This morning, FDA’s Center for Biologics Evaluation and Research (CBER) published six draft guidances relating to gene therapy, three of which cover products for specific disease categories (hemophilia, rare diseases, and retinal disorders), and three of which address manufacturing and clinical study design issues related to gene therapy: chemistry, manufacturing and control (CMC) information in INDs, long term follow-up study design, and testing of retroviral vector-based products.

In a press release, FDA Commissioner Scott Gottlieb, M.D., highlighted “rapid advancements” and “great promise” in the gene therapy space, saying the guidances “are aimed at fostering developments in this innovative field.” Dr. Gottlieb acknowledged that for some gene therapies, FDA “may need to accept some level of uncertainty” at the time of approval regarding questions related to durability of response, as well as product manufacturing and quality. He acknowledged the need, however, to assure patient safety and to assure that potential risks are adequately characterized and benefits are adequately demonstrated.

Dr. Gottlieb also stressed that one key to advancing the gene therapy field will be effective tools for reliable post-market follow up, including post-market clinical trials. The three guidances on manufacturing and clinical trial design issues attempt to address the balance between accelerating approval of therapies for rare diseases with no existing treatments and the uncertainties of novel therapies, such as questions about the durability of treatment effects and the theoretical potential for off-target effects. The draft guidances also address certain definitional issues, such as by including “engineered site-specific nucleases used for human genome editing” among the examples of gene therapy.

The individual guidances are briefly summarized below.

CMC Information for Gene Therapy INDs (available online here)

The lengthiest of today’s guidances at 54 pages, titled “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs),” provides sponsors with recommendations on how to provide sufficient CMC information to assure safety, identity, quality, purity and strength/potency of investigational gene therapy products. This guidance also applies to combination products that contain a human gene therapy in combination with a drug or device. Once finalized, this guidance will replace April 2008 guidance.

Long Term Follow-Up After Administration of Human Gene Therapy Products (available online here)

Dr. Gottlieb expressed concern that “the additional uncertainty intrinsic to a novel platform like gene therapy — including questions related to the durability of the treatment effects as well as the theoretical potential for off-target effects if the genes do not insert correctly,” establishes “an increased need for robust long term follow-up of patients in the post-market period.” As a result, this guidance describes product characteristics, patient-related factors, and the preclinical and clinical data that should be considered when assessing the need for long term follow-up (LTFU) observations and describes the features related to effective post-market follow up. Once finalized, this guidance will replace November 2006 guidance.

Retroviral Vector-Based Testing for RCR (available online here)

The guidance titled “Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up” will replace November 2006 guidance, once finalized. Notably, the draft guidance omits FDA’s previous recommendation for Replication Competent Retrovirus (RCR) testing on working cell banks for retroviral producer cells. FDA also revised its recommendations regarding the amount of vector that should be tested, advising that sponsors should demonstrate that their vector contains <1 RCR per patient dose rather than testing based on production lot size.

Human Gene Therapy for Hemophilia (available online here)

This guidance shows the FDA’s thinking on preclinical and clinical considerations to support development of hemophilia gene therapies. Dr. Gottlieb highlighted the new gene therapy products for hemophilia being developed as single-dose treatments that may enable long-term production of the missing or abnormal coagulation factor in patients, reducing or eliminating the need for coagulation factor replacement. Accordingly, this guidance advises on how surrogate endpoints could be used in the pursuit of accelerated approval. As with the other disease-specific guidances, this draft guidance encourages sponsors to explore opportunities for reducing, refining, and replacing animal use in the preclinical program, and FDA encourages sponsors to collect patient experience data during product development.

Human Gene Therapy For Retinal Disorders (available online here)

This draft guidance advises on how gene therapy products for retinal disorders should take into account CMC considerations specific to the treatment of retinal disorders, and offers lists of elements to consider when developing preclinical programs, clinical studies, and clinical trials for an investigational gene therapy product. These recommendations build on the June 2015 FDA guidance “Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products.”

Human Gene Therapy for Rare Diseases (available online here)

Dr. Gottlieb emphasized that “most rare diseases have no approved therapies,” saying “there is a significant unmet need” in this space, and that this guidance is “intended to assist sponsors in the design of clinical development programs, where there may be limited study population size, potential feasibility and safety issues, as well as issues relating to the interpretation of effectiveness.” Yet, this draft guidance stresses how a sponsor of a gene therapy product for a rare disease should “establish a well-controlled manufacturing process along with suitable analytical assays to assess product critical quality attributes (CQA) as early in development as possible.”