FDA Perspective on Developing Novel Combination Therapies

As we learn more about the network of cellular pathways that function in the proliferation of cancer cells, it is becoming abundantly clear that there is no “magic bullet” cancer treatment. The latest oncology treatments being developed are often targeted drugs that block the activity of a specific molecule that contributes to tumor growth. However, as we have learned over the last 10 years, targeted treatments can often lead to resistance as redundant or alternative pathways are activated due to selective pressure from targeted agent exposure. It is becoming more and more apparent that combination therapies for cancer will be more efficacious in destabilizing tumor growth. 

In the March edition of the New England Journal of Medicine (NEJM), Janet Woodcock, M.D. and director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA), has written a perspective on this topic, highlighting the goals and current developments at the FDA to progress the combination clinical trial process (DOI:10.1056/NEJMp1101548). 

The perspective is In response to concerns that the policies of the FDA are too rigid to facilitate efficient and effective combination clinical trials, especially because the established policies are focused on combined treatments within the same tablet (fixed-dose combinations) of drugs that are already on the market. Currently, the FDA is in the process of revamping its regulations for drug development. The focus is specifically the co-development of two or more distinct investigational drugs intended to be used in combination, but not in fixed dose combinations.

Going Beyond Single Agent Development

Even for diseases for which combination therapies are necessary, new drug development has historically been pursued linearly, one agent at a time. Add-on clinical trials have been used to test the efficacy of combination treatments in which a standard regimen plus a new drug is compared to the standard regimen alone. As the head of the CDER states in her perspective, “Successful development of future targeted therapies will require modernizing this paradigm to provide the flexibility needed to rapidly evaluate combination regimens involving new targeted agents in a single development program." 

FDA Takes Necessary Steps to Aid the Process of Combination Therapy Drug Development

“Innovative drug development requires science and regulation to advance in concert,” writes Janet Woodcock, MD.

The first step was the June 2010 Federal Register request for public comments on the co-development of investigational drugs. The FDA specifically requested comments on both the methodology and regulatory issues that arise when developing investigational drugs in combination, particulary for oncology and other therapeutic areas in which co-development is more likely to occur.

Arthur D. Levinson, Chairman of Genentech, had stated that this is “an important step in the development of guidance” and stressed the importance of “decreasing both real and/or perceived barriers to bringing novel combination therapies to patients with serious and unmet medical conditions.” 

The next step was the release of the “Guidance for Industry Co-development of Two or More Unmarketed Investigational Drugs for Use in Combination” in December 2010. The guidance is intended to ensure that regulatory expectations are transparent and provides recommendations on preclinical testing, safety, pharmacology studies, and phase 1 through 3 efficacy studies for co-development. Importantly, the guide carves out the type and amount of data that the FDA requires to demonstrate the contribution of each drug to the overall efficacy of the combination. The result is a road map for co-development for appropriate therapeutic categories.

Uncertainties in Co-Development Process

The head of the CDER points out that co-development will not make it possible to fully characterize the effects of a single drug component, resulting in less information about both safety and effectiveness. Dr. Woodcock stresses that co-development should be used only for treatment of life-threatening disease for which there is no satisfactory standard of care. Additionally, there should be “compelling biologic rationale for use of the combination” writes the author. 

Janet Woodcock points out that co-development will likely mean increased collaboration, and increased private-private and private-public partnerships. Importantly, the perspective emphasizes the FDA’s commitment to the therapeutic potential of innovative combination therapies and their development as well as mitigating the risks associated with such development programs.