FDA Gives Drug Codevelopment Guidance

As drug combinations play a steadily increasing role in cancer treatment, the U.S. Food and Drug Administration (FDA) is encouraging the development of investigational agents that will be used only as part of a novel combination, even if the agents show minimal efficacy on their own.

In one example of the promise of such combinations, researchers from Massachusetts General Hospital in Boston and Wellcome Trust Sanger Institute in Hinxton, UK, reported in March that the BH3 mimetic ABT-737 and the deacetylase inhibitor vorinostat (Zolinza; Merck), when combined, synergized to kill squamous cell carcinoma (SCC) cells in vitro and dramatically shrank established SCCs in vivo(Cancer Discov 2013;3:324–37). The findings support the idea of testing the combination in patients with head and neck SSC (HNSCC), a disease with poor overall survival.

Although vorinostat is approved for cutaneous T-cell lymphoma, a related commentary noted that both drugs “are likely to fail (or have already failed) in single-agent trials in HNSCC. Only the combination therapy is expected to show benefit. However, it is very difficult to initiate a clinical trial using two failed therapeutics” (Cancer Discov 2013;3:258–9).

In June, the FDA issued a guidance document, “Codevelopment of Two or More New Investigational Drugs for Use in Combination,” that should help create a smoother clinical-trials process for such novel therapies.

Codevelopment is the concurrent development of multiple drug products intended only to be used together and not as monotherapies. It might be an appropriate option if, for example, therapy with one of the agents rapidly leads to drug resistance, or if the agents are likely to have limited efficacy when used alone, making their individual approval unlikely, the document notes.

One goal of the guidance document is to “address general uncertainty in industry about how the existing regulatory paradigm for single-agent development would apply to development of a novel combination,” says Stephen King, an FDA spokesperson. He adds that there are also concerns that current FDA regulations “would be an impediment to development of combinations of novel agents where it may not be possible to extensively study and characterize the activity of individual components of the combination in clinical trials. The guidance is intended to signal that there is flexibility in the amount and types of data that could be relied on to demonstrate the contributions of the components.”

According to the guidance document, codevelopment may be appropriate if these criteria are met:

• The combination is intended to treat a serious disease or condition.

• There is a strong biologic rationale for the use of the combination.

• A full nonclinical characterization of the activity of the combination and the individual drugs suggests that the combination may provide a significant advance over available therapies and is superior to the individual agents.

• There is a compelling reason why the new drugs cannot be developed independently.

Although industry has shown some interest in the codevelopment of drugs for use in oncology, infectious diseases, and other specialties, no codeveloped drug combinations have been approved yet, says King.

Given the financial risk of developing drugs for use in a combination when they show minimal efficacy as single agents, codevelopment is “virtually unnavigated” by industry, says Fadlo R. Khuri, MD, deputy director of the Winship Cancer Institute of Emory University in Atlanta, GA, and codirector of its Cancer Discovery and Developmental Therapeutics Program.

“I can't overstate how important it is that the FDA put out this document and supports this approach,” Khuri continues, noting that codeveloped drugs “present an unrealized opportunity” for pharmaceutical companies. “Hopefully, it will encourage companies to move such work forward.”

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.