FDA Aims to Bolster Gene Therapy Development with New Guidance

US Food and Drug Administration (FDA) recently issued six final guidances and draft guidance to advance gene therapy development by clarifying the policy framework for development and manufacturing. 

The six guidances finalize draft policies the agency proposed in 2018. The finalized versions of the guidances released on Tuesday address chemistry and manufacturing of the drugs and provide policy clarification on how to control information for human gene therapy investigational new drug applications, long-term follow-up post administration of human gene therapy products, as well as the testing of retroviral vector-based gene therapy products for replication competent retrovirus. The remaining three final guidances are on human gene therapy for hemophilia, retinal disorders, and rare diseases.

The draft guidance also released on Tuesday is intended to help interpret the sameness of gene therapy products under the orphan drug regulations for evaluating orphan-drug designation or orphan-drug exclusivity.

“Scientific development in this area is fast-paced, complex, and poses many unique questions during a product review; including how these products work, how to administer them safely, and whether they will continue to achieve a therapeutic effect in the body without causing adverse side effects over a long period of time,” Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said in a press release. 

FDA’s guidances is a step toward supporting safe innovation, Marks emphasized. 

FDA has been working to speed development in an effort to keep pace with the growth of gene therapy. The federal department has specifically aimed to help avoid unnecessary preclinical testing or unnecessary clinical investigations. 

The new guidances aim to bolster previous efforts to support safe gene therapy development as the field booms. More than 900 INDs for gene therapies are ongoing, the agency said on Tuesday. The growing initiative resulted in a new designation and a new program last year. 

The final guidance versions offer more color on the agency’s expectations compared to their respective 2018 draft versions, particularly the final guidances about INDs and rare diseases. 

The IND final guidance adds certain policy clarifications on the mandatory use of the electronic Common Technical Document format for devices used in gene therapy product delivery or combination products, which are not excluded from the eCTD requirement on INDs. It clarifies policies on the Quality Overall Summary and CQAs to help ensure product quality. It also offers new recommendations on conducting batch analysis and assessing drug product compatibility.

Revisions to the draft guidance expand on the recommendation to include a description of a firm’s or academic sponsors’ quality unit as part of an IND for a gene therapy product. PhRMA took issue with this recommendation in its comment on the draft guidance version. “Review of quality systems and practices is usually a matter for inspection,” PhRMA said at the time.

FDA finalizes language in the IND final guidance that further encourages accelerated timelines for gene therapy products to reach the market. “We acknowledge that limits may be broader during early development when you are still gaining information about your product,” the final section on pharmaceutical development adds. Other guidances similarly push for expedited programs. 

The two final guidances on gene therapies for rare diseases and retinal disorders further stress expedited programs to facilitate and expedite development and review. “For example, regenerative medicine advanced therapy designation and breakthrough therapy designation call for increased FDA attention to these potentially promising therapies, offering sponsors more frequent interactions with FDA on efficient trial design and overall drug development,” they state. 

Additional revisions to the final guidance on rare diseases fall under study population, study design, dose selection and efficacy endpoints. The final guidance on gene therapies for retinal disorders is otherwise largely similar to its draft version, except for the information on expedited programs and a few new details under considerations for preclinical studies and clinical trials. 

The final guidance on the testing of retroviral vector-based therapies is nearly identical to its draft. Among other RCR-related revisions, its new section on vector product cell working cell back clarifies when FDA advises replication competent retrovirus testing of the VPC WCB. 

Additionally, the final guidance on long-term follow-ups is largely unchanged from its draft version. It adds a few new recommendations under the duration of long-term follow-up observation based on five product types, up from three. FDA now also recommends the duration of an LTFU protocol to be up to 15 years for certain herpes virus vectors and microbial vectors. “FDA recommends sponsors make every effort to prevent patient loss to follow-up to the extent feasible for completion of LTFU observations,” the final guidance on LTFU protocols clarifies.

The draft guidance on interpreting "sameness" explains how orphan-drug designation and orphan-drug exclusivity will be awarded when there is more than one gene therapy product intended for the same indication. It notes FDA evaluates such “sameness” per 21 CFR 316.3(b)(14)(ii) based on products’ principal molecular structural features but the definition of the term “same drug” does not apply to gene therapies.

A route for FDA to evaluate the difference between two gene therapy products for purposes of awarding orphan-drug designation and eligibility for orphan-drug exclusivity is proposed via the draft guidance, with three scenarios based on whether different transgenes or vectors are used. 

The agency said it has received important questions from gene therapy product developers “about orphan-drug designation incentives to develop products for rare diseases with very small patient populations,” citing “the large volume of products currently being studied.” The draft guidance introduces “potential positive implications both for product developers and patients.”