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Gene Therapy: New Draft Guidance Will Impact Clinical Trial Designs

On July 11, the FDA released six new draft guidances on the development of gene therapies. Two of the guidance documents, Human Gene Therapy for Rare Diseases and Long-term Follow-up After Administration of Gene Therapy Products, have the broadest relevance for the design and conduct of clinical trials. These two guidances extensively describe specific considerations that will require significant attention for anyone designing new clinical trials with gene therapy products.

The category of rare diseases includes over 7,000 different conditions, the majority of which have an inherited genetic basis. The Draft Guidance on Human Gene Therapy for Rare Diseases includes a number of notable points specific to rare disease indications and to gene therapy clinical trials in general. In rare disease research the target population is often children. In accordance with the regulations on research in children, children should not be enrolled in a clinical trial involving more than minimal risk unless there is evidence of a prospect of direct benefit to the participant. Therefore, in addition to considerations of toxicology and biodistribution, preclinical studies for these indications should be designed to demonstrate a potential clinical benefit in animal models. The guidance also states that it is generally not acceptable to enroll healthy volunteers into gene therapy studies. Inclusion criteria should address confirmation of a genetic defect in each participant as well as the potential for pre-existing immunity to gene transfer vectors.

With regard to study design, a randomized, concurrently-controlled trial design is heavily favored. Ideally, such a trial will be designed to show efficacy at an early phase, will be stratified by disease stage/ severity, and will incorporate an endpoint outcome never seen in the natural course of disease (for example, improvement in a clinical sign unlike what might be seen in the expected variation of the disease signs and symptoms). However, the guidance recognizes that these ideals are not always possible, especially in rare diseases in which the patient population may be very small, and allows for alternatives such as historical controls based on natural history and surrogate endpoints. The guidance also strongly recommends including endpoints that are meaningful to the patient, as well as collection of patient experience data as part of clinical trial design.

The Draft Guidance on Long Term Follow-Up [LTFU] After Administration of Human Gene Therapy Products states that development of all gene therapy products should include consideration of the risk of delayed adverse events. For products where such a risk is identified, the guidance lays out a fairly detailed and extensive program for up to 15 years of follow-up for all participants.

The information used in this assessment should include preclinical data from in vitro and animal studies as well as clinical data from previous trials using similar products.

 For products that qualify for LTFU, there are extensive recommendations for data collection to identify and mitigate the long-term risk to patients including a dedicated LTFU protocol, a scheduled plan for comprehensive collection of accurate and adequate case histories, and a method for health care providers to record and report new clinical events and conditions.  Subjects should be contacted at least once a year, and those who test positive for the presence of the gene transfer vector should be tested again at the following visit.

For gene therapy products that integrate into the chromosome, or modify the chromosome by genomic editing, there should be extensive and specific tracking of on- and off-target genetic changes, as well as possible activation of oncogenes.

Overall, the publication of these draft guidances demonstrates that the FDA anticipates an acceleration of new developments in gene therapy products, and recognizes the need to adapt regulatory expectations to address new technologies. Comments on the draft guidances should be submitted by October 10, 2018.