FDA Expands Advice on Testing Gene Therapies

The potential for innovative gene therapies to treat and even cure a range of serious diseases is prompting FDA to ramp up support for developing and testing new products efficiently and effectively. FDA issued six new draft guidances July 11, 2018 that provide scientific advice to sponsors developing novel treatments for hemophilia, retinal disorders, and rare diseases. Additional advisories update agency policy for when study protocols should include a plan for long-term follow-up of approved therapies and what manufacturing information is needed to support clinical development.

These guidances build on a policy framework for regenerative medicine issued by FDA last September, as well as experience gained by FDA staff in reviewing and approving three gene therapy products over the past 12 months. With more than a hundred INDs filed last year for these products, and multiple development programs underway, FDA seeks to ensure that sponsors design testing programs that meet the agency’s gold standard for drug safety and efficacy. Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), emphasized at a recent cell and gene therapy symposium sponsored by CASSS that FDA is “open to novel endpoints,” as was the case in measuring visual acuity to advance the development of a new therapy for a mutation-associated retinal dystrophy. Marks also noted that FDA is collaborating with the National Institutes of Health (NIH) to reduce the regulatory burden on sponsors from parallel oversight by the NIH Recombinant DNA Advisory Committee (RAC).

FDA seeks input from stakeholders on the draft advisories as part of the process for making gene therapy development more efficient. The guidances are “building blocks of a modern, comprehensive framework” for advancing the field of gene therapy, said FDA commissioner Scott Gottlieb, in unveiling the new policies. Some of these products “are almost certainly going to change the contours of medical practice,” he commented, and FDA seeks to ensure the safety and effectiveness of resulting treatments to build confidence in this novel area of medicine [see https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm613026.htm].

Advancing therapies

Such optimism is apparent for developing single-dose gene treatments that enable production of coagulation factors for hemophilia A and B, reducing the need for frequent injections to reduce bleeding. FDA guidance offers recommendations on designing clinical trials and addressing preclinical issues, including clinical and surrogate endpoints, study design and population, and statistical considerations that could lead to accelerated approval of gene therapies for this condition [see https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610801.pdf].

The guidance for developing gene therapies for retinal disorders advises sponsors to prepare natural history studies, to explore a wide spectrum of possible endpoints in early studies, and to include a control group in randomized studies to reduce the potential for bias. FDA also highlights the importance of validating manufacturing processes and testing methods prior to the initiation of clinical trials that may involve intravitreal or subretinal injections or implants in the eye [see https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610803.pdf].

As about 80% of some 7000 rare diseases are caused by a single-gene defect, FDA emphasizes the importance of advancing R&D in this area. Because limited study populations make clinical testing difficult, the guidance offers advice on designing small clinical studies and on assessing potential safety issues and challenges related to interpreting outcomes, especially as many rare diseases exhibit multiple variations and diverse rates of disease progression [see https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610802.pdf].

Sponsors also gain broad recommendations on how to provide sufficient chemistry, manufacturing, and control (CMC) information during clinical development to assure the safety, identity, quality, purity and strength/potency of investigational gene therapies [see https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610795.pdf]. An additional guidance addresses the proper testing for replication competent retrovirus (RCR) during production [see https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610800.pdf].

And because gene therapies may have permanent or long-acting therapeutic effects on patients, FDA guidance here explains how sponsors should assess when and how they need to monitor the long-term safety of a new product. The advisory discusses when sponsors should design protocols for later observational studies to assess delayed adverse events, including the scope and duration of such follow-up and policies for informing patients of these plans through informed consent [see https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610797.pdf].

More hand-holding

All these complexities have prompted FDA to offer early, less formal meetings for firms developing novel gene and cellular therapies to gain advice on initial development programs. A new INTERACT program (Initial Targeted Engagement for Regulatory Advice on CBER products) replaces current pre-pre-IND meetings for all CBER products and offers an opportunity for CBER staffers to help less experienced sponsors and investigators better understand issues related to preclinical testing, aspects of manufacturing for first-in-human trials, and initial clinical development strategies.

The goal is for sponsors to avoid unnecessary studies by better understanding agency expectations for product development programs. At the same time, CBER staff hopes to gain early insight into new products and technologies entering the R&D pipeline. As early testing progresses, sponsors still will be expected to meet more formally with FDA experts at pre-IND and pre-BLA meetings as has been the case. See https://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/Industry/ucm611501.htm for more information.