Needed: A National Agenda for Advancing Therapies for Chronic Progressive Diseases
Every day, we are failing patients with chronic progressive neurological, neuromuscular, and genetic diseases.
The brouhaha about Sarepta and Elevidys[1][2] is just a reminder that we are not systematically addressing the common plight of these patients: 1/ their disease is progressive and they cannot wait for safer and more effective treatments to be developed and approved, 2/ they are willing to take on a lot more “safety risk” and “efficacy uncertainty” for even the slightest chance of a benefit, and 3/ they are dealing with complex heterogenous diseases that, regardless of patient population size, will make drug discovery and development difficult.
It is past time to help these patients with something responsive to their situation. We need: 1/ a regulatory structure and 2/ scientifically and statistically-based evaluatory standards that address chronic progressive disabling and fatal diseases and
responds to patient needs, and
encourages research and innovation
While rare disease patients will benefit greatly from such an approach, it attempts to respond to a more personal need. For the parent of a child with Duchenne’s Muscular Dystrophy the most compelling challenge is that the disease is progressive, not whether there are 75 or 3,000 other children.
FDA doesn’t have to give in to chaos; it just needs to provide a more comprehensive and thoughtful framework that is “fit for purpose” and responsive to the plight of these patients.
FDA’s longstanding vehicle--treatment IND’s--is a necessary and helpful response, but not a sufficient one.
We never seem to get to the central problem with constructing a framework for chronic progressive debilitating and fatal diseases: our lack of knowledge and paucity of tools to develop and evaluate therapies for these diseases.
FDA’s new Rare Disease Innovation Hub[3] and Office of Regulatory and Emerging Diseases[4] are addressing some of the issues, but neither has the resources nor authority to comprehensively approach the unique patient impact of chronic progressive diseases. A good approach would be for FDA or the patient community to seek the help of the Reagan-Udall Foundation for the FDA.
In sum, there is a compelling class issue (therapies for progressive debilitating and fatal diseases) that never gets addressed if we continue to insist on it being dealt with exclusively by one-off, product-by-product decisions, as we have with Sarepta.
Sarepta. With limited knowledge and tools, clinical trials for chronic progressive disease therapies are often going to produce less robust efficacy data than other products. What went wrong two weeks ago was an attempt to use unevaluated patient deaths in ongoing clinical trials of an unapproved indication (a safety issue) as an excuse to re-litigate the efficacy component of Sarepta’s approved indication. Ultimately, things worked out the way they should have: a stop-order on the clinical trials…and only a short hold for the approved indication while the company and FDA determined whether the death of a patient on the approved indication was treatment related.
In the interim, there were unattributed reports that FDA, regardless of the outcome of the safety review, was going to insist on a new study of efficacy and safety before allowing the product back on the market.[5] That was not appropriate and maybe wouldn’t have been a possibility if there were a larger framework in place. Good regulatory decisions need to start with an acknowledgment of the gaps in what is known and the lack of good measuring tools for progressive debilitating and fatal diseases….and the recognition that decisions often need to be made on less than perfect data, especially for patients whose time is running out.
We need to build a future that advances knowledge and develops tools for progressive diseases. At least one commentator posed the Sarepta situation as a dichotomy: either the drug doesn't work, or it does work, and the company/advocates have not worked hard enough at finding the right study design.
There is a third possibility--especially relevant to progressive debilitating neurological, neuromuscular, and genetic diseases---that we don’t yet have the tools and understanding to construct study designs that accurately evaluate efficacy in some of these complex diseases, especially those with very small orphan populations (such as DMD) and/or heterogenous progression (such as ALS).
A couple of examples from the recent past illustrate the impact of new knowledge and tools. Better and less controversial regulatory decisions are made today because 1/ someone decided 20 years ago to examine whether Bayesian statistics[6] might contribute fresh insights to clinical trial analysis and 2/ someone decided 10 years ago to examine whether umbrella and basket trials[7] could produce more insights with a smaller resource investment.
Drugs for progressive debilitating and fatal diseases will always involve tough decisions because “delaying for more certainty” has such a cruel impact.
But if we see the problem as one of inadequate knowledge and too few tools, maybe we can build a framework and standards that will enable a future where we 1/ treat these patients more compassionately and 2/ make drug development in this area more productive and less controversial.
[1] Elevidys is Sarepta’s gene therapy for Duchenne’s Muscular Dystrophy.
[2] I have been in and out of this issue over the years. Sometimes, I was helping clients with orphan products targeted at progressive diseases; other times, I have been working on potential policy solutions. I have no current or recent clients interested in this topic and I have not, to my recollection, ever done work for Sarepta.
[3] https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/fda-rare-disease-innovation-hub
[4] https://www.fda.gov/science-research/science-and-research-special-topics/advancing-regulatory-science
[5] https://endpoints.news/sarepta-would-have-to-conduct-new-studies-to-get-back-on-market-fda-official-says/
[6] “.....with the advent of powerful computers and new algorithms like Markov chain Monte Carlo, Bayesian methods have gained increasing prominence in statistics in the 21st century.”