Dockets Management Staff (HFA-305)
Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852
To Whom It May Concern,
I AM ALS is a community-led 501(c)(3) non-profit with a mission to support individuals living with ALS, caregivers, and loved ones; empower people living with and impacted by Amyotrophic Lateral Sclerosis (ALS) to build awareness; and increase federal funding and strengthen federal policies for the ALS community.
As you are aware, ALS is a neurodegenerative disease that currently affects 1 in 300 people in the United States. It is a 100% fatal disease with no cure or significant treatment options. The impact of ALS on our nation’s Veterans, who are two times more likely to develop ALS compared to civilians, is significant. Post-9/11 deployed Veterans are ten times more likely to develop ALS. We urgently need to push forward innovative systems, including financial resources and support, to develop new technologies and find a treatment that can make ALS a chronic disease rather than a death sentence.
While we recognize the intent of this guidance to strengthen the accelerated approval (AA) pathway, we remain deeply concerned that this regulatory pathway does not currently work for ALS and other rapidly progressing, fatal diseases without established biomarkers that can serve as surrogate endpoints. The average life expectancy of a person living with ALS once they are diagnosed is 2-5 years. For people living with ALS, time is not a luxury. The current framework for accelerated approval relies heavily on the ability to measure a drug’s impact on a surrogate endpoint that is reasonably likely to predict clinical benefit. However, the majority of ALS lacks a validated biomarker that meets this threshold, leaving our community without a meaningful way to leverage this pathway. This creates a disparity where diseases with validated biomarkers can access earlier approvals, while those without, like ALS, are left with limited or worse, no options.
Key Concerns and Recommendations
- Flexibility in Surrogate Endpoints for ALS and Similar Diseases.
Given the unique challenges in ALS, we urge the FDA to provide greater flexibility in considering potential surrogate markers, including emerging biomarkers (such as neurofilament light), composite endpoints, or other measures that could serve as reasonable predictors of benefit.
Additionally, the FDA should provide clearer guidance on how novel biomarkers could be incorporated into the AA pathway and offer regulatory clarity for companies developing treatments for ALS.
- Alternative Approaches When Biomarkers Are Not Available.
The guidance should address how accelerated approval can be applied when validated surrogate endpoints do not exist.
Consideration should be given to clinical outcome assessments and other endpoints that, while not traditional biomarkers, may provide meaningful evidence of treatment impact in ALS.
- Balancing the Need for Confirmatory Trials Without Delaying Access.
While we support the importance of confirmatory trials, we are concerned that requiring these trials to be fully underway at the time of accelerated approval could inadvertently delay access for ALS patients.
We urge FDA to ensure that requirements for confirmatory trials do not create additional barriers for therapies that have demonstrated compelling early evidence of benefit in ALS.
- It is imperative that the 2019 Regulatory Guidance for ALS applies to your final guidance for accelerated approval. To quote from the transcript of the September 7, 2022, Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee:
Finally, regulatory flexibility is a prominent factor in our consideration of these data. It is important, critically so, and deserving of some focused discussion. Our underlying legal authority is clear and not only allowing but also endorsing and encouraging the application of regulatory flexibility in the setting of serious and life-threatening diseases. It is unquestionably relevant to ALS drug development, in general, and to our specific consideration of the data.
Conclusion
The ALS community remains hopeful that the accelerated approval pathway can be a viable option for ALS treatments. However, as it stands today, the lack of validated biomarkers prevents our community from fully benefiting from Accelerated Approval. This fact requires the community to search for novel pathways for approval because current options do not meet patient needs. We urge FDA to incorporate additional flexibility in determining what constitutes a reasonable surrogate endpoint and to ensure that this framework does not unintentionally exclude diseases like ALS from accelerated approval.
We appreciate FDA’s commitment to patients living with ALS and look forward to continued dialogue on how regulatory pathways can be adapted to better serve those facing rapidly progressing, fatal diseases.
Sincerely,
Andrea Goodman, CEO
I AM ALS