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The agency is releasing six new draft guidances to provide a regulatory framework for handling gene therapies.
In a July 11, 2018 statement FDA Commissioner Scott Gottlieb, MD, highlighted the agency’s efforts to support the development and regulation of gene therapies. The agency is issuing a suite of six scientific guidance documents that will serve as the foundation for a modern, comprehensive framework for how the agency will help advance the field of gene therapy while ensuring that these new products meet FDA’s standard for safety and effectiveness.
The new policies are part of the agency’s efforts to communicate the steps it is taking to provide clear recommendations to sponsors and researchers to better support innovation. The guidance documents are being issued in draft form, and FDA will solicit public input on these new policies. As with all of FDA’s draft guidances, all comments received will be carefully considered prior to finalizing the documents.
“Once just a theory, gene therapies are now a therapeutic reality for some patients. These platforms may have the potential to treat and cure some of our most intractable and vexing diseases. The policy framework we construct for how these products should be developed, reviewed by regulators, and reimbursed, will help set the stage for the continued advancement of this new market,” Gottlieb said in the statement. “Last year, we announced our comprehensive policy framework for regenerative medicine, including a draft guidance that describes the expedited programs, such as the breakthrough therapy designation, and the regenerative medicine advanced therapy (RMAT) designation, that may be available to sponsors of these therapies. Today, we’re unveiling a complementary framework for the development, review, and approval of gene therapies.”
Three separate gene therapy products were approved by FDA in the past 12 months, which reflects the rapid advancements in the field, such as the development of vectors that could reliably deliver gene cassettes in vivo into cells and human tissue. The field of gene therapy is expected to expand in the future, with the potential approval of new treatments for many debilitating diseases, according to Gottlieb.
“These therapies hold great promise. Our new steps are aimed at fostering developments in this innovative field,” Gottlieb said.
Gene therapies are being studied in many areas, including genetic disorders, autoimmune diseases, heart disease, cancer, and HIV/AIDS. FDA expects to work with academic and research communities to make safe and effective products a reality for more patients. However, there is still much to learn about how gene therapy products work, how they can be administered safely, and whether they will continue to work properly in the body without causing adverse side effects over long periods of time.
In contrast to a traditional drug review, some of the more challenging questions when it comes to gene therapy relate to product manufacturing and quality, or questions about the durability of response, which often cannot be fully answered in a reasonably sized pre-market trial. “For some of these products, we may need to accept some level of uncertainty around these questions at the time of approval. For example, in some cases the long-term durability of the effect won’t be fully understood at the time of approval. Effective tools for reliable post-market follow up, such as required post-market clinical trials, are going to be one key to advancing this field and helping to ensure that our approach fosters safe and innovative treatments,” Gottlieb stated.
“Even when there may be uncertainty about some questions, we need to make certain we assure patient safety and adequately characterize the potential risks and demonstrated benefits of these products. In part because of the added questions that often surround a new technology like gene therapy, these products are initially being aimed at devastating diseases, many of which lack available therapies, including some diseases that are fatal. In such cases of devastating diseases without available therapies, we’ve traditionally been willing to accept more uncertainty to facilitate timely access to promising therapies,” he added.
In such cases, drug sponsors are generally required to conduct post-marketing clinical trials, or Phase IV confirmatory trials, to confirm clinical benefit of the drug. “This is the direction Congress gave [FDA] by creating vehicles like the accelerated approval pathway,” Gottlieb said.
“When it comes to novel technologies like gene therapy, FDA is steadfastly committed to a regulatory path that maintains the agency’s gold standard for assuring safety and efficacy. As we develop this evidence-based framework, we’re going to have to modernize how we approach certain aspects of these products in order to make sure our approach is tailored to the unique challenges created by these new platforms,” he remarked.
Among the six new draft guidances that FDA is issuing are three draft guidance documents related to the development of gene therapy products for specific disease categories: hemophilia, retinal disorders, and rare diseases. These are the first three disease-specific guidances that the agency is issuing for gene therapy products.
Human gene therapy for hemophilia: Gene therapy products for hemophilia are now being developed as single-dose treatments that may enable long-term production of the missing or abnormal coagulation factor in patients. This may reduce or eliminate the need for coagulation factor replacement. Once the draft guidance for hemophilia-targeted gene therapy is finalized, it will provide recommendations on FDA’s current thinking on clinical-trial design and preclinical considerations. Among other elements, the draft guidance provides recommendations regarding surrogate endpoints that could be used by sponsors pursuing accelerated approval.
Human gene therapy for retinal disorders: Another area of fast-paced activity is gene therapy products targeted to the treatment of retinal disorders. The human gene therapy for retinal disorders guidance, once finalized, will assist those developing gene therapy products for a wide variety of retinal disorders affecting both adult and pediatric patients. Gene therapy products currently undergoing clinical trials in the United States for retinal disorders are commonly delivered by intravitreal injections or subretinal injections. In some cases, the gene therapy products are encapsulated in a device to be implanted within the eye. This new guidance document will focus on issues that are specific to gene therapies for retinal disorders and will provide recommendations related to product development, preclinical testing, and clinical trial design for such products.
Human gene therapy for rare diseases: Rare diseases are those that affect fewer than 200,000 people in the US and that typically have no approved therapies. The National Institutes of Health reports that nearly 7000 rare diseases affect more than 25 million Americans. About 80% of rare diseases are caused by a single-gene defect, and about half of all rare diseases affect children. The human gene therapy for rare diseases guidance, once finalized, will provide recommendations on preclinical, manufacturing, and clinical trial design for all phases of the clinical development program for these types of gene therapies. The information 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.
The other new guidance documents will involve comprehensive updates to three existing guidances that address manufacturing issues related to gene therapy. These updates reflect input from many stakeholders, and additional feedback is encouraged by the agency during the comment period for the drafts.
The first draft guidance, 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. The guidance applies to human gene therapies and to combination products that contain a human gene therapy in combination with a drug or device. In addition, this guidance is organized to follow the structure of FDA guidance on the Common Technical Document.
The second draft guidance, Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up, provides additional recommendations regarding the proper testing for RCR during the manufacture of retroviral vector-based gene therapy products, as well as during the follow-up monitoring of patients who have received retroviral vector-based gene therapy products. Specifically, the draft guidance recommends the identification and amount of material to be tested. The guidance also provides advice on general testing methods.
The third draft guidance, Long Term Follow-Up After Administration of Human Gene Therapy Products, provides recommendations regarding the design of long-term follow-up (LTFU) observational studies for the collection of data on delayed adverse events following administration of a gene therapy product. 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-leads to an increased need for robust long-term follow-up of patients in the post-market period. This guidance describes product characteristics, patient-related factors, and the preclinical and clinical data that should be considered when assessing the need for LTFU observations as well as describes the features related to effective post-market follow up.
Once finalized, these updated draft guidances will replace previous guidances issued by FDA in April 2008 (CMC) and November 2006 (RCR and LTFU). Because the field of gene therapy has progressed rapidly since these guidances were first issued, FDA must update these guidances to provide sponsors with the agency’s most up-to-date thinking.
“Our goal is to help promote safe and effective product development in this field. We’ll continue to work with the product sponsors to help make the development and approval of these innovative gene therapies more efficient, while putting in place the regulatory controls needed to ensure that the resulting therapies are both safe and effective. We’ll also make full use of our expedited programs, such as breakthrough therapy designation and regenerative medicine advanced therapy designation, whenever possible,” Gottlieb said.
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