Combination Products High on Regulatory Radar Screen

The EpiPen eruption plus the emergence of more cutting-edge therapies with drug and biotech components has put combination products under the spotlight. Combination products were barely recognized 25 years ago, say FDA officials, but now more complex injectibles and cellular and gene therapies appear every day.

This growth, though, has generated multiple challenges. Manufacturers complain of delays in decisions by FDA’s Office of Combination Products (OCP) on which agency Center should take the lead in evaluating a new combo. Medical device makers are particularly unhappy that stents and transdermal patches are classified in most cases as drugs based on primary mode of action. At the same time, biopharma companies are struggling to design human factors studies and evaluate risks related to intended use. A hot issue is how much the device portion of a generic drug-device combo has to be the “same” as the innovator product.

These concerns have prompted FDA commissioner Robert Califf to seek ways to clarify policies and to streamline OCP’s system for designating which center should oversee a new combination product. In April, Califf formed a Combination Products Council, composed of senior-level officials from OCP, CBER, CDER and the Center for Devices & Radiological Health (CDRH), to address cross-cutting issues and resolve disagreements. A new OCP early advisory process offers an opportunity for sponsor to discuss product classification issues with the agency. And final guidances on GMPs and on human factors studies for combination products are high on OCP’s priority list.

PDUFA support

Rising industry interest in these developments is apparent in the decision to direct a portion of drug user fees to support combination product development and regulation. A new provision in the revised Prescription Drug User Fee Act (PDUFA VI) provides funds to expand and train OCP and Center staff, including combination product experts housed in CDRH. The program also will promote more coordination between OCP and product centers, support drafting and publication of guidances on bridging studies and labeling, set goals for timely review of human factors study protocols, and fund an independent third-party evaluation of the combination products program [New PDUFA initiatives will be discussed further in the October issue of Pharmaceutical Executive’s Washington Report].

Meanwhile, OCP staffers seek to better inform sponsors of policies and programs that can help prepare combos for market. The draft guidance on conducting human factors studies raises many “live issues,” commented OCP deputy director Patricia Love at the recent PDA/FDA Joint Regulatory Conference in Washington, D.C. And OCP senior manager Melissa Burns emphasized that drug companies don’t have to “reinvent the wheel” in documenting design controls for marketed products.

These and other questions related to developing and testing combination products in the U.S. and Europe will be addressed further at a conference sponsored by the Drug Information Association (DIA) in late October. And provisions in the 21^st Century Cures Act aim to reduce barriers to developing these more complex therapies, ensuring continued discussion of combos in the coming months.