The State of Gene Therapies: The FDA Perspective
Authors: Daniel Takefman, Wilson Bryan
Journal: Molecular Therapy (2012)

Clinical development of gene therapy began over 20 years ago. Currently there are more than 320 ongoing gene therapy clinical trials that are regulated by the Office of Cellular, Tissue, and Gene Therapies (OCTGT) in the Center for Biologics Evaluation and Research of the US Food and Drug Administration (FDA). The FDA's mission is to advance the public health by helping to speed innovations that make medicines safer and more effective. The diverse gene therapy products in clinical development for a wide range of disorders offer an opportunity for the FDA to fulfill that mission. The recent history of gene therapy has been a mixture of promise and disappointment. Gene therapy products often initially appear promising because they reflect strong scientific rationale when they are proposed as treatments for specific, well-defined genetic disorders. In addition, some gene therapy products have been well publicized because they offer hope for the treatment of rare, disabling, or life-threatening disorders. Despite strong scientific rationale and publicity-generated enthusiasm, the field has not yet produced any products that have gone through clinical development and provided the evidence of safety and effectiveness necessary for FDA marketing approval. In addition, the death of Jesse Gelsinger in 1999 resulted in a period of circumspection in the field of gene therapy. Subsequent enthusiasm generated by exciting scientific results from a trial for treatment of X-linked severe combined immunodeficiency (X-SCID) was tempered by reports of insertional mutagenesis.1Hacein-Bey-Abina S Von Kalle C Schmidt M McCormack MP Wulffraat N Leboulch P et al.LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.Science. 2003; 302: 415-419Crossref PubMed Scopus (3000) Google Scholar More recently, the field has been rejuvenated by several reports of encouraging results in clinical trials. Many of these results were presented at the National Institutes of Health Gene Therapy Symposium that took place in September 2011.2American Society of Gene & Cell Therapy. NIH Gene Therapy Symposium Natcher Conference Facility, National Institutes of Health, Bethesda, MD <http://www.asgct.org/meetings-educational-programs/nih-gene-therapy-symposium>(26–27 September 2011)Google Scholar The FDA shares the field's optimism based on the scientific data reported from these recent clinical trials. The OCTGT is committed to working with sponsors as these new products make their way from early-phase trials into confirmatory phase III trials and to marketing approval. Gene therapies are novel and complex products that can offer unique challenges in product development. Hence, ongoing communication between the FDA and stakeholders is essential to meet these challenges. For sponsors of clinical trials, the OCTGT encourages both formal meetings (e.g., at the end of phase I, end of phase II, or pre-biologics license application) and informal communications. Such communications are necessary to ensure that the overall clinical development program and specific clinical trials are designed to provide the necessary evidence of safety and effectiveness. Moreover, such communications are critical to ensuring that product development addresses the good manufacturing practice requirements for a licensed product. Investigators and trial sponsors are encouraged to visit the FDA website on the regulation of gene therapies (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/OtherRecommendationsforManufacturers/ucm094338.htm). This site provides general information about the OCTGT and the regulatory process, as well as a link to OCTGT Learn, a series of educational "webinars" specific to products regulated by the OCTGT. The FDA recognizes that many gene therapy products are being developed for rare disorders and that clinical development of a product for these indications can present unique challenges. The agency's regulations provide the flexibility necessary to meet these challenges and facilitate the development of therapeutics for rare disorders.3F Sasinowski Quantum of effectiveness evidence in FDA's approval of orphan drugs. Cataloguing FDA's flexibility in regulating therapies for persons with rare disorders <http://www.rarediseases.org/docs/policy/NORDstudyofFDAapprovaloforphandrugs.pdf>(October 2011)Google Scholar,4Kesselheim AS Myers JA Avorn J Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer.JAMA. 2011; 305: 2320-2326Crossref PubMed Scopus (168) Google Scholar,5Mitsumoto J Dorsey ER Beck CA Kieburtz K Griggs RC Pivotal studies of orphan drugs approved for neurological diseases.Ann Neurol. 2009; 66: 184-190Crossref PubMed Scopus (57) Google Scholar However, consistent communication between sponsors and the OCTGT throughout drug development, as outlined above, is essential to optimizing the development of gene therapies for rare disorders. In addition, manufacturers of gene therapy products for rare disorders are eligible to apply for orphan drug designation by the FDA's Office of Orphan Product Development; such designation comes with tax credits, marketing incentives, and the opportunity to apply for support through the Orphan Products Grants Program. Because gene therapy products are being developed around the world, the FDA is engaged in a number of international harmonization activities in this area. The agency works with the International Conference on Harmonisation on Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Specifically, the FDA has participated in the ICH Gene Therapy Discussion Group and published three relevant documents (on inadvertent germline integration, oncolytic viruses, and virus and vector shedding), which are available on the ICH website (http://www.ich.org/products/consideration-documents.html). There is also a formal cooperation and confidentiality arrangement between the FDA and the European Medicines Agency (EMA). Through this arrangement, the FDA and EMA have bimonthly meetings to share views on regulatory approaches to both general and specific issues in gene therapies (referred to as "advanced-therapy medicinal products" in Europe). Additionally, the FDA and the EMA participate in a program to provide parallel scientific advice. Its goal is to provide a mechanism for EMA and FDA assessors and sponsors to exchange views on scientific issues during development of new medicinal products. The OCTGT will continue to work with sponsors, investigators, and other regulatory bodies to navigate the challenges of therapeutic development. Despite the setbacks of the past, the OCTGT shares the enthusiasm of the field and is confident that ongoing clinical investigations will lead to commercially available gene therapy products that are safe and effective and advance the public health.