There are many reasons why several diseases--including many types of cancer and most progressive neurological diseases--have no effective treatments today. One key reason is the regulatory/legislative framework that affects the attitude of pharmaceutical companies toward combination therapies.
For example, there are dozens of drugs to treat high blood pressure, high cholesterol or diabetes. Much is known about these disorders, the variables are easy to measure and represent excellent endpoints in fairly short clinical studies and the duration of the disorder is not a critical factor in patient selection for the studies. When developing new drugs in hypertension, one can show in a few days whether a new drug lowers blood pressure. Once this is clear, what remains to be proven is that the drug is safe, the effect is maintained over several months and that it interacts well with other drugs for hypertension. In this case, as well as in diabetes, asthma, arthritis etc., developing drugs one at a time is logical and appropriate.
When dealing with neurological diseases, for example--especially those associated with the death of brain cells such as Alzheimer's disease (AD), Parkinson's disease, ALS ("Lou Gehrig Disease"), Autism and others-- the calculus is different: there are many theories for disease origin and causation, poorly defined biomarkers and endpoints, diseases take years to progress, and the stage of disease is important for studies because at some point the damage to the brain becomes irreversible.
Currently, there is no drug on the market that can slow down the progression of any of the chronic neurological disorders. In recent years there were numerous high-visibility failures of drugs in late stage clinical development for AD. Given that there are likely multiple cellular abnormalities at work (and hence many potential drug targets), the likelihood that a single new agent will on its own lead to clinical benefits are slim to none. In addition, if one chooses patients with their disease at an early stage, the slow clinical progression requires years of clinical studies, and if one chooses patients with late stage disease, it may be too late to intervene successfully. While a lot of work is devoted to finding disease markers that can shorten and facilitate studies, it will still not solve the issue of multiple potential drug targets present in every patient.
That's why we need to expand the simultaneous drug development route. Developing a combination of two or three or four drugs at once, from the get-go, is the only way to break through. Each drug can target a different cellular pathway so that a multi-pronged attack cannot be thwarted by any single 'wrong' cellular target. This is not much different than other human endeavors, be it war or a game of chess, where one needs to attack or create two targets or weaknesses in order to win.
So why isn't this being done? There are many reasons. One has to do with the mindset of most--if not all--drug development companies, a mindset that has been trained and primed to discover one new chemical at a time. This is where creative collaboration between companies can flourish. I contend that a combination of existing (and often marketed) drugs can also fit the bill. Finally, the FDA has strict rules on developing new compounds, requiring that each of combination of new drugs show some effectiveness and that the contribution of each member of the combination to the clinical outcome be clearly documented. However, when dealing with the difficult-to-treat diseases, the point of the combination is precisely that each component is not effective on its own and it requires the actions of the other component(s) to be successful.
In addition to the neurological diseases mentioned above, cancer should be another condition for which special rules need to be created. To keep adding one drug at a time to a treatment regimen cannot be (and in fact isn't) the right approach for many types of aggressive cancers.
It's time that our health institutes, FDA and congress issue guidelines and legislation to facilitate and stimulate the development of potentially life-saving combinations. It was done successfully for HIV-AIDS and could be expanded to other diseases. For example, an exclusivity period of 7-10 years (maybe more) should be granted to the developer of combination therapy for serious, untreatable diseases, even if the patent for each component of the combination has expired. Tax preferences should also be considered. NIH should facilitate the organization, conduct and funding of the combination studies, which in many cases could be fairly complex, sophisticated and expensive.
I'm sure that that the 'purists' among us can find flaws in this approach--diseases not understood enough, unexpected safety risks in combinations etc. A case-by case approach, combined with the incentives outlined above (one could think of other incentives) could lead to a much brisker pace of progress in treating and possibly curing those difficult-to-treat conditions.
Boas Gonen MD
Physician and a clinical investigator
Author of "A Midlife Intermezzo"
Boas Gonen is a physician who specialized in diabetes and cholesterol disorders. He has published several medical papers, spoken at medical conferences and professional lectures, been a teacher, and provided care to thousands of patients. He is the author of "The Third Patient." "A Midlife Intermezzo" will be apart of the Foreword's exhibit at the Book Expo America in New York City. Gonen enjoys writing and finds happiness in music.
For the fictitious physician Vip Van Buren, the opera becomes a significant part of his life after a chance encounter with the world's most famous opera singer, Svetlana Borisenko. From there, their complicated and exciting romance begins. In "A Midlife Intermezzo," Vip Van Buren risks his career and family in pursuit of love that may be clouded by the opera. Does he love the singer or the character she portrays?
"A Midlife Intermezzo"
By Boas Gonen
Published December 19, 2013