By STEVEN ZECOLA
If asked, the leaders of the research organizations working on Parkinson’s disease would say that they have made tremendous progress and are optimistic on finding a cure for the disease.
In truth, this viewpoint understates the magnitude of the challenge and results in insufficient resources being devoted to PD. Given the size of the challenge versus the available resources, most research studies today don’t even include finding a cure for PD as part of their objective.
The time is ripe to get everybody on the same page when it comes to the objectives, resources, and timelines for PD research.
What We Know About Parkinson’s Disease
Parkinson’s disease (PD) is a chronic, progressive movement disorder that affects the lives of almost one million Americans. Roughly 50,000 of the inflicted people die each year, often by injuries from falling. The incidence of PD is expected to expand to 1.6 million in the U.S. by the year 2037.
The characteristic motor symptoms of PD are tremors, stiffness, slowed movement and impaired balance. Over time, people with PD also experience non-motor symptoms including changes in mood, problems with attention and memory, sleep disturbances, fatigue, and changes in bowel and bladder function. PD has a considerable impact on the quality of life.
The cost to treat PD has been estimated to be $50 billion a year, split equally between the direct cost of care and the indirect costs of lost opportunities for the patients and caregivers.
PD is a complex disease which is thought to result from an interaction between genetic and environmental risk factors. More than 20 genes have been identified as having an impact on the onset of PD. However, genetic variation is estimated to contribute only about 25% to the overall risk of developing PD. Moreover, like the majority of neurodegenerative disorders, little insight is available on how specific sequence variations contribute to disease development and progression.
In short, the exact cause of PD is unknown. However, we know that that there is more than one manifestation of the disease. We can also reasonably conclude that more than one single element or therapy will be required to cure the disease.
What We Know About Parkinson’s Disease Research
PD was first discovered and described by James Parkinson in 1817 in London, England.
In 1911, the efforts of Kazimierz Funk, a Polish biochemist, paid off with the identification of Levodopa as a potential treatment.
By 1970, the FDA approved the use of Levodopa combined with Carbidopa for the treatment of PD. Since then, this combination has remained the gold standard for treatment.
During the last 50 years, many attempts have been made to improve this treatment and avoid its long-term complications. While several enhancements have been approved by the FDA and have helped patients, no treatment has cured or slowed the progression of the disease.
The U.S. Federal Government’s National Institute of Health is the largest funder of Parkinson’s research at roughly $250 million per year, with the National Institute of Neurological Disorders and Strokes (NINDS) funding about half of that amount.
A typical Funding Opportunity Announcement (FOA) by NINDS would invite applications for program funding. According to its website, “the overarching goal of this program is to support specialized research Centers that work collaboratively as well as independently to define the causes of and discover improved treatments for Parkinson’s disease”. This goal doesn’t address finding a cure.
A number of other organizations also fund Parkinson’s research through grants. For example:
Michael J Fox Foundation (MJFF) – $1 billion since inception
Parkinson’s Foundation – $350 million since 1957
Aligning Science Across Parkinson’s (ASAP) – $161M over three years
American Parkinson Disease Association – $51 million over the past decade
Very few of the independent Foundation Grants are focused on finding a cure to PD, with the exception of the MJFF.
The ClinicalTrials.gov website lists 2959 clinical trials of Parkinson’s disease with 534 trials actively recruiting.
The vast majority of these trials are either unfunded or do not address the issue of finding a cure for Parkinson’s disease.
Moreover, the report simply does not pass the numerical “smell test”. First, there aren’t enough PD volunteers in the United States or elsewhere to support 534 on-going clinical trials. Second, there are not enough funds to support 534 ongoing trials. The average Phase 1 trial costs about $5 million in out-of-pocket costs.
It would require at least $2.5 billion to support 534 trials. The annual research spending on Parkinson’s disease is about $350 million. The numbers don’t jive and therefore the report is misleading, at best.
The typical FDA drug approval process requires three phases of successful testing with increasing patient enrollment.
On average, getting the approval of one drug from the FDA costs over $1 billion in research and results in over 12 years of regulatory scrutiny. To make matters worse, this delay does not include FDA’s involvement in pre-clinical research such as what occurred with embryonic stem cells or with the tests of gene variations (of which there are many).
The large pharmaceutical companies support this regulatory structure because it reduces competitive entry from new drugs and helps to maintain high prices for drugs. On the other hand, as smaller companies show success in Phase 1 and/or Phase 2 trials, Big Pharma often provides resources for completing the trials in exchange for an ownership interest, or they simply acquire the company. This dynamic has been at play for decades to the immense benefit of Big Pharma, and not to many others.
The FDA’s objective in this process is to prevent harm to the public, not to find a cure for costly diseases – and it does a very good job at achieving its objective.
What’s Wrong with the Current Research Approach?
There are several problems with the current research approach for PD.
First, after 50 years of trying, there is no clear path to a cure. In fact, it is hard to find any condition that makes it easier to cure PD. The people in charge of PD research must acknowledge that there is something wrong with this picture. Without that acknowledgement, their organizations will have no incentive to change what they are comfortable doing.
Second, the “numbers” related to PD research reflect a large disconnect. On the current course, there will over $650 billion in costs incurred by society from Parkinson’s disease over the coming decade. Out of the NIH’s $40+ billion annual research budget, about $250 million is allocated each year to research for PD. If that amount were doubled and resulted in a cure being identified within 5 years, the payback on the incremental funding would be $520 for every incremental $1 invested. What business would not invest $1 now to achieve $520 in cost-savings in the not-to-distant future? Obviously, there is an imbalance between opportunity and investment when it comes to funding PD research. It appears that the NIH allocates research dollars based, in large part, on the number of deaths from a disease (of which PD is not a high producer) and not from the overall cost to society of the various diseases (for which PD ranks relatively higher).
Third, most researchers are testing only one element (e.g., a protein, a drug, a genetic correction) in clinical trials. However, there is likely to be a combination of elements required to cure the disease. Getting the right combination could take ten or more tries after the initial approval. Each try would be subject to the FDA’s costly and time-consuming processes. In other words, the present course is likely to entail several decades of additional research before achieving an FDA approval of a multi-faceted cure.
Fourth, even if the current research budget were significantly increased, there is no guarantee that the funds will be used effectively and efficiently in pursuit of a cure. While there is a smattering of communications and collaboration in the field, PD research endeavors are not well coordinated. For example, many funded programs are directed to basic research, while promising approaches from the lab face “The Valley of Death” due to a lack of funding.
A Better Approach to Finding a Cure for PD
The first step to finding a cure is to recognize that a change in approach is needed. At the top of the list is that PD is likely to require a combination of therapies to enable a cure. As with other fields, the leaders should look to “technology” to give significant improvements in productivity to address this challenge.
In fact, improvements in DNA sequencing, genome editing based on the microbial CRISPR-Cas adaptive immune system, human pluripotent stem cell technology, and genome-wide association studies (GWAS) have opened the possibility of finding a complex solution to a complex problem. Further progress will require an increased focus on the tools needed to make that happen.
Second, Parkinson’s disease research needs an industry-wide organization to enhance communications, collaboration and focus. As an important component, there should be a Parkinson’s Research Council (PRC) that sets the direction of research and approves the funding initiatives of its five members for PD projects above $2 million.
The Research Council should be composed of one member elected from each of the NINDS, the Parkinson’s Foundation, the Michael J. Fox Foundation, Aligning Science Across Parkinson’s and an annual rotating seat elected by a university with an expertise in PD. A representative from the FDA should hold a non-voting seat.
Additionally, a newly-formed virtual organization under the PRC should be created with an appointee from each accredited PD research organization. There would be regular communications of PD research findings, and an annual meeting held via video conference to address performance versus expectations for the prior year, lessons learned, and plans for the coming year.
The third step to finding a cure for PD on an expeditated basis is to change the FDA regulatory paradigm. The FDA should be foreclosed from involvement in pre-clinical PD research. Also, the FDA should be removed from its self-imposed position of approving genetic health and carrier information. Finally, FDA’s role in Phase 1 and Phase 2 PD trials should be limited to observation.
PD research is spread out in many directions, but after 50 years of trying, it is still decades away from finding a cure. That realization must sink in to its participants before a change in approach is accepted.
The requisite changes are: 1) a focus on multivariate solutions; 2) an overlay industry structure that coordinates the focus and funding of PD research and tracks performance and 3) a modified approach to FDA regulation. Once these changes are put in place, the funding of PD research should be increased substantially over the next several years with the singular objective of finding a cure.
Steven Zecola is the managing director of Competitive Strategies and has held executive positions in large companies and the federal government.