Desperately Needed: Special Risk-Benefit Calculations for Relentlessly Progressive Chronic Diseases
Every day, our country is failing patients with relentlessly progressive chronic neurological, neuromuscular, and genetic diseases. Their plight necessitates a significantly different risk-benefit calculation than that of patients with other types of diseases.
Defining the Unique Needs of Patients with Chronic Progressive Diseases
Patients with relentlessly progressive chronic diseases can be characterized by:
Their disease is relentlessly progressive, and they cannot wait for “profoundly beneficial or curative therapies” that are unlikely to be developed in time to help them,
They are willing to take on significantly more “safety risk” and “efficacy uncertainty” for even the slightest chance of “an incremental benefit,” and
They are dealing with complex heterogeneous diseases that, regardless of patient population size, will make drug discovery and development difficult.
This past summer’s brouhaha about Sarepta’s Elevidys for Duchenne’s Muscular Dystrophy is a stark reminder that we have no systematic way of thinking about these patients and the clinical trials they participate in. FDA’s risk-benefit calculations need to be more context-sensitive to accommodate their situation.
Relentlessly progressive chronic diseases require:
A regulatory framework that reflects the different risk-benefit considerations; and
Scientifically and statistically-based standards for evaluation.
Without those, FDA will not be able to move past its current situation: unable to appropriately respond to the needs of these patients and failing to encourage the types of research and innovation needed to make regulatory decisions for these diseases easier in the future.
FDA’s Ongoing and Promised Response
The agency is constantly pressured to permit access to therapies that are intended to treat relentlessly progressive chronic diseases and either unapproved or approved under various alternative pathways or standards.
Whatever the reality is inside the agency....from the outside it appears that some companies and rare disease patients succeed in gaining access, while others are ignored or denied access with no discernible reason for the differing outcomes.
Instead of the chaos and inconsistent responses of today, FDA can step up by:
acknowledging the issue,
developing the aforementioned regulatory framework, and
stimulating research and consensus on evaluatory standards.
It is worth the effort to build a more comprehensive and thoughtful approach that is “fit for purpose” and responsive to the plight of these patients.
The agency should not yield to every group and patient lobbying for access. Instead, this approach would lend authority to those occasions on which “no” is the agency’s appropriate response.
Current and Related FDA Efforts
FDA’s longstanding vehicle--"treatment INDs” (Investigational New Drugs)--is a necessary and valuable response, but not a sufficient one.
FDA’s comparatively new Rare Disease Innovation Hub (here) and the Office of Regulatory and Emerging Science (here) are addressing some of these issues. Still, neither has the resources nor the authority to comprehensively approach the unique patient impact of relentlessly progressive chronic diseases.
The Rare Disease Policy and Portfolio Council (RDPPC) was established around the same time as these other programs and can play a valuable role in addressing rapidly progressive chronic diseases.
Commissioner Makary and his leadership team are working on several initiatives. The FDA Law Blog had a helpful analysis of the Administration’s initiatives (here).
The recently-released “CDER/CBER Rare Disease with New Evidence Principles” (here) is a limited-access consultation program for companies developing therapies for ultra-rare diseases. One of the criteria for participation is that the disease involves “progressive functional deterioration, leading to rapid and/or significant disability or death in a relatively short period of time.”
I applaud this initiative and its focus on relentlessly progressive chronic diseases. I am hopeful that the unique risk-benefit considerations for these diseases--and not just evidentiary standards--will be part of the discussion and that some thought will be given to the implications for larger relentlessly progressive chronic diseases.
Addressing the Paucity of Tools and Metrics
Good regulatory decisions must begin with 1/ an acknowledgment of the gaps in what is known and the lack of reliable measuring tools for relentlessly progressive, debilitating and fatal diseases, and 2/ a 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 addressing rapidly progressive chronic diseases. At least one commentator posed the Sarepta situation this summer as a dichotomy: 1/ either the drug doesn't work, or 2/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 relentlessly progressive, debilitating neurological, neuromuscular, and genetic diseases. That is, we don’t yet have the tools and understanding to construct study designs that accurately evaluate efficacy and safety in some of these complex diseases. That is especially the case with exceedingly small orphan populations (such as DMD) and with highly-variable heterogeneous progression (such as ALS).
A couple of recent examples illustrate the potential impact of new knowledge and tools for addressing relentlessly progressive chronic diseases. Specifically, better, and less controversial regulatory decisions are made today because
someone decided 20 years ago to examine whether Bayesian statistics might contribute fresh insights to clinical trial analysis, and
someone decided 10 years ago to determine whether umbrella and basket trials (https://pmc.ncbi.nlm.nih.gov/articles/PMC8220876/) could produce more insights with a smaller resource investment.
Conclusion:
Drugs for relentlessly progressive, chronic debilitating and fatal diseases will always involve tough decisions because “delaying for more certainty” has such a cruel impact.
However, if we view the problem as one of inadequate knowledge and insufficient tools, perhaps we can develop a framework and standards that will enable a future where we
treat these patients more compassionately through more realistic risk-benefit calculations, and
make drug development in this area more productive and less controversial.
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