Rare Daily Staff

The U.S. Food and Drug Administration has released six final guidances on gene therapy manufacturing and clinical development of products and a draft guidance, Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations.

FDA has already approved four gene therapy products and anticipates many more approvals in the coming years, as evidenced by the more than 900 investigational new drug applications for ongoing clinical studies in this area, and says these guidances will help innovators to answer critical questions as they research and design their gene therapy products.

“The growth of innovative research and product development in the field of gene therapy is exciting to us as physicians, scientists and regulators,” said FDA Commissioner Stephen Hahn. “We understand and appreciate the tremendous impact that gene therapies can have on patients by potentially reversing the debilitating trajectory of diseases. These therapies, once only conceptual, are rapidly becoming a therapeutic reality for an increasing number of patients with a wide range of diseases, including rare genetic disorders and autoimmune diseases.”

The six final guidances provide the agency’s recommendations for product developers on manufacturing issues and recommendations for those focusing on gene therapy products to address specific disease areas:

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up

Long Term Follow-Up After Administration of Human Gene Therapy Products

Human Gene Therapy for Hemophilia

Human Gene Therapy for Retinal Disorders

Human Gene Therapy for Rare Diseases

The agency said these guidances will help advance the field of gene therapy while helping to ensure that these innovative products meet the FDA’s standards for safety and effectiveness.

The clinical review of gene therapy products frequently pose more challenging questions to regulators than reviews of more conventional drugs. This includes questions about the durability of response, questions that can’t be fully answered in pre-market trials of reasonable size and duration.

For some gene therapy products, the agency may need to accept some level of uncertainty around questions of the duration of the response at the time of marketing authorization. The FDA says effective tools for reliable post-market follow up, such as post-market clinical trials, are going to be critical to advancing the field and helping to ensure that its approach fosters safe and innovative treatments.

“As the regulators of these novel therapies, we know that the framework we construct for product development and review will set the stage for continued advancement of this cutting-edge field and further enable innovators to safely develop effective therapies for many diseases with unmet medical needs,” said Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research. “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.”

The draft guidance on interpreting sameness of gene therapy products under the orphan drug regulations provides the FDA’s proposed current thinking on an interpretation of sameness between gene therapy products for the purposes of obtaining orphan-drug designation and eligibility for orphan-drug exclusivity. The draft guidance focuses on how the FDA will evaluate differences between gene therapy products when they are intended to treat the same disease.

The draft guidance said the agency will consider the principal molecular structural features of the gene therapy products, which includes transgenes (the transferred gene) and vectors (the vehicle for delivering the transgene to a cell).

With the large volume of products currently being studied, gene therapy product developers have asked the agency questions about orphan-drug designation incentives to develop products for rare diseases with very small patient populations. The draft guidance has potential positive implications both for product developers and patients by providing insight into the agency’s most current thinking on the sameness of products, which is not to discourage the development of multiple gene therapy products to treat the same disease or condition.

The FDA says it will continue to work with product innovators, sponsors, researchers, patients, and other stakeholders to help make the development and review of gene therapy products more efficient, while putting in place the regulatory controls needed to ensure that the resulting therapies are both safe and effective.

It also encourages developers of new gene therapy products to make full use of expedited programs available for products intended to address unmet medical needs in the treatment of serious or life-threatening conditions, including breakthrough therapy designation, regenerative medicine advanced therapy designation, and fast track designation, as well as priority review and accelerated approval.

Photo: Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research

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