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FDA Issues Draft Gene Therapy Regulatory Guidance

Editing DNA

(LaCasadeGoethe, Pixabay)

11 July 2018. Food and Drug Administration issued a series of draft documents spelling out its processes for reviewing gene therapies for three types of diseases, as well as producing and testing these treatments. The six new guidance documents released for public comment were announced today in a statement by FDA commissioner Scott Gottlieb on the agency’s web site.

The proposed regulatory framework covers new drug applications for therapies where healthy genes are transferred into a patient’s genome that replace missing or defective genes, as well as those that change genetic sequences, such as with genome editing. These treatments are being tested for inherited disorders, as well as autoimmune conditions, cardiovascular disease, cancer, and HIV/AIDS. Gottlieb says in his statement that even though the agency already reviewed and approved three gene therapies, the field is still new and its staff is still learning. He notes …

In contrast to 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 can’t be fully answered in any 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.

Three of the documents address gene therapies for specific sets of diseases. One document spells out the agency’s thinking for review of gene therapies for hemophilia, an inherited blood disease. People with hemophilia lack a protein called a clotting factor that helps blood platelets coagulate around a wound. The two main types of the disorder are hemophilia A and B, where individuals lack clotting factor 8 or 9 respectively. About 8 in 10 people with hemophilia have type A. The guidance document outlines recommendations for designing clinical trials to test gene therapies, measurements for clotting factors 8 and 9, and preclinical steps for gene therapy developers. As reported in Science & Enterprise, FDA recently stopped a clinical trial from beginning in a test of genome editing for sickle cell disease, another inherited blood disorder.

A separate document highlights the agency’s approach to reviewing gene therapies for diseases of the retina, the layer of nerve cells on the back wall inside the eye that senses light and sends signals to the brain. One of the gene therapies approved by FDA in December 2017 is a treatment for inherited retinal disease made by Spark Therapeutics, also as reported by Science & Enterprise. The draft guidance provides recommendations for product development, as well as manufacturing considerations that take into consideration the fragile nature of eye tissue. The document also recommends preclinical studies with larger animals than lab mice or rats, to better approximate human eye size and complexity.

Another document covers gene therapies for rare diseases, while individually having small numbers, affect some 25 million people in the U.S., with children making up about half of that population. FDA says some 80 percent of rare diseases are caused by defects in single genes, making them good candidates for gene therapies. Because of small numbers of people affected with individual rare diseases, however, clinical trials of their treatments, including gene therapies, are more challenging. As a result, FDA recommends in the document more emphasis on preclinical studies to determine risks and benefits of proposed therapies. In clinical trials, the agency may consider alternatives to the classic randomized design testing experimental treatments against a placebo, such as single groups of patients with results compared to historical records, within specified limits.

FDA issued three other guidance documents on gene therapies for comment: (1) chemistry, manufacturing, and control information required for investigational new drug applications for gene therapies, (2) special requirements in retroviral vector-based gene therapies to protect against replication-competent retroviruses that pose serious risks to patients, and (3) long-term follow-up studies of gene therapies, looking particularly for delayed adverse effects.

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