Increasingly it has become obvious to me and to many other individuals that our current drug approval and development process has a basic flaw. If you go to research conferences you quickly learn that there is probably no magic bullet to stop any type of cancer, including advanced prostate cancer.

Current drug development focuses on targeted activities and pathways, but cancer is too “smart” for this as it seems to always develop alternative pathways and becomes drug resistant. When we do find a drug or treatment that seems to work, we soon find that its ability to “work” is time limited. This is because the cancer finds an alternative pathway that gets around our treatment.

Chemotherapy, Ketoconazole and of course even the basic hormone therapy are time limited. They work for some period of time and then the PSA rises and the cancer progresses. To many of us it is becoming clear that combination therapies would be more efficacious.

To put a perspective on this we need only to look to the tremendous advances that have been made in the treatment of HIV/AIDS. Through the use of drug cocktails we have been able to turn this fatal disease into what is now more like a chronic disease. Isn’t the goal of cancer treatment to do the same, make cancer into a chronic illness?

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

Dr. Woodcock clearly states 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.

She states that for diseases for which combination therapies are necessary (cancer being a prime example), 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…….Innovative drug development requires science and regulation to advance in concert,” writes Janet Woodcock, M.D.”

The good news is that the FDA is currently 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.

In the June 2010 Federal Register the FDA has a 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, particularly for oncology and other therapeutic areas in which co-development is more likely to occur.

Then, in December of 2010 there was the release of the “Guidance for Industry Co-development of Two or More Unmarketed Investigational Drugs for Use in Combination”. The document is intended to ensure that regulatory expectations are transparent as well as providing recommendations on preclinical testing, safety, pharmacology studies, and phase 1 through 3 efficacy studies for co-development. The most important function of the document is that it defines the type and amount of data that the FDA requires to demonstrate the contribution of each drug to the overall efficacy of the combination. It will hopefully serve as a road map for co-development for appropriate therapeutic categories.

Where this will go and how quickly it will yield any fruit is still very much up in the air. However, Dr Woodstock has said 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.

Joel T. Nowak, M.A., M.S.W.