On March 13th, 2018, I, along with members of the Parkinson’s Research Advocacy Group (P.R.A.G.), published an opinion piece in the British Medical Journal calling for reform in Parkinson’s disease research.
Below are selected responses to the piece from researchers in the field. We hope to stimulate more discussion on these issues as well as some creative thinking on how to bring about some of the changes we call for.
Peter Schmidt, PhD, Senior Vice President, Chief Research & Clinical Officer, at the Parkinson’s Foundation
This is a great piece. It covers a lot of difficult issues. One of the challenges that I am seeing is a failure to understand epistemology — the science of knowing what we know. Scientific knowledge is getting to the point where it has breached the limits of the typical human mind — even the very educated human mind — and we need teams of collaborators to advance knowledge. This is in part why we need patients on those teams (but not the only reason). People will latch on to subtle “signals” in a scientific study but fail to recognize the difference between statistical irrelevancy, a “hint” at an avenue for future study that falls below our threshold for knowledge, and true knowledge that emerges from a study…. And of course, most studies show that a patient who is engaged in a study where patients hope for success and expert clinicians have a financial interest in patients demonstrating benefit will result in an overall improvement in health, whether patients are randomized to the study drug or placebo.
This is why I have long advocated for the development of very large cohort, long-term follow-up studies. This gives us great insight into the the subtleties that are often lost when we study the “average” PD patient, as you guys mention. We can look at groups of 50 or 100 people who have comorbid diabetes and think about what helps them most, or how the winter is different from the summer, or people between the ages of 30 and 40. We need to ensure that a clear understanding of how meaningful a difference observed is, and build systems to systematically ensure that hints of a specific benefit to a subpopulation are studied for confirmation (or disconfirmation) of the effect quickly so that patients in that group can understand and enjoy that benefit.
There is an opportunity to take the reigns on some of this stuff yourself through advancing the development of shared decision making tools. These are scientifically-informed guided questionnaires that help patients to share in making informed choices among the many options that we’ve shown, in the past, are beneficial to the “average” patient. How do you choose whether or not to take an MAO-B inhibitor as monotherapy before you need levodopa? Today, most patients are told to take one (or not) by their doctor, but this choice has implications. Should you take a dopamine agonist as monotherapy instead of levodopa early in the disease? Most clinicians make this choice relying on a conventional wisdom that is based on evidence that is now questioned. Amantadine for dyskenisa? Which form?
All these things are evidence-based treatments that have risks, benefits, and harms (the difference between “risks” and “harms” is that “harms” are not stochastic — they always happen). There are few decision aids that are designed to help patients to share in the process of deciding on an approach with these and other care decisions so that the choices made reflect the preferences of the individual, not the neurologist.
When we identify a treatment that slows Parkinson’s, it is quite likely that that treatment will also have risks and harms, and we may find that some people won’t want that, either. The decision to participate in an infusion therapy that slowed Parkinson’s by 50% or even 99% would be different for someone diagnosed at 30 versus 90. (I avoid saying 100% because I suspect that natural aging would progress Parkinson’s pathology even if we stopped the pathogenic process.) I think that we would all benefit from work done to develop shared decision making tools around decisions in Parkinson’s.
Here’s a paper on shared decision making: https://link.springer.com/article/10.1007/s11606-012-2077-6
Roger Barker, PhD, MRCP, Professor of Clinical Neuroscience and Honorary Consultant in Neurology at the University of Cambridge and at Addenbrooke’s Hospital.
I really liked this piece. Clear, honest and necessary!! I think it makes clear how important the patient voice is, in all this. I think that the way to start changing how decisions are made over funding such work is by looking at how some organisations do this- such as the Cure Parkinson’s Trust. By so doing I would hope that less “patient friendly” organisations can start to change how they review and fund trials and translational research.
Patrik Brundin, MD, PhD, Director of the Center for Neurodegenerative Science and the inaugural holder of the Jay Van Andel Endowed Chair in Parkinson’s Research at Van Andel Research Institute in Grand Rapids, Michigan, USA.
There is always room for improvement, and clinical development of new therapies is no different. For example, outcome measures for Parkinson’s disease clearly can become more sensitive and relevant to how people experience the disease in their daily lives. Wearable devices might offer some help in that regard, but they are not the only way forward and significant input from the PwP (people with Parkinson’s) community is essential when new tools are developed. Study endpoints that are truly relevant to PwP also need to be chosen. Further, it is critical to ensure patient heterogeneity is taken into account—no two patients are the same and we need to design trials to better reflect this. Lastly, we all must be good stewards of our resources and use them efficiently, particularly given the costly nature of conducting trials. Indeed, the cost of clinical trials have escalated in recent years and there might exist several innovative ways to curb this development.
Lysimachos Zografos, PhD, co-founder and CEO of Parkure, a drug discovery company which has set out to discover a cure for Parkinson’s disease.
Interesting points and a very concisely written piece.
WRT personalised approaches: I think the only “excuse” there is the fact that there no broad consensus on biomarkers of PD, beyond the classics. That said sequencing those taking part in clinical trials should be an enforced practice – even just for retrospective sample and meta-analyses. Not sure how widespread it is though. I can think of (bad) reasons why a pharma would not want to do this. The obsession with specific mechanisms and the lack of pre-clinical models that sensibly translate to clinical reality is another issue.
At the end of the day I think that it all (sadly) ties with health economics. High R&D risk, not enough people (now) to justify it. That sets back not only clinical trials but also all the R&D supporting them – e.g. pre-clinical models. I think there is space for patient advocacy and charities to lobby for adopting different approaches, but I think there’s more point to do this focusing on all stakeholders other than pharmaceutical companies.
Joel Watts, Ph.D., Assistant Professor Tanz Centre for Research in Neurodegenerative Diseases in the Department of Biochemistry at the University of Toronto
I agree with almost everything you say in the piece. The points you mention about clinical research and clinical trials are outside my jurisdiction, but I wholeheartedly agree with your comments on funding agencies and the need for everyone to work together. From my own research standpoint, I am very much in favour of a “personalized medicine” approach for Parkinson’s disease and I sincerely hope that the field moves in this direction.
As a PPI voluteer with both Parkinson’s UK and the Cure Parkinson’s Trust, I agree wholeheartedly with the thrust of the argument. It soon became clear to me that there was a lot of variability in people who are lumped together under the Parkinson’s banner, and that this causes confusion in clinical trials. [ However, I regret that I am not qualified to offer a solution to the dilemmma.]
Evroneye would benefit from reading this post
I was diagnosed five years ago at the age of 51. I had symptoms for 3-4 years prior to that but did not know anything about Parkinson’s. I first noticed a slight twitch in my left hand, finger and thumb, which became pill rolling. We attended a lot of sports events and I would lose my balance in the moving crowd. I then started seeing a neurologist. I started falling a lot when losing my balance and had a hard time walking normal. I finally froze up in the doorway at church. I told my Neuro and he said that I had Parkinson’s. Started me on entacapone,levodopa, carbidopa, and pramipexole and I still didn’t feel or get better January 2017 my neurologist and I decided to go with natural treatment and was introduced to Green House Herbal Clinic natural Parkinson’s disease Herbal formula, i had a total decline of symptoms with this Parkinson’s Herbal formula treatment.
Visit Green House Herbal Clinic official web-site ww w. greenhouseherbalclinic. com. The tremors, Shaking, Joint Stiffness and other symptoms has subsided. I am very pleased with this treatment. I feel very well now and exercise regularly, sometimes i totally forget i ever had Parkinson’s,Don’t give up hope, fellow sufferers. Share with friends!!