FDA plans to draft its first-ever guidance on the co-development of two or more novel drugs to be used in combination to treat cancer and other life-threatening diseases and is seeking stakeholder

help in how to tackle regulatory issues. Cancer advocates said they see the agency’s recent outreach as the first step to establishing a clear regulatory pathway for these combination therapies and a move that advances targeted therapeutics in personalized medicine.

The agency indicated in a Federal Register notice this week that there is interest in using combination therapies for the treatment of cancer, chronic hepatitis C and tuberculosis, but there is uncertainty about the evidentiary and regulatory requirements for these efforts. As a result, the agency states it is planning to develop guidance that is applicable to multiple disease types to address the co-development of investigational drugs. It also poses a series of questions for public comment.

FDA specifically wants advice on how the agency should tailor its regulatory approach for two or more drugs intended to be used in combination that treat the same symptoms, drugs that are directed at the same disease but act on different symptoms, a drug that enhances the effectiveness of another drug and drugs intended to be used in combination for specific therapeutic categories, such as oncology or anti-infectives.

Combination treatments are important to cancer patients because they can target two different molecular pathways and cripple tumor cells in multiple ways, said Jeff Allen, executive director at Friends of Cancer Research. However, he and other sources noted that while these treatments might provide a “synergistic” benefit, they also present the potential of increased toxicity — something that FDA will have to wrestle with as it determines how to properly oversee these products.

Combination therapies are different from “fixed combination” drugs that are physically combined and regulated under FDA’s “combinations rule.” FDA drug center chief Janet Woodcock said at a conference last September that the agency needed to “pursue a public process” to develop policy related to the new combination regimens.

The Engelberg Center for Health Care Reform at the Brookings Institution and Friends of Cancer Research hosted last year’s Conference on Cancer Clinical Research, which included a panel discussion on the development of two novel therapeutics targeting multiple pathways.

The panel concluded that there is a need to modify FDA’s regulatory approval process “such that it is more in alignment with the reality of new therapies in development” and also called for FDA to consider combining clinical trials, “whenever feasible,” to enhance clinical development time lines, according to an issue brief the panel prepared.

“There are other facets of this issue that require further discussion, such as determining the optimal doses of the agents in the combination, labeling and packaging to ensure safe and effective usage, etc.,” the brief stated. The brief was published earlier this year in The Oncologist and was authored by representatives from the Mayo Clinic, the Lance Armstrong Foundation, Washington University, Genentech and the National Cancer Institute.

Adam Clark, director of science and health policy at the Lance Armstrong Foundation and a member of the Brookings panel, said he thinks the agency’s request for comments will ultimately lead to a regulatory pathway.

“(The) scientific community will respond with enthusiasm if there is merit here for moving a new type of drug design forward,” he said. He also suggested that FDA’s interest in combination therapies aligns with the growing emphasis on personalized medicine.

Allen explained that stakeholders are looking to FDA for guidance on how the drug development process can be modified, while still ensuring patients receive the best treatment option. He added that there are also questions about the level of information the agency requires for approval decisions on the individual drugs used in a combination treatment and the combination treatment itself.

From a regulatory standpoint, Allen said the agency faces the challenge of how to ensure safe delivery of the combination treatments, as alluded to by the Brookings panel, and added that he anticipates FDA will need a “degree of flexibility” to consider drugs on a case-by-case basis. In terms of methodology, he said stakeholders want to know how the agency will utilize adaptive clinical trial designs.

Jon Retzlaff, managing director of science policy and government affairs at the American Association for Cancer Research, said his organization is putting together a task force to address the agency’s request for comment. Other stakeholders also declined to provide specific recommendations at this point, saying they needed time to consider the issues where the agency seeks feedback.

However, stakeholders suggested that FDA might be able to address some of the scientific complexities related to co-developing new drugs through the initiative it launched earlier this year with the National Institutes of Health. — Alyah Khan (akhan@iwpnews.com)

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