Dear FDA Center for Biologics Evaluation and Research (CBER):
On behalf of the Cystic Fibrosis Foundation and the Cystic Fibrosis Therapeutics Development Network (TDN), we write to request a meeting to discuss novel approaches to clinical trial design for cystic fibrosis nucleic acid-based therapies (NABTs).
CF is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The emergence of CFTR modulators, which directly target defects in the processing, trafficking, and function of the CFTR protein in a highly efficacious manner, has effectively divided the CF population into two groups: those who are eligible for CFTR modulators (modulator eligible, or ME) and those who, based on their specific CFTR variant, are unable to benefit from CFTR modulators (non-modulator eligible, or NME). Of the nearly 40,000 people with CF in the United States, approximately 94% are projected to be eligible for CFTR modulators. The remaining 6% of people with CF — functionally, an ultra-orphan disease population — have access to traditional symptomatic therapies, such as mucolytics and bronchodilators, but not to therapeutics that treat the underlying cause of CF.
Significant disparities exist in health and survival outcomes between ME and NME people with CF and are expected to increase further. Recent adult lung function data from the CF Foundation Patient Registry indicate a mean FEV1 of 70.8 % predicted for NME adults with CF compared to 77.8 % predicted for ME adults with CF in 2022. The disparities in terms of lung transplantation and survival are even more striking. In 2012, just prior to the approval of the first modulator therapy, approximately 6% of first lung transplants were reported among NME people with CF. Ten years later, while overall total lung transplants have declined among the CF population, the NME CF population now accounts for 51% of first lung transplants reported. From 2020-2022, the mortality rate for the NME CF population was 10.8 deaths per 1,000 person-years compared to 5.7 deaths per 1,000 person-years for the ME CF population. In accordance with these data, though the median predicted survival age of a person with CF born between 2018 and 2022 is 56 years, compared to 38 years in the four-year period just prior to the approval of the first modulator therapy, the latter figure is much more reflective of the current median predicted survival in the NME population. Based on these data, there remains a significant unmet need for effective therapies for the NME population of people with CF — approximately 25% of whom are non-white, compared to 15% in the overall CF population. The difficulty of living with this unmet need is compounded by the clear difference in outcomes between NME and ME people with CF across the same monogenic disease.
The CF Foundation and Therapeutic Development Network are committed to advancing multiple approaches to developing novel therapeutics to meet the needs of NME people with CF. A significant focus of these efforts are NABTs. The CF NABT pipeline is robust and continues to grow; multiple CF NABTs, including both mRNA and gene therapies, have either entered into clinical trials or are approaching IND submission, with even more in preclinical development. However, the size of the ultra-orphan population of NME people with CF is exceedingly small. It is estimated that only ~1100 of the NME population are eligible for CF NABT clinical trials based on traditional inclusion/exclusion criteria. Furthermore, only a small proportion (<25%) of this population has experience participating in clinical trials. These facts pose a significant challenge for the design and execution of traditional, placebo-controlled, randomized clinical trials for these products.
With this in mind, the CF Foundation and TDN have devoted substantial effort to exploring innovative clinical trial design approaches to facilitate the progression of multiple promising therapeutic programs for the population not benefitting from modulators. These include master protocols, adaptive clinical trial designs, and externally-controlled trials. We thank CBER for its contributions to this work — the feedback we received during our December 2022 meeting to discuss the landscape, challenges, and clinical trial strategies for CF NABTs, particularly with regard to clinical trial design and how the CF Foundation and the TDN can effectively work with sponsors to design and execute feasible clinical trials for CF NABTs, has been critical in shaping our subsequent efforts.
We have developed a proposal for a novel initiative entitled Research Expansion to Advance the CF Therapeutic Pipeline for People without Modulators (REACH). The purpose of REACH is to increase clinical trial engagement and streamline clinical trial designs to support the robust therapeutic pipeline for the NME CF population. REACH includes a framework for utilizing the Critical Path Institute’s Rare Disease Cures Accelerator Data Analytics Platform (RDCA-DAP) to support collaboration with industry partners to conduct hybrid randomized clinical trials, in which data from small placebo cohorts can be augmented by high-quality external control data from other CF clinical trials, prospective observational studies, and natural history studies, such as the CF Foundation Patient Registry. The rationale for this approach for a given clinical development program importantly must be substantiated by both demonstrating a lack of feasibility to conduct a traditionally sized placebo-controlled trial, and a robust hypothesized treatment effect anticipated for a successful late phase NABT.
We greatly appreciate the feedback that we have received from CBER in the past on this topic and believe that the Center’s perspective will be invaluable for assessing the feasibility of REACH. In particular, we seek the Center’s input on the suitability of hybrid and externally controlled trials for CF NABTs; the use of the RDCA-DAP as a secure data repository to facilitate collaboration with industry; and the examination of clinical development and analysis plans suitable for supporting regulatory approval of CF NABTs.
We propose the following agenda for a half-day hybrid meeting involving representatives from the CF Foundation, TDN, and the FDA as key stakeholders:
- Introduction and Overview of the CF Landscape
- Clinical Development Planning for CF NABTs
- Trial Design Approaches for Progressing Multiple Therapeutic Programs in Parallel
- Discussion
On behalf of the CF Foundation and the TDN, we greatly appreciate your consideration of this request and look forward to continuing this important conversation on behalf of the greater CF community.