pharmacologic effect that’s relevant, but do have such an effect when you put them together, that might be enough,” Dr. Temple said.

Suggestions from Various Workshop Participants to Address Regulatory Challenges

•   Focusing on combinations with a compelling biological rationale and strong preclinical data

•    Seeking dialogue with FDA early in the development process, and frequently as development progresses

•    Establishing more dialogue between FDA and the European Medicines Agency, to enhance harmonization of regulations

•    Obtaining more clarification from FDA regarding the types and levels of evidence needed for combination therapies

•    Getting better guidance from FDA on how sponsors should best interact with multiple FDA offices involved in combination product development

FDA DRAFT GUIDANCE

FDA recently released a draft guidance for industry on the codevelopment of two or more unmarketed investigational drugs for use in combination.1 At the conference, Drs. Sherman and Temple discussed the major premises on which this guidance is based. These premises include the need for combination therapy, the agency’s flexibility in ascertaining the contributions of individual agents in a combination, the need to demonstrate the biological rationale for the combination, and the case-specific nature of IND submissions and labeling issues for which FDA encourages sponsors to consult with the agency as early as possible and frequently throughout the development process (Woodcock et al., 2011).

Drs. Saber, Temple, and Sherman all stressed that FDA recognizes the need for combination therapy and has experience with regulating combination therapy with investigational agents, not just for cancer, but for many other diseases, including infectious diseases and hypertension. Dr. Sherman added that there are times when it is even unethical or impossible to study agents as single therapies because the agents are much more likely to be effective in combination due to the rapid development of resistance to single therapy or other factors. “With hepatitis C, resistance develops within days, so it’s only possible to expose patients with

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1 See http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM236669.pdf (accessed December 14, 2011).



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