Reporter: Aviva Lev-Ari, PhD, RN
Eric Topol: Get Rid of the Randomized Trial; Here’s a Better Way
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.[1] 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 [300][1] 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.
Thanks so much for your attention and your continued support of The Creative Destruction of Medicine series on Medscape.
References
- Banner Alzheimer’s Institute. Groundbreaking Alzheimer’s disease prevention trial announced. Press release.http://banneralz.org/media/28067/api_prevention_trial_release_5_15_12_final.pdf Accessed July 31, 2012.
On other topics in Medicine:
Topol on The Creative Destruction of Medicine
Great points about improving clinical trials. A couple comments though- we are still struggling to find good surrogate markers for many disease states. Additionally, you still have the fda and other agencies along for hard endpoints like overall survival instead of progression free survival.
Your comments about moving towards approve first then monitor in detail is interesting- someone else at the fda made a claim a couple months back that the fda should just approve based on safety and monitor while it’s on the market. Do you believe they will actually move towards something like that?
The following two points (from the above post) are excellent, I certainly would like to see something like this in the near future to minimize the costs at every level primarily and reach the right patients with right medicines and in right time.
1. ” 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.”
2. “it would be great if we could get rid of the randomization and the placebo-controlled era going forward.”
The above comments made by Daniel took care of 1 and 2.
The following truly makes sense to me on the humanity point of view:
“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?”
Again, as pointed out by Daniel above, aggressive R&D on Biomarkers and molecular diagnostics should be given highest priority and utilize (test) the existing products, already FDA approved, in the market for various disease conditions (based on the established markers), to achieve the set (two) goals above while making efforts to discovering new molecules.
I do agree with both comments made. Thank you both for voicing a valid concern. Let’s hope that chnages in regulation will occur sooner than later.
There has been aggressive work on biomarkers for over a decade. I’m sure that the FDA will address the biomarkers issue as it has to have a way to measure clinical progression. The result is that introduction of new medications will undoubtedly be tied to the ability to see improvement or regression.
There was pressure in the last decade to accelerate approval, and this was happening when Dr. Bernard Statland was in charge of devices. Dr. Statland was very famous and in adition to his academic credential he had been Director of Medical Affairs at Roche Diagnostics and at wht became Roche Molecular, and got North Shore University Hospital Labs off the ground.
The most messy part of current evaluations is not a biomarker issue at all. There is considerable confusion now about the high sensitivity troponins and the use of natriuretic peptides is not where it should be.
We are still chasing the “magic bullet”. That has to change.
Thank you. I agree that it has to change.
Hopefully this approach will become mainstream in the near future. Patients are already experimenting with new treatments and dosages on their own, They would help researchers if they could share information in structured ways.
Thank you for your comment.
I agree with you.
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Aviva Lev-Ari, PhD, RN
Very interesting approach. However I do not think this is going to work in the real world. Having a follow up on each and every patient who is taking or trying a new drug or device is impossible. It will require tremendous investment from both the sponsor (pharma, biotech or medical device companies) and the health systems, it needs huge amount of education to the patients, doctors ,medical staff..etc to infornot hem of the importance of follow up. The other major problem is to actually creatng and maintaining these databases, and find ways to make it work, especially in less fortunate nations and patients where more studies are being conducted.
safety while drugs are on the market is (in my opinion) an unethical conduct, the case of the late breast implants exposed how the medical devices regulation are very incompetent as it is following proving efficacy without long term safety model.
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Dr. Omar. I respect your opinion, which I assume is based on experience with the drug and device industry, and with the FDA.
I think that there has been substantial damage done to the industry in the fast tracking of new drugs, and the FDA is underfunded to carrying out the assigned tasks, and still heap on more. That is a political reality that takes in no regard to safety or outcome. In order to move forward, Eric Topol has seen an opportunity that has reasonable viability.
San Diego, where his Institute resides, is now the mecca of the wireless world, and it has long been a leader in biotechnology. San Diego has a remarkable density of Nobel Laureates, members of the NAS, a world-class university in UCSD, Scripps and Salk Institutes, and the awesome Quallcome, which created a top quality Technical High School.
Having spent the last year working with Prof. RR Coifman at Yale and his postdoc from Technion, which resulted in a vastly superior “inference engine” that is as cutting edge as it gets, I just plain reject excuses that are not based on what is already known to be possible, and that fits a national priority in health care. The data can be transmitted wireless, and it can be maintained in a CLOUD repository. The analysis of the data can be done with protection of privacy. The amount of data that can be used far exceeds what you are accustomed to in “your” real world model. The number of variables monitored can be quite large, which puts pressure on the ability to have confidence in all of the classes formed. The basic mathematics for classification was developed long ago.
Dr. Larry,
Great comment. We are on the same page. Surprisingly, it is not for the first time.
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette