With more than 900 investigational new drug (IND) applications for ongoing clinical studies related to gene therapies, and with the number of advanced therapy medicinal products at clinical stage worldwide exceeding 1,000, the US Food and Drug Administration (FDA) this week released a number of policies.
The policies, addressed to developers and manufacturers, include six final guidance documents on gene therapy manufacturing and clinical development of products, following up to respective draft guidance documents released in 2018, and a draft guidance related to orphan drug designations for therapeutic candidates.
“Scientific development in this area is fast-paced, complex, and poses many unique questions during a product review,” commented Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, adding “The framework we construct for product development and review will set the stage for continued advancement of this cutting-edge field.”
Regarding the draft guidance ‘Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations’, the agency explained that it focuses on how the FDA will evaluate differences between gene therapy products when they are intended to treat the same disease.
The final guidance titled ‘Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)’ aims to inform sponsors on how to provide sufficient CMC information, in order to assure product safety, identity, quality, purity, and strength (including potency) of the investigational product and to be able to claim market authorization from the regulatory body.
Addressed to developers and manufacturers of retroviral vector-based human gene therapy products, the second document titled ‘Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up’ determines testing for RCR during manufacture, as well as the regulations for follow-up monitoring of patients who have received such treatments.
Titled ‘Long-Term Follow-Up After Administration of Human Gene Therapy Products’, the third document includes recommendations by the FDA regarding the design of long-term follow-up studies for the collection of data on delayed adverse events.
Specifically, the FDA suggests that, as a result of long-term exposure to an investigational gene therapy, patients may be at increased risk of ‘undesirable and unpredictable’ outcomes, and therefore they may be monitored for ‘an extended period of time’ past the active follow-up period. The document outlines several factors based on which a risk assessment should be performed to determine the necessity of long-term monitoring for each product.
Another guidance of the FDA is focused on ‘Human Gene Therapy for Hemophilia’, and it provides recommendations regarding the clinical trial design for such therapies, as well as addressing discrepancies between Hemophilia A and B coagulation factors activity assays.
Focusing on ‘Human Gene Therapy for Retinal Disorders’, the fourth FDA guidance includes recommendations related to product development, preclinical testing, and clinical trial design for such gene therapy products.
Finally, the guidance on ‘Human Gene Therapy for Rare Diseases’, with suggestions on the clinical design for such products, is needed, according to the FDA, due to the limited study population size and potential feasibility and safety issues. Moreover, the FDA cites issues related to the interpretability of bioactivity/efficacy outcomes that may be unique to rare diseases or to the nature of the product.
