Comments of Michael Gollin in response to FDA’s notice of Public Hearing
(February 25, 2013) [Docket No. FDA-2013-N-0035]
Considerations Regarding Food and Drug Administration Review and Regulation of Drugs for the Treatment of Amyotrophic Lateral Sclerosis
See (MDA ALS Newsmagazine, 2/25/2013, “FDA Hearing Highlights ALS Drug Development Concerns”)
Accelerate innovation for ALS therapies
by building public-private partnerships around
patient centered, positive benefit-risk ratios
My name is Michael Gollin. I am a patent attorney in private practice. I also teach a business school course in strategic management of intellectual property, and write extensively about innovation. I work regularly with inventors, drug companies, and research institutes seeking to find cures for diseases, and techniques for diagnosis, and so I understand the many obstacles to be overcome in research, development, and delivery of new medicines.
But I came here today as an individual who is personally familiar with this cruel and frightening disease called ALS, to speak about the unique needs of ALS patients. I hope my comments can help accelerate innovation towards finding a cure for ALS, and save lives.
As with any disease, medical progress for ALS involves coordinated effort by both the private and public sectors, and innovation requires people to take risks — not foolish risks, but calculated risks. How should we calculate the ratio of risk and reward? The answer varies dramatically among three sets of stakeholders: innovators, regulators, and ALS patients.
Innovators (whether in industry or academia) face the risk of being wrong, of being criticized by their peers, of wasting time and money. They take these risks in expectation of rewards from their creative work — fame, fortune, and pride in doing work that can improve people’s lives. Industry, because of its need for profit, uses financial models of “return on investment” to calculate risk-benefit ratios in a decision such as whether to invest in ALS research, and failure is measured by economic loss. Academic researchers of ALS focus on different risk-reward calculations based on peer reviews of quality of science and likelihood of interesting outcomes. Failure is measured by loss of grants and poor results.
FDA regulators use a strict clinical risk-benefit calculation centered on safety and efficacy of new drugs. Simply put, FDA regulators focus on the risk that an approved drug may turn out to be unsafe or ineffective. To be approved for sale, a new drug must first be shown to be safe as used by a patient, and then the drug must have proven clinical efficacy in treating the particular disease. An FDA-centered view of risk centers on the possibility that an approved drug may turn out to be unsafe. However, FDA makes no risk-benefit calculation at all about the many therapies that are not considered “drugs” – alternative treatments, dietary supplements, compounded pharmaceuticals, and so on. And FDA is not focused on the innovator’s risks –wasted money and wasted time.
ALS patients confront a very different calculation. The risk of doing nothing is overwhelming. The risk of taking an unproven drug or therapy pales in comparison to the certainty of creeping paralysis and premature death. The only approved drug, Riluzole, was shown to provide, on average, an extension of only 2-3 months before tracheostomy or death. But even such a short survival improvement is invaluable to ALS patients and their families. It is good that Riluzole was approved, and more approvals are needed. FDA needs to modify its risk-benefit calculation to be consistent with the patient-centered perspective.
First and foremost, ALS patients desperately want to find new and better ways to slow disease progression, and they want a cure — now. In the meantime, they are willing to try new diets, nutritional supplements and other alternative therapies. The risk presented by ALS and the lack of available drugs makes ALS patients susceptible to questionable or unscrupulous vendors providing completely untested pseudo-therapies, which may be useless, present substantial health risks, and come with great financial costs that ALS patients can ill afford.
Second, ALS patients need biomarkers and other surrogates to track disease progress better than the antiquated and subjective ALS Functional Rating Score. Moreover, earlier diagnostics would give patients more time to adapt their lives to their new central reality. FDA should explore and encourage new diagnostics and measures of disease, and I urge such support.
To put my point simply –there are no good therapies available to reduce the severity of ALS and prolong life, and inadequate measures of disease progress, so it is to be expected that patients will try just about anything. The risk of doing nothing outweighs the risk of possible side effects. FDA should have a bias toward approving any drug for an ALS clinical trial if it has a plausible biological mechanism, adequate markers of clinical outcomes, and an absence of major toxicity.
In addition to representing pharmaceutical industry clients, my work has included participating as a lawyer in numerous alternative therapy/shaman/dietary supplement projects, including efforts to link protection of biodiversity to herbal medicine production in Belize, India, and other developing countries, and I have patented natural product formulations. This experience leads me to conclude that there is strong evidence that the placebo effect (which may be a form of hope) is demonstrably therapeutic in many situations, and that some care is generally better than none, as long as it is not toxic (or expensive). As with sick people around the world, many ALS patients want to do something more therapeutic than taking Riluzole and maintaining a healthy diet.
From a patient centered view of risk-reward ratios, anything FDA can do to accelerate approval of new ALS drugs will improve upon the current standard of care– Riluzole alone or Riluzole plus unproven possibly dangerous alternative therapies.
FDA should adopt a variable risk model for approval of new drugs, taking the patient-centered view into account. As long as a drug holds reasonable promise, even if it is less than the standard that may be required for other drugs, ALS patients want access to it. Other speakers can detail the regulatory options, which include fast Phase I safety tests, expanded Phase II trials to allow more patients to participate, quicker approvals with post-approval Phase IV surveillance, and expanded off-label drug use for potential therapeutics.
Because the fastest progress results from cooperation between industry and the public/academic sectors, FDA should find ways to make it easier and more productive for both sectors to work together, and to center that public-private cooperation on patient concerns.
When there are no approved effective therapies, patients are prepared to take more chances. FDA can play an important role by helping filter the untried remedies through clinical standards.
For example, FDA should support the efforts of ALSUntangled.com, an excellent example of patient-centered risk-reward analysis. (www.alsuntangled.com) Despite incomplete data, and the absence of blinded clinical trials, these doctors do their best to weigh the risks and benefits of therapies patients are already pursuing – because of patient interest in these therapies. Their reports show for example that spirulina is ineffective for ALS and potentially toxic, bee stings are impractical in any dose that might conceivably be effective, coconut oil is potentially therapeutic, and cannabis and intravenous sodium chlorite warrant further research. Another several dozen alternative and off-label ALS treatments are pending review.
The patient advocacy groups, MDA and ALSA, also serve as vital channels of information for the ALS community, and sponsors of research. However, these groups have limited resources to conduct research and metadata reviews.
There are several Cochrane Reviews of ALS therapies (see http://www.cochrane.org/search/site/amyotrophic%20lateral%20sclerosis), but these are not patient-centered, and are primarily focused on the quality of the research. ALSUntangled is better focused on the interests of ALS patients.
Cochrane Reviews and ALS Untangled are inadequate for ALS patients because they (a) most often conclude that “the science is inconclusive”, (b) lack any review of most of these types of approaches, and (c) take far too long to complete a single review. The question ALS patients face is not “how good is the quality of the science” or “can the science be improved in the future” but rather “is this particular approach worth trying now. rather than doing nothing”.
FDA could help by convening expert panels that could add FDA expertise and resources to leverage and accelerate the crucial work of ALS Untangled and other groups.
By using its public resources to help answer the questions presented by ALS patients, FDA can help stimulate productive private efforts. For example, more companies may be able to attract funding to advance a product to clinical trials for FDA approval if public-generated information validates their product. With publicly validated data, more companies may invest in developing dietary supplement and other alternative therapies that are not subject to FDA approval. And validated data may successfully prevent some companies and practitioners from offering useless or dangerous products. Finally, access to such expanded information will empower ALS patients, help them be wise consumers of health care products and services, help them be strong advocates, and improve the quality of their lives.
Because the fastest progress results from cooperation between industry and the public/academic sectors, FDA should find ways to make it easier and more productive for both sectors to work together, and to center that public-private cooperation on patient concerns. Thank you.