March 25, 2013
Margaret A. Hamburg, M.D., Commissioner
Office of the Commissioner
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
Janet Woodcock, M.D., Director
Center for Drug Evaluation and Research (CDER)
Food and Drug Administration
10001 New Hampshire Avenue Hillandale Building, 4th Floor
Silver Spring, MD 20993
Russell Katz, M.D., Director
Office of Drug Evaluation I – Division of Neurology Products (DNP)
Food and Drug Administration
10903 New Hampshire Avenue Bldg. 22, Rm. 4200
Silver Spring, MD 20993
Re: Docket No. FDA-2013-N-0035, Considerations Regarding Food and Drug Administration Review and Regulation of Drugs for the Treatment of Amyotrophic Lateral Sclerosis; Public Hearing
The ALS Association (ALSA) and Muscular Dystrophy Association (MDA) applaud the Food and Drug Administration’s Division of Neurology Products and Office of Special Health Issues for providing the national ALS community of patients, health care providers, researchers, caregivers, academia, federal agencies and industry the opportunity to share the ALS story, our concerns, perspectives and recommendations to the Agency during the ALS Public Hearing on February 25, 2013, as well as during the public comment period. We are especially grateful to the personnel of the Office of Special Health Issues led by Drs. David Banks and Steve Morrin for their leadership and extraordinary accommodations on the day of the Public Hearing. The needs of every member of our community were anticipated and the Agency proactively worked to meet them on the hearing day. This was evident by the fact that the Agency made every effort to accommodate the more than 200 people in attendance and the nearly 60 individuals who provided testimony, as well as the hundreds of comments submitted by community members who were physically unable to travel to White Oak on February 25. We believe that the Agency’s efforts — and the significant efforts of the ALS community to participate in the hearing — reflect a recognition that there is tremendous urgency within the ALS community to establish policies that not only help to expedite the development and review of new treatments, but also patient access to those treatments.
The ALS Association and MDA are the two largest organizations representing and serving people with ALS in the United States. Both organizations help lead the fight against the disease through programs that include funding and directing worldwide ALS research and therapy development, providing care and services to people with ALS and their families, raising awareness of the disease and working with members of Congress and government agencies to advocate legislative and regulatory policies that benefit the ALS community.
Despite the resources leveraged by our organizations, federal partners and other nonprofit groups, as well as the exemplary care offered by multidisciplinary clinical teams throughout the country, the unmet medical needs of this disease are staggering. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. It is a particularly cruel disease that destroys a person’s ability to control all muscle movement, typically striking adults in the prime of their lives. As the disease progresses, its victims become trapped inside a body they no longer can control, often unable to walk, talk, eat, breathe or even blink an eye. There is no effective treatment for ALS, typically no known cause and no cure. Military veterans are approximately twice as likely to die from ALS as those who have not served in the military, although the disease can affect anyone, regardless of their age, gender, race or ethnicity. ALS is 100 percent fatal — in an average of two to five years following diagnosis.
While we were extremely pleased with the momentum leading up to and throughout the February 25 FDA ALS Hearing, we must ensure that there are real outcomes from this Hearing and the open Docket ID: FDA-2013-N-0035. To that end, the following are the most immediate action items that The ALS Association and the Muscular Dystrophy Association feel would help accelerate ALS therapy development with leadership from the FDA.
- FDA ALS Hearing and public comment follow-up. We ask that the FDA convene a follow-up meeting of key stakeholders to review the priority themes raised during both public comment forums, and to develop a Plan of Action to respond to those themes and to chart a course forward that ensures a regular dialogue between the community and the Agency with the goal of maximizing the opportunities to bring effective and safe new treatments to ALS patients as soon as possible.
- Refining preclinical development and clinical trial design in ALS
- We encourage the FDA to work with our community and industry to identify ways in which we can be more creative and flexible in the design of trials, including considerations such as trial length and size; instances in which fewer trials would be acceptable; determine and provide clarification on what data should be analyzed in order to demonstrate efficacy and safety throughout the clinical trial process; identify and approve surrogate endpoints and biomarkers, and provide guidance on adaptive clinical trial design.
- We encourage the FDA to communicate earlier and more frequently with industry and the ALS community during the drug development and review process. Open, frequent and consistent communications between the Agency and those investigating new treatments for ALS will help to facilitate and expedite development by establishing mutual expectations, identifying and addressing challenges and concerns earlier in the development and review process, and will foster a partnership relationship between the Agency and those working to bring new treatments to people with ALS. Both ALSA and MDA recognize the Agency’s role as regulator, but we believe, with the assistance of our organizations and the greater ALS community, that together we can establish a treatment development and review process that is characterized by collaboration, trust, and a shared commitment to bringing effective and safe treatments to patients as soon as possible. We welcome opportunities to discuss with you and industry stakeholders how we may facilitate this partnership relationship, including assisting the Agency in identifying patients to participate on review panels.
- We encourage the FDA to work with our community to determine a way for conducting shorter, hypothesis-driven trials that look at biomarkers as surrogate endpoints.
In order to move faster toward effective therapeutics, it may be necessary to develop shorter, less-expensive trials to determine if a drug can hit a therapeutic target in order to test therapeutic hypotheses, prior to the initiation of efficacy trials. This will give a quicker answer to whether a potential therapeutic has any chance of success in treating ALS. We need to work with you on how to design such trials to answer these questions in a timely and cost-effective manner.
Within the last six years, genome-wide association and genome-sequencing studies have enabled us to identify new potential therapeutic targets for ALS. These studies support the long-held belief that sporadic ALS may not actually be "one disease," but a number of different diseases which are all manifested along a similar pathway. Thus treatments that work for one subset of patients may not be universally effective, and trials may need to be performed in small subgroups of patients, and then extended to larger groups.
In partnership with you, the ALS community needs to determine new rapid and cost-effective ways to conduct hypothesis-driven trials to answer key questions about the probability of success of novel therapeutics, which may require new and novel trial designs.
- We encourage the FDA to develop a guidance document for ALS clinical trials. Such a document could significantly help facilitate and speed ALS drug development, while also stimulating the field and encouraging more industry partners to enter the ALS market. We welcome the opportunity to collaborate with you on this document along with other ALS community and industry stakeholders.
- Benefit-risk assessment
ALS is 100 percent fatal. The risk of no treatment intervention bears inherent side effects that would otherwise be categorized as "intolerable", and — in clinical trial terms — "SAEs" (or "serious adverse events"). In other words, the symptoms of ALS rival most side effects from experimental drugs: paralysis, loss of speech, loss of ability to swallow, loss of ability to breathe. The risks of the disease itself almost always outweigh the risks of the side effects from legitimate investigational treatments. Therefore, the willingness of ALS patients to assume a significant amount of risk must be considered at every step of the development and review process, whether that be clinical trials, expanded access programs or marketing approval.
It is important to note that most practicing ALS physicians realize that the earlier their patients are treated, the better the chance of deriving benefit. However, we also suggest that the risks of therapeutic intervention increase as the disease progresses to compromise breathing and swallowing. Withholding experimental therapy for those with advanced disease to prevent severe complications is assumed to be best practice, but a more informed validated risk-benefit analysis would be of value both to ALS patients and physicians. We must better understand the benefit-risk tolerance of the ALS population and how that risk tolerance may change as the disease progresses. We look forward to working with the FDA on this vital issue and to submitting comments on the Agency’s recently released draft five-year plan that describes the FDA’s approach to developing a structured benefit-risk assessment framework. In advance of those comments, we would like to urge the agency to work with the ALS community to expedite the development of this framework as it applies to ALS especially considering that the average life span for someone diagnosed with ALS is just two to five years from diagnosis.
- Accelerated review of devices that impact the quality and length of life in ALS patients.
Careful studies have documented that respiratory dysfunction from diaphragm and intercostal muscle weakness in ALS patients responds to respiratory therapy, and more specifically to the use of bilevel positive air pressure (BIPAP) and average volume-assured pressure support (AVAPS) devices. With the use of these devices, there is documented improvement in quality of life and length of life. Our patients often have difficulty adjusting to the masks used with these devices, and by trial and error finally find the right one. Furthermore, cough-assist devices that help immobilize secretions provide meaningful therapy preventing aspiration and pneumonia.
ALS can progress very rapidly and time is of the essence in assisting respiratory function. Our patients suffer when such devices are not available because of the time it may take to get something approved. Accelerated review of such devices, and rapid implementation would be of tremendous value to the ALS patients and would help prolong meaningful quality and length of life.
The ALS Association and the Muscular Dystrophy Association recognize that the FDA is charged with regulatory oversight of over 25 percent of the products used by the country’s citizens, yet is significantly underfunded. We continue to support additional appropriations for the Agency to ensure that it has the resources necessary to fulfill its mission and, as part of that mission, to help ensure people with ALS have access to effective and safe treatments as soon as possible.
Again, The ALS Association and Muscular Dystrophy Association appreciate the opportunity to participate in this landmark public hearing and comment period and are grateful to the FDA for making the acceleration of ALS therapy development a priority. We look forward to continuing to work with the Agency to ensure that all available resources are leveraged as best as possible in this effort and that people with ALS have a voice in the drug development and approval processes. This is not just the goal of our two organizations. It is the goal of the entire ALS community. As you are aware, people with ALS and those who have been touched by the disease and who have submitted a considerable number of comments to the docket for this initiative do not have time to wait. Their message is clear: ALS patients, and those who represent them, want to be heard and are looking to the Agency to help them access treatments that may save their lives. The ALS Association and Muscular Dystrophy Association support them, and we look forward to continuing to work with you as we search for the treatment and cure for Lou Gehrig’s Disease.
President & CEO
The ALS Association
1275 K Street, NW, Suite 1050
Washington, DC 20005
Steven M. Derks
President & CEO
Muscular Dystrophy Association
3300 E. Sunrise Drive
Tucson, AZ 85718