Dear Commissioner Califf:
On behalf of the Cystic Fibrosis Foundation, we write to provide comments in response to the Food and Drug Administration’s draft guidance on Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence. We greatly appreciate the FDA’s responsiveness to the evolving needs of the modern drug development ecosystem and commend the Agency’s willingness to exercise regulatory flexibility, while maintaining its standards for safe and effective drug products.
Background on Cystic Fibrosis and the Cystic Fibrosis Foundation
Cystic fibrosis is a rare genetic disease that affects nearly 40,000 adults and children in the United States. In people with CF, mutations in the CFTR gene result in a buildup of thick mucus in multiple organ systems, leading to lung damage, life-threatening infections, and other complications. CFTR modulators, which directly target defects in the processing, trafficking, and function of the CFTR protein, have drastically altered the CF therapeutic landscape and the lives of the 90% of people with CF who are eligible for and able to tolerate these drugs. However, the development of these CFTR modulator therapies and the resulting decrease in the CF population available for clinical trials has necessitated the exploration of innovative clinical trial designs and potential regulatory flexibilities.
The CF Foundation is engaged in virtually every element of the research and development process — from preclinical discovery and identification of new therapeutics, to conducting clinical trials and post-marketing surveillance. Our research and investment portfolio includes CFTR modulators, symptomatic treatments, and a growing array of biologics, such as mRNA and gene therapies. The Foundation frequently provides sponsors developing these CF therapeutics with advice regarding trial design, endpoints, and other aspects of their clinical development programs. We therefore offer the following considerations for the FDA as it develops its guidelines for sponsors seeking to demonstrate substantial evidence of effectiveness of drug products with one adequate and well-controlled trial and confirmatory evidence.
I. Background and Scope
Cell and Gene Therapy Products:
Guidance on demonstrating substantial evidence of effectiveness of drug products with one adequate and well-controlled trial and confirmatory evidence is highly relevant to the emerging field of cell and gene therapies (CGTs). This is evidenced by the fact that, though the specifics of each approval varied, Luxturna, Skysona, Hemgenix, and Roctavian each received approval based on what was deemed by the FDA to be a “single adequate and well-controlled trial.” Because CGTS differ substantially from other therapeutics and frequently entail a different set of regulatory considerations, we believe that this document would be strengthened by providing specific guidance on the appropriateness of demonstrating substantial evidence of effectiveness of CGTs with one adequate and well-controlled clinical investigation and confirmatory evidence, including where the Agency’s recommendations may differ from those provided for small molecule therapeutics, antisense oligonucleotides, and biologics other than CGTs.
II. General Considerations Regarding Confirmatory Evidence and the Demonstration of Substantial Evidence of Effectiveness
Quality of Evidence from the Single Adequate and Well-Controlled Clinical Investigation:According to the 2019 FDA guidance on Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, the endpoints studied over the course of an adequate and well-controlled clinical investigation are a critical aspect of “evidence quality.” Within the modern drug development ecosystem, sponsors are increasingly proposing to utilize biomarkers, including protein expression, as surrogate endpoints to support the accelerated approval of CGTs and other drug products. Though these types of biomarkers and surrogate endpoints may have great utility, we believe that the use of confirmatory evidence to demonstrate substantial evidence of effectiveness is most appropriate when paired with a single adequate and well-controlled clinical investigation able to demonstrate either a direct clinical benefit or a meaningful effect on an endpoint validated to predict clinical benefit. We therefore recommend that the Agency put considerable weight on trial endpoint selection when determining whether one adequate and well-controlled clinical investigation with confirmatory evidence is sufficient for demonstrating substantial evidence of effectiveness of a drug or biological product.
Disease- or Condition-Specific Factors, Including Unmet Patient Need:
Rare diseases, such as CF, are defined by small patient populations and often suffer from a lack of available therapies. With this in mind, we agree it is appropriate for sponsors to take these factors into consideration when planning their clinical development programs. This includes clinical trial design and determining the most suitable approach for establishing substantial evidence of effectiveness. However, we wish to emphasize that proposals to demonstrate substantial evidence of effectiveness with one adequate and well-controlled clinical investigation and confirmatory evidence should require a strong scientific and clinical rationale, with factors such as unmet patient need taken into consideration but not used as primary justification for such an approach. Patients deserve to have access to treatments that are both safe and effective; sponsors must still strive to prove that a drug product is effective to the fullest extent possible, even for diseases and conditions with unmet needs.
III. Types of Confirmatory Evidence
Data Access Requirements for Natural History Evidence:
Importantly, this draft guidance notes that natural history data used as confirmatory evidence should be distinct from data used as a control for the single adequate and well-controlled clinical investigation. The FDA’s draft guidance regarding Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products notes that sponsors utilizing external control data, including data derived from natural history studies, must include patient-level data in their marketing applications and ensure that the FDA has access to relevant source documents and source data. This access to patient-level data is understandably critical in the context of externally-controlled trials. However, it may be possible to acquire the type of natural history data suitable for use as confirmatory evidence as described by this document, such as data demonstrating the failure of a disorder to spontaneously resolve with subsequent high morbidity and mortality or confirming that the amount of deterioration seen in a control group is an expected outcome for a period of observation, from third-parties in the form of aggregate patient data (such as through registries operated by patient organizations) or from previously-published literature. Given that, we ask the Agency to clarify how data access requirements for natural history data used as confirmatory evidence may differ from data access requirements for natural history data utilized as control data in the context of an externally-controlled trial.
Once again, the Cystic Fibrosis Foundation appreciates the FDA’s dedication to providing sponsors with the regulatory flexibilities needed to tackle the challenges of modern drug development and advance safe and effective products through the pipeline, especially in the rare disease space. We look forward to working with the Agency as it continues to refine its thinking on demonstrating substantial evidence of effectiveness for drug and biological products.