therapeutic and diagnostic products under the FDA’s regulatory authority. These products, that combine drugs, devices, and/or biological product (“constituent parts”) with one another, come in three configurations. The constituent parts may be physically or chemically combined, co-packaged, or separately distributed with specific labeling for their combined use.
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. 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. Combination products pose unique challenges – both because they may involve new, complex technologies – and because their review at the FDA often involves the expertise of more than one Center.
While review of these 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 the FDA’s Center for Drug Evaluation and Research.
Effective coordination among the FDA staff, and between the FDA and the company, is essential – and depends on identifying the proper experts across Centers, supporting processes for communication, and implementing systems for efficient data access and sharing the FDA’s Office of Combination Products (OCP), within the Office of Special Medical Programs, oversees and coordinates the FDA’s regulation of combination products. This includes helping to resolve differences of opinion between Centers or with sponsors, developing guidance and regulations, and working with the medical product Centers to develop processes and policies.
Congress has expressed interest in the FDA’s regulation of combination products as part of the 21st Century Cures legislative initiative, with one major theme being the assurance that the premarket review process runs smoothly. While there are already policies and processes in place to address such issues, the agency knows it can do more.
The study was conducted from September 2014 to January 2015 at the FDA’s White Oak, MD campus. The study team first received input from industry representatives affected by combination product review. Then four focus group discussions were held; two each with staff from the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) respectively. Groups were comprised of individuals that were regularly involved in the review of premarket submissions for combination products.
The issues most frequently identified by study participants were:
- Different Policies, Practices, and Application Types—Differing review timelines, and differing approaches to managing the review process (e.g., using project managers or not) between Centers make it difficult for reviewers to develop a shared understanding of priorities and timelines during a review and thus inhibit effective coordination between Centers. Differences in application review standards – particularly between 510(k) submissions and approval applications – and in data requirements and expectations among Centers create complexities that make it difficult to achieve consistency in the outcome of a combination product review and present challenges to timely response.
- Separate Review and Tracking Systems between Centers—Being unable to access other Centers’ data systems in a timely manner and lack of a shared technical platform were seen as a significant source of delays and inefficiencies in the consult process. The lack of rapid access to review information and application tracking systems present challenges to effective project management and results in communication gaps and reduced traceability of combination product submissions.
- Unclear Communication Channels Between Centers—There is a lack of clarity regarding cross-center communication channels, resulting in problems where staff are not sure where to direct consult requests or how to appropriately follow-up on prior requests. In addition, consult requests are often incomplete and have insufficient specificity, requiring additional follow-up and resulting in response delays.
- Lack of Resources to Review Consults—Lead Centers do not reimburse time spent by staff of other Centers on intercenter consult requests, presenting workload challenges for the consulting Center. The increasing demand for intercenter consults without any additional funds has stretched already limited resources.
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. The report also recommended actions to take, confirming the value of efforts already underway. Consistent with these findings, the FDA is taking a number of steps to clarify regulatory requirements and improve the internal processes and IT systems. These steps include:
- Issuing clear guidance for review of combination products (e.g., the pending draft guidance document on human factors);
- Enhancing and simplifying data access and sharing for internal staff;
- Making it easier for staff to request and monitor inter-center consults;
- Updating and maintaining the internal contact directory for experts to review a combination product; and
- Improving the internal standard operating procedures for premarket reviews and compliance activities.
Some improvements are already in place and others will be coming this year and next. The FDA continues to want to hear ideas for enhancing how to work on combination products. They are listening — and excited to do their part by evaluating innovative combination products and helping to improve the well-being of patients by approving new safe and effective therapies.
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