The plausible mechanism framework draft guidance requirement for “well-characterized natural history” could be too high a bar for many rare diseases and more clarity is needed on the patient populations that would qualify, advocacy groups said.
Key Takeaways
- Patient advocates said the requirement for “well-characterized natural history” is vague and may preclude many rare disease therapeutics from leveraging the plausible mechanism framework.
- Rare disease groups asked for clarity on the scope of therapeutic modalities and patient populations that fit within the framework and questioned whether treatments that help stabilize disease would be left behind.
- It is important to understand how the plausible mechanism framework fits together with the FDA’s existing tools to spur rare disease drug development, NORD said.
The US Food and Drug Administration’s view that only diseases with a “well-characterized natural history” may leverage the plausible mechanism framework could severely limit the new program’s applicability in rare diseases, patient advocacy groups said.
In comments on the FDA’s plausible mechanism draft guidance, advocacy groups also raised concerns about the scope of therapeutic modalities and patient populations potentially eligible for the framework. They want to ensure therapeutics that slow disease progression, not just demonstrate dramatic treatment effects, will qualify.
In addition, patient advocates suggested the guidance does not offer sufficient flexibility on chemistry, manufacturing and controls issues for individualized therapies. (See sidebar.)
The February draft guidance described considerations for generating substantial evidence of effectiveness and safety of individualized therapies based on a plausible mechanism framework, and the circumstances where the data may be adequate to support approval.
What Is A ‘Well-Characterized’ Dataset?
The FDA described five qualifying criteria for the framework, including that the disease have a well-characterized natural history in the untreated population.
“Robust” natural history information may serve as an external control if it allows the treatment effect to be reasonably distinguished from natural variability in the disease phenotype, the guidance states.
The guidance does not provide sufficient operational clarity on what constitutes a well-characterized natural history dataset, Friends of Cancer Research said.
“Limitations in data quality and completeness, including missingness, may impact both evidentiary sufficiency within the plausible mechanism framework and a sponsor’s ability to meet this threshold,” FOCR’s comments state.
The group requested clarification on the defining attributes of well-characterized data, including minimum data elements such as disease progression metrics, variability thresholds and duration of patient follow-up.
FOCR also urged the agency to “clarify how treatment effects should be interpreted relative to natural history variability, including what magnitude or consistency of deviation from expected disease trajectory may be considered sufficient to support evidence of effectiveness.”
The Muscular Dystrophy Association said natural history data are critical to understanding and developing therapies for neuromuscular diseases due to slow, variable, and often age-dependent progression, but “most of the ultra-rare n-of-1 populations for which the plausible mechanism framework may be most promising may not have the ‘well-characterized natural history in the untreated population’ that the agency may be looking for.”
“FDA should offer greater clarity on what natural history data will be needed for a bespoke genetic therapy to use the plausible mechanism framework,” MDA’s comments state. “FDA should also clarify how such data should be used to contextualize treatment effects and distinguish therapeutic impact from disease variability.”
Despite the FDA’s existing guidance on natural history studies, “the agency’s acceptance of those studies remains unclear,” the National Organization for Rare Disorders’ comments state.
“We have seen FDA reject natural history studies for various reasons, even those conducted by [the National Institutes of Health] or other august bodies,” NORD said. “This issue may be exacerbated in the context of individualized therapies for very rare diseases and patients with unique mutations.”
Natural history studies are not feasible for very small populations and may not be useful for heterogenous diseases, NORD said.
“We recommend that FDA include language that a patient can be its own control,” the group said.
More Clarity Needed On Therapeutic Modalities …
Rare disease advocacy groups also want the types of products and patient populations that fit within the framework clarified.
The guidance defines individualized therapies as products targeting a specific pathophysiologic abnormality serving as the root cause of a disease, such as specific pathogenic genetic variants causing a severely debilitating or life-threatening disease or condition in a small number of patients where a randomized controlled trial typically is not feasible.
The guidance specifically discusses genome editing and RNA-based therapies but states the general concepts may apply to other types of individualized therapies.
NORD said that based on numerous inquiries it received from the rare disease community, more clarity on the kinds of products that can use the proposed framework is needed.
“Is it only those that address somatic mutations, or can other non-genetic diseases be treated by products that go through the plausible mechanism framework?” NORD said.
The FDA should clarify that the framework applies to non-genetic medicines, NORD said, adding that treatments such as enzyme replacement therapies could benefit.
Noting the guidance’s heavy focus on gene editing and antisense oligonucleotide technologies, the EveryLife Foundation for Rare Diseases said the FDA should provide additional information about eligible treatment modalities.
“This will help ensure certain modalities are not excluded or deprioritized by developers,” the comments state.
The Cure Sanfilippo Foundation raised similar concerns, saying that if application of the framework is limited to select technologies, “it may inadvertently create bias favoring selection of GE and RNA-based approaches as explicitly supported in the guidance for further development.”
“We encourage the agency’s refinement of the guidance to reflect prioritization of an efficiency and disease specific needs model while remaining agnostic to therapeutic modality,” the foundation’s comments state.
Biopharma industry comments also urged the FDA to ensure the framework is technology-agnostic.
… And Population And Benefits
The guidance’s reference to “individualized” therapies should be removed, NORD said, because not every treatment developed under the proposed framework will be unique.
“NORD recommends that FDA clarify that there is no limit to the number of patients who can be treated by these therapies,” the comments state. “In addition, FDA should clarify that there are no limits to the number of mutations/variants that can be added after the first approval.”
The EveryLife Foundation said the draft guidance is unclear on how the framework will apply to conditions with small but non-singular patient populations, such as those with five, 20 or 50 patients.
The agency should explain how it will assess the population characteristics eligible for the framework, including qualitative and quantitative considerations used to evaluate suitability, EveryLife said.
“Rather than relying solely on a numerical definition, we believe the FDA should consider other factors, including disease severity, clinical trial feasibility, and ethical obligations, to inform eligibility determinations,” EveryLife said.
Several groups raised concerns that the framework may exclude serious diseases that are characterized by slow progression and therapeutics that help stabilize disease or slow the rate of progression.
MDA said many neuromuscular diseases are monogenic, but may not meet the severely debilitating or life-threatening threshold described in the guidance.
“FDA should elaborate on how this framework can apply across the broader rare disease spectrum, including conditions with slower progression and substantial morbidity or how flexibility may vary across different disease severity tiers,” MDA said.
The guidance states that a “substantial improvement” in symptoms or change in disease trajectory that is inconsistent with the natural history may provide substantial evidence of effectiveness.
“We ask FDA to clarify whether incremental but meaningful clinical benefits, not only dramatic or irrefutable responses, can meet this requirement and how FDA will assess that,” EveryLife’s comments state. “Often, slowing progression relative to a more rapid worsening in untreated patients/natural history is what patients most desire from future therapy, so we request that the FDA use this framework to ensure such products have a path to approval.”
Interlocking Regulatory Pieces
Rare disease groups and the biopharma industry have questioned how the plausible mechanism framework fits within the FDA’s various expedited programs and rare disease drug development initiatives.
“FDA has numerous guidances and tools to assist in review of treatments for rare diseases, including the platform technology designation program, the accelerated approval pathway, FDA’s guidances on natural history, single enzyme deficiencies, platform designation, ASOs, umbrella trials, and master protocols,” NORD’s comments state.
“We recommend FDA clarify how existing tools, in particular, platform technologies, can be leveraged for products that have a plausible mechanism of safety and efficacy,” the group said. “It will be critical to understand how all of these guidances fit together in practice.”
The agency has said that two new gene therapy guidances also will help clarify the plausible mechanism framework.
A guidance on safety assessment of genome editing using next-generation sequencing was released in April shortly after Office of Management and Budget clearance. A guidance on leveraging prior knowledge in the development of products incorporating genome editing also cleared OMB review but has not yet been published.