Perry D. Cohen PhD
May 2002
Background
Corporate Strategies
Paying for prescription drugs
Parkinson Pipeline Project
Parkinson’s Research Partners
The emphasis on brain science in the “Decade of the Brain” and the growing investments in basic science at NIH and elsewhere have created a reservoir of neuro-science knowledge now ripe for translation into dramatic improvements in treatment for neuro-degenerative diseases. Dramatic increases in research on Parkinson’s Disease have been spurred by the NIH Parkinson’s Research Agenda and stepped up private fund raising. With momentum building in genomics and understanding of the disease process at the cellular level, cures could be found in the next 5 years, but there's a catch. Tacked on to scientific discovery is a lengthy ‘pipeline,’ regulated by FDA, of translational research to create a new treatment, followed by extensive testing in animal models and evaluation of safety and effectiveness for humans. The Tufts Center for the Study of Drug Development estimates that the time from scientific discovery to market now averages 14.2 years for neurology this time is longer. Fortunately for those of us who already have PD, a new class of neuro-protective compounds, which promise to slow the progression is now reaching clinical phases of evaluation by FDA. As the disease progresses for each of us with PD, getting these new treatments through the pipeline is to me a critical task to buy time until the promised cures are available.
My professional background is health services research and consulting, including NIH and other public health agencies and recently with PDF on Quality, Access, and Delivery of Parkinson’s Care (Quadpac) where we working on much needed ‘care initiatives’ to make today’s best treatment more available to PWP by demonstrating the effectiveness of models comprehensive care that integrate medical care, rehab and long term care services. I have PD, but I am not ready personally to settle for long term care, even that offered by the best integrated care system. Diagnosed in 1996, I don't feel I have time to wait for the 'cure' given the pace of science and the pipeline to treatment. If we cannot pin our hopes on basic research, what can we do?
When advocates in Washington met 3 years ago with Dr. Harold Varmus, Director of NIH, he said, "you should be lobbying industry." He was right. Working from the knowledge produced by science (NIH’s primary mission), industry has the role of developing, manufacturing and distributing the treatments. I have been involved with PD advocacy in Washington for all of the 6 years since my diagnosis (See the wonderful book by Herman and Krebs, When Parkinson’s Strikes Early). I had worked with NIH in the past and indeed the meeting with Dr. Varmus lead to establishment of a strong partnership with NIH, particularly with Dr. Gerald Fischbach Director of NINDS, who embraced the NIH Parkinson’s Research Agenda and made PD a priority for NIH. I had learned a little about lobbying for NIH on Capitol Hill through my work on passing the Udall Act, but I did not know how to lobby industry.
A year later in March, 2000, I became a patient representative at FDA for PD when I was recruited to serve on the advisory committee which reviewed Deep Brain Stimulation. After meeting with other patient representatives, mainly from AIDS and Cancer, and going through FDA reviewer training, I realized the way to influence industry is through FDA and the process of regulating the evaluation and approval of new treatments.
Last year, I initiated a program for the Parkinsons Disease Foundation (PDF), called the pipeline project (AKA Parkinson-FDA-Industry initiative, see , to facilitate and expedite new treatments through the regulatory process. The intention is to add the unique patient perspective, insight and credibility to the process of development of safe, effective, and ‘timely' new treatments for people with Parkinson's (PWP). The goal will be attained through collaboration with sponsors and researchers for Investigational New Drugs (IND) or other treatments and with the FDA . The project has three integrated components: 1) Consultation to sponsors of clinical research, 2) Consultation to FDA, and 3) Consultation to researchers and constituencies. These components are supported by a national intelligence gathering system which provides up-to-date information on the dozen or more promising treatments in the pipeline and educational materials for the patient advocates and the community.
The Patient Advisor (PA) program has been the first component of the Pipeline project to get started. Similar to “community advisors” for AIDS), PA’s assist the companies with elements of the design of clinical trials pertinent to our expertise and perspective. These panels provide a channel for information from the company to the PD population. We also provide independent advice to the FDA, similar to oncology, where advocates are now being recruited to serve as “patient consultants” in the pre-approval, clinical trial phase of cancer drug development. These patient advisors provide guidance to the FDA and to the drug sponsor on topics such as clinical trial design, endpoint determination, expanded access protocol development, and clinical trial patient recruitment strategies. More flexible regulatory mechanisms, such as accelerated review and fast tracking procedures, introduced into the FDA process for serious and life threatening illnesses, including PD, can also be influenced by patient advisors and outside patient groups.
Our intention is to be a strong independent voice with respect to both the sponsor and the FDA for the needs of potential research subjects and patients generally starting as early as possible in the clinical phases of drug evaluation and approval. As an independent voice we will have greater credibility with FDA and the patient population. The Director of the Neuro-pharmacological Products Division of FDA has agreed in concept to recognize the patient advisors as a independent role provided that appropriate confidentiality agreements are in place, and these agreements allow direct communication between FDA and the Advisor. This patient advisory activity has been initiated with two bio-tech firms working on development of neuro-protective medications.
To support the goals of the project, a workgroup has been formed to create an extensive database and tracking system designed to monitor the development of PD drugs and other new treatments in the pipeline using public information. There are more than a dozen members of the design team, including a UK PWP who intends to extend this project to the European Medical Evaluation Agency, EMEA.
As patients with a chronic degenerative condition, our interests are almost totally aligned with industry in the desire for safe, effective, and timely new treatments. While the FDA’s mandate is to ensure that treatments are safe and effective, thanks to patent law and intellectual property protection, pharmaceutical companies are highly motivated by big profits to get improved treatments to market fast. Working with FDA we need to try to find ways to accelerate the process (using fast-tracking and accelerated review provisions of FDA law and working to speed recruitment and process of clinical research ) without sacrificing a reasonable assessment from the patient perspective of risk - benefit tradeoff of safety and effectiveness.
The dynamics of the pharmaceutical industry are an important element in the delivery of the cure. Development of a new drug is a very long and costly endeavor with highly uncertain outcome. Murphy’s law, “whatever can go wrong will go wrong,” is in full force when it comes to intervening in the biochemistry of the brain. In addition corporate strategies, investor expectations, and the size, maturity, and profitability of the company are also important factors in determining the amount of investment devoted to developing a drug.
The case of development of neuro-immunophilins, a very promising new treatment for PD, illustrates the enormous risks and costs involved in the process. Much of the innovation in the development of new medications comes from small biotech firms, often with no revenues or profits, devoted to R&D on a good idea of a scientist. For example, Guilford Pharmaceuticals was formed by scientists from Johns Hopkins who were working on neuro-immunophilin ligands (NIL) and raised money in capital markets to develop these ideas. The nerve regeneration properties of neuro-immunophilins ligands (NIL) were first identified in 1990!! Four years ago Guilford licensed development and marketing to Amgen, a large biotech firm. After going through several variations a compound called NIL-A was selected for human tests. Last summer, this compound finished the phase II testing required by the FDA for safety and some indication of efficacy, but is still 3+ years from the market as the rights are being transferred back to Guilford from Amgen. As we know, the testing often presents great challenges to be overcome. For example GDNF worked well in animals, but Amgen was not able to get it to the right spot in the brain so new methods are being studied by independent researchers. Risk capital for start-up companies is looking for 100 to 1 returns to pay for all the failures. When we see a blockbuster drug, we don’t see all the ideas that were pursued with varying costs to dead ends. Developing new drugs is so costly and so risky, financial advisors recommend owning several companies' stock to diversify the risk. It could be a good idea to start an investment pool among PWP to diversify the risk and provide needed capital to companies like Guilford who lose money on operations, spending their capital on research for new products.
Recent phase II clinical trials (to demonstrate safety and some indication of efficacy) for NIL-A showed a very safe compound, but failed to show statistically significant improvements in treatment groups over the placebo group on the UPDRS clinical rating scale for PD. While the headline was negative from what I could glean from the press release and talking with knowledgeable people, there were a number of indications of efficacy. One example is the results from imaging studies (spect scans). The placebo effect is known to be very strong in PD. Recent research, which links the placebo effect to expectations of rewards which releases dopamine in the brain, provides an explanation of the phase II findings. Instead of declining 7% in 6 months as expected, the imaging studies of the nerve endings in placebo group increased 3% after 12 weeks and showed almost no change after 24 weeks. The high dose group increased 9% after 12 weeks and 2.5% after 24 weeks. Increasing nerve growth for a degenerative condition is a positive result, but the placebo group also fared well so differences were not detectable. Given the extraordinarily high expectations we all had for this trial the placebo effect was apparently greater than previous studies which indicated a minimum 6 months to wash out the placebo effect. Further study is needed. Also, anecdotal reports of improvements in non motor symptoms of PD, not treatable by sinemet including mood, cognition and autonomic failures such as constipation, were not explicitly studied in the Amgen trial. These effects also deserve further investigation.
Corporate strategy played a big role in Amgen’s decision to drop NIL-A and in the negative spin on the headlines of the press release on the trial results. Amgen wanted a home run, so they weren't satisfied with the single they got (still a base hit). They were moving out of neuroscience after many years and large investments in research that did not have much pay back. I heard on CNBC that Amgen has found it difficult to develop new drugs to continue its high growth so it is using its elevated stock price to buy growth. It is interesting that a company that became the largest Biotech through R&D is now moving out of that mode of operation. This change in strategy is partly a result of size (its harder to grow at the same rate as you get bigger), which may also be reflected in the change in senior management earlier this year (including the Chairman who retired and many of the senior executives changed jobs). I had contacts with the Vice President for Clinical Development who switched jobs with the Professional Relations VP. The sell off in Amgen stock (down 8 points in the first 2 days after announcing the merger) could be Investors recognizing that the big rewards from home runs aren't going to come from Amgen, but rather from companies like Immunex, and hopefully Guilford or another firm which finds and develops a cure for PD.
The Amgen case points out that our fate is not a function of science alone. But how do you lobby private industry? Management doesn't run for office and directors are elected by investors on the basis of shares of ownership. Although patients are the ultimate beneficiary of the products, drug companies do not view patients as customer; rather physicians and 3rd party payers are the main customers. While a group of advocates could buy single shares each and be noticed in an annual meeting, this strategy would likely be effective in a limited range of situations if at all.
Working with the FDA will give us one avenue to at least get the attention of industry. I have been meeting with the Director of the Neuro-pharmacological Products Division of the FDA on a regular basis, where we have been discussing how to have our PWP Advisors work with FDA as well as industry to be a independent voice of the views of patients in the clinical phases of drug evaluation and approval for PD.
Corporate strategies and investors decisions can undermine our fate.
We need to develop strategies to counter this risk. If Guilford
were not available with resources to pick up the ball, neuro-immunophilins
may be dead without an adequate test. The non-scientific consensus of people
who have taken the drug or placebo is that it helps at least some of the
people dramatically.
When it comes to price our interests diverge from industry. The questions are who pays for prescription drugs and how much? how much profit is needed to provide incentive to industry? and are price controls the answer? The issue is a concern for the individual depending on which insurance group if any he/she falls into. This question can also be addressed on a macro level of relative payment by different countries as well as the total cost to consumers versus profits to producers.
Individuals with PD of course need very good insurance coverage for medications. Medicare does not cover prescription drugs except for the minority of seniors who have signed up for managed care plans. For non-medicare as well as medicare, the coverage for medications seems to be going in the wrong direction as health plans raise copays and put caps on coverage so the sickest people who are lucky enough to have effective treatments (that’s us) pay the most. With no government intervention requiring minimum coverage the health plans are motivated to limit coverage in order to attract the healthier people with low premiums. Although it is a form of tax, I think it would be fair for the society to set a standard minimum coverage including catastrophic coverage after a certain level of out of pocket costs to protect people with very high costs from dire choices of food or medicine. Ironically medicare recipients had such catastrophic coverage in the 80's but in what I believe were terribly misguided protests over paying the few hundred $ in premiums, the senior lobby pressured the congress to rescind this coverage.
The Innovation Imperative. Bolstered by the engine of basic science largely funded by NIH and the system of patent protections and insurance coverage for health care provides powerful economic incentive for taking huge risks of developing new treatments. We who benefit from this development especially don’t want to throw out the baby (innovation) with the bath water (the high cost of drugs). Among developed countries, whether the US should pay far more than Europe and Canada is another issue as is the obligation toward lesser developed countries.
My view is that market forces and the free exchange of information and products is the most efficient and effective, although not perfect, method to set prices. So if Canada and Europe enjoy lower prices, loosening restrictions on mail order or other ways to import prescription drugs will give consumers in the US more leverage in transactions to squeeze excess profits from industry. Unfortunately, just last year an effort to do this was turned back by the Secretary of HHS, citing lower manufacturing standards and inability to control the quality of the product produced overseas. It appears that we have our work cut out for us politically to level prices across countries by loosening restrictions on buying from outside the US.
Price controls are not the answer in my view. I do not think price controls have ever worked effectively in a market economy because of the distortions they cause in economic activity, When it comes to who pays and how much, I think forming buyer cooperatives, large groups of consumers, by state or multi state will also give consumers in the US more leverage in transactions to squeeze excess profits from industry.
For Example, the DC Prescription Drug Task Force is considering joining
the New England Consortium. Formed by the Insurance Commissioner
in DC, this task force is taking a three step approach to address the issue
of lack of coverage and the high and increasing cost of medicine.
In addition to buying cooperatives, a consumer counseling service is contemplated
to help people with high drug costs can understand the complex of choices
available from patient assistant programs of drug companies and charities.
The third component is a subsidy for catastrophic coverage. One source
of revenue contemplated is the income from the 8 figure proceeds from the
conversion to for-profit status of a large tax exempt health plan.
Parkinson’s Research Partners - Consultation to Researchers and Patients
Drawing on our most valuable asset, the people with Parkinson's (PWP), the “Research Partners” program establishes a network of patient advocates that work on the front lines in clinical research settings to preform a number of functions aimed at facilitating research, and in general putting the face of the patient and the urgency that we feel in contact with our various constituencies. This plan is wonderfully simple and has a great many pieces already in place. It is simply to formally link up a Parkinson's patient advocate with one or more principal Parkinson's clinical researchers at each of the major Parkinson's research facilities in the country. The partners are trained and linked together by the program staff which not only cross fertilizes the education of the partner, but in the process also promotes collaboration among researchers. There are eleven Udall centers and maybe another 15 or 20 areas where major Research in Parkinson's is taking place. By coincidence, these 30-35 centers are located in the top metropolitan areas (where the votes in congress are).
This network would accomplish a number of goals:
- Facilitate clinical research processes, particularly informed consent and recruitment of subjects
- Educate patients and providers on processes for drug evaluation and approval
- Keep the Parkinson's community informed of the latest research
- Keep the researchers aware of the latest funding sources and priorities
- Serve as the background of a political advocacy network
- Make sure that the researchers put a human face on Parkinson's disease
Grassroots PD Partners would perform a variety of functions in
their local settings including research advocacy and educational activities
for patients and providers in each site. People who would fill these
roles are for the most part experienced advocates at national and local
levels. Many have been trained as advocates and have come together
to work for the Parkinson's cause at the annual policy forum of PAN.
Training and sharing of information for this new role will be coordinated
with or carried out in conjunction with the PAN Forum. Specifically for
liaison to industry and the FDA, the grassroots representatives would work
to enhance clinical trials through such activities as:
- assisting in recruiting in educating subjects for clinical trials
- assisting in preparation of the IRB approvals
- assisting on-going safety surveillance and adverse event reporting.
- educating patients on the requirements of processes of drug evaluation
and approval
A national level PWP assembly will be formed to link the vast talent pool available in the Parkinson’s community to ongoing efforts of PD organizations. Similar to the original conception of the Parkinson’s Alliance, this group will serve as a vehicle for communication to the field as well as for incorporation of the perspectives of the field into the national policy agenda for PWP. As the voice of PWP, this assembly will work with all PD organizations to promote a more unified and balanced effort to address the continuum basic research and clinical service for the million Americans with PD. These grass roots representatives will provide a collective voice of patients in discussions with policy makers, industry, and regulators on the issue of evaluating the risk and benefit trade-off in the approval of new treatments for PD and other issues of vital concern to PWP.
Research partners are an essential component of finding and delivering the cure. The outcomes of the partnership between PWP and clinical/basic science will be manifested in the research process specifically by facilitating interactions between patients and researchers and more generally by fostering collaboration among researchers. Partners provide a resource to recruit and maintain participants in clinical trials with particular attention to safety of human subjects. The Committee on Assessing the System for Protection of Human Research Subjects of the National Academy of Sciences, Institute of Medicine has identified the patient counseling and advocacy role as an important component of an effective system of human subjects protection.
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This essay appeared in Parkinsonian People, Spring 2002. Much of the content is derived from my postings on the MGH Braintalk Forum on Parkinson's Disease. I would like to acknowledge my fellow participants in that forum for the information and stimulation from which this essay is derived.