We've been talking about this on MPT for a while, but a few weeks ago Eric Topol, director of the Scripps Translational Institute, and author of the new book The Creative Destruction of Medicine, explains why we should and can eliminate long, expensive, and cumbersome randomized clinical trials in the age of genomics and targeted diagnostics:
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.
Of course, I think this is a splendid idea. It would slash drug development times and allow patient's much faster access to therapies that were matched to the underlying biochemistry of their disease.
Cancer is the area where we're seeing this "molecular hammer, meet molecular nail" approach develop fastest. Take Seattle Genetics drug Adcetris, a CD30 inhibitor approved by the FDA in 2011 for Hodgkin's lymphoma and anaplastic large cell lymphoma (ALCL).
If you're a cancer researcher, the first thing you want to know is how many other cancers overexpress CD30? It turns out, according to Xconomy, that researchers at MD Anderson and Stanford started looking at Adcetris as a treatment for a disease that wasn't even on Seattle Genetics radar screen, cutaneous T-cell lymphoma (CTCL). If researchers get a hit, and they did, Seattle Genetics can then turn around and run a larger trial to confirm the benefit.
But here's the rub. Assuming you've got a molecular hammer like Adcetris, and the molecular taxonomy of your disease - maybe it's cancer, maybe it's something else - implicates CD30 you know that you've got a high likelihood of some efficacy. Do you want to wait for a Phase III trial? No. Are you going to want to go into a placebo controlled trial? Or even a standard of care trial where you might get an untargeted treatment with serious side effects? No. And is your physician likely to prescribe the drug to you off label anyway? You betcha.
In these circumstances, the randomized clinical trial just doesn't make much sense. It's going to be overtaken rapidly by patients who know their own genomes, and the diagnostic tools that allow them to run N=1 trials that will allow them to rapidly screen drugs that might help them battle these diseases.
The key here is that you want a map of all the diseases that implicates this gene (or really, constellations of genes), and then you want to test the drug in these populations and find out what happens. Capturing that information and rapidly distributing it will be the coin of the genetic realm, leading to success for patients, regulators, and companies.
Safety, as Topol suggests, is something that we'll follow in the postmarket, because we'll have a confirmatory efficacy signal very early on with targeted therapies. Right now, the requirement for large trials that parse increasingly rare safety signals is the Berlin Wall facing drug developers, particularly for chronic diseases like obesity.