“I was stunned and deeply honored by this recognition. More importantly, I take the award to indicate that the ideas in “Embracing failure” are being taken very seriously by others…”
Translational traumatic brain injury (TBI) research is in crisis. Despite 40 years of clinical trials and many dozens of drugs tested, all trials seeking a neuroprotective treatment for TBI have failed.
I have spent my career studying recovery from brain damage, primarily how the neurosteroid progesterone can enhance morphological and functional recovery from TBI and stroke. This work, along with many corroborative reports, led to small, single-center clinical trials whose positive results led to two multi-center Phase III trials. These Phase III trials failed.
Among many problems cited by the study authors, one was that the pre-clinical science was too flawed to inform clinical investigation. Naturally, after so many years of work, I was deeply disappointed in the trial outcomes and claims that all the basic science was flawed. Why was so much lost in translation?
This question prompted me to undertake months of research asking (1) why all TBI trials fail and (2) whether the problem is limited to TBI or more pervasive. In 2014 in the immediate aftermath of the announcement that both Phase III trials had been stopped for futility, I gave a talk to the International Brain Injury Association about these failures, and Dr. Nathan Zasler, the editor of Brain Injury, was in the audience. He suggested I write a review of the literature based on my presentation and submit it to the journal.
His invitation led to “Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials,” which underwent peer review and some very helpful and thoughtful requests for revision. The research and writing took longer than I expected because there was so much to learn about how clinical trials are currently done, not just for TBI but also for cancer, heart disease, stroke and many other fields.
My biggest challenge was assembling a factual and comprehensive overview of a vast literature without sounding defensive. I tried to keep in mind Senator Daniel Moynihan’s dictum that “people are entitled to their own opinions, but not their own facts.” I wanted the facts to speak for themselves but I also wanted to convince the TBI community that trials can be better designed and, knowing full well that it will be a long shot, I strongly believe that progesterone deserves another look. After several revisions, my article was accepted in 2015 and I have been happy to learn that it is attracting the attention of colleagues here and abroad. I continue to lecture and write when I can on how to improve clinical trial design.
In February 2016, I was notified by Drs. Jeffrey Kreutzer and Nathan Zasler that, by unanimous decision, the awards Committee named me the first place winner of the Stonnington prize for the best review paper of 2015! I was stunned and deeply honored by this recognition. More importantly, I take the award to indicate that the ideas in “Embracing Failure” are being taken very seriously by others. I believe this is the very basis of how translational science should work. I am now very hopeful that we will learn from our failures, design better pre-clinical and clinical research, and develop a safe and effective treatment for TBI in the almost-foreseeable future.
Read Donald G. Stein’s winning article Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials
Find out more about the journal Brain Injury