Dr. Weeks’ Comment: My mentor and friend, Abram Hoffer, Ph.D., M.D. (1917-2009) who was responsible for the first double blind studies in psychiatry, eventually argued against the format (and ethics) of the double blind, placebo controlled clinical trial (DBPCT) over 50 years ago. He astutely asserted that “double-blind medical trials create only the illusion of scientific credibility.” Thirty years ago, my friend Harold Foster, Ph.D. ( 1943-2009) reinforced Dr. Hoffer’s concern. As any clinician will tell you, no patient struggling with serious illness is pleased with participation in such a trial. Yet it persists as the standard of research. Now Dr. Eric Topol, M.D. reinforces Dr. Hoffer’s position and suggests the need for ” an innovative spirit, a whole new way of a conditional and then final approval in phases in the real world, rather than continuing in this contrived clinical trial environment”. safety is the issue. Too often new unproven drugs are unleashed care-less-ly upon trusting patients only to be recalled rapidly. This is not a new failing of the FDA and the DBPCT process. Almost 30 years ago, my medical school professor George Wolff cautioned me, tongue in cheek “Brad, when a new drug hits the market, use as much of it as you can before it is recalled….” In today’s world of “Predictive, Preventive, Personalized, and Participatory Medicine” (see www.p4mi.org , thanks to Dr. Lee Hood, co- founder of of the world class Institute of Systems Biology ), patients deserve better. Time for a change. Past time, actually.
Get Rid of the Randomized Trial; Here’s a Better Way by Dr. Eric J. Topol, M.D.
Aug 20, 2012
Hi. I’m Dr. Eric Topol, Director of the Scripps Translational Science Institute and Editor-in-Chief of Medscape Genomic Medicine and theheart.org. In our series The Creative Destruction of Medicine, I’m trying to get into critical aspects of how we can Schumpeter or reboot the future of healthcare by leveraging the big innovations that are occurring in the digital world, including digital medicine.
But one of the things that has been missed along the way is that how we do clinical research will be radically affected as well. We have this big thing about evidence-based medicine and, of course, the sanctimonious randomized, placebo-controlled clinical trial. Well, that’s great if one can do that, but often we’re talking about needing thousands, if not tens of thousands, of patients for these types of clinical trials. And things are changing so fast with respect to medicine and, for example, genomically guided interventions that it’s going to become increasingly difficult to justify these very large clinical trials.
For example, there was a drug trial for melanoma and the mutation of BRAF, which is the gene that is found in about 60% of people with malignant melanoma. When that trial was done, there was a placebo control, and there was a big ethical charge asking whether it is justifiable to have a body count. This was a matched drug for the biology underpinning metastatic melanoma, which is essentially a fatal condition within 1 year, and researchers were giving some individuals a placebo.
Would we even do that kind of trial in the future when we now have such elegant matching of the biological defect and the specific drug intervention? A remarkable example of a trial of the future was announced in May. For this trial, the National Institutes of Health is working with [Banner Alzheimer’s Institute] in Arizona, the University of Antioquia in Colombia, and Genentech to have a specific mutation studied in a large extended family living in the country of Colombia in South America. There is a family of 8000 individuals who have the so-called Paisa mutation, a presenilin gene mutation, which results in every member of this family developing dementia in their 40s.
Researchers will be testing a drug that binds amyloid, a monoclonal antibody, in just  family members. They’re not following these patients out to the point of where they get dementia. Instead, they are using surrogate markers to see whether or not the process of developing Alzheimer’s can be blocked using this drug. This is an exciting way in which we can study treatments that can potentially prevent Alzheimer’s in a very well-demarcated, very restricted population with a genetic defect, and then branch out to a much broader population of people who are at risk for Alzheimer’s. These are the types of trials of the future and, in fact, it would be great if we could get rid of the randomization and the placebo-controlled era going forward.
One of things that I’ve been trying to push is that we need a different position at the FDA. Now, we can find great efficacy, but the problem is that establishing safety often also requires thousands, or tens of thousands, of patients. That is not going to happen in the contrived clinical trial world. We need to get to the real world and into this digital world where we would have electronic surveillance of every single patient who is admitted and enrolled in a trial. Why can’t we do that? Why can’t we have conditional approval for a new drug or device or even a diagnostic test, and then monitor that very carefully. Then we can grant, if the data are supported, final approval.
I hope that we can finally get an innovative spirit, a whole new way of a conditional and then final approval in phases in the real world, rather than continuing in this contrived clinical trial environment. These are some things that can change in the rebooting or in the creative destruction, or reconstruction, of medicine going forward.