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

Dear Sir/Madam:

The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments regarding the draft guidance titled “Long Term Follow-Up After Administration of Human Gene Therapy Products”.

BIO is the world's largest trade association representing biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial, and environmental biotechnology products.

BIO applauds the FDA on the work done to develop this Draft Guidance along with its companion documents on the topic of Gene Therapies. The Draft Guidance is reflective of the Agency’s experience gathered over the past decade on the evaluation of safety of gene therapy products. This important Draft Guidance is well written and provides instrumental recommendations on how to determine and develop long term follow-up after administration of human gene therapy products. Below we have provided general comments as well as detailed comments in the table attached.

General Comments

• The Draft Guidance appropriately describes the primary rationale of gene therapy (GT) product development being the offering of therapeutic effect through permanent or long-acting changes in the human body. However, the document assumes that long-term persistence of the GT product increases their safety risk, which BIO believes overstates the concern. The safety risk, whether short-term or long-term, will be different between the carrier (e.g., vector) or the protein encoded by the transgene.

• BIO believes the Draft Guidance should recognize some of the challenges associated with viral vector persistence and safety risk. With respect to the persistence of the viral vector in GT products, it should be noted that if the viral vector does not persist then the efficacy may wane. In such circumstances it may be necessary to re-administer the viral vector. This comes with the additional risk of immune-mediated toxicities (as described in the Human Gene Editing for Retinal Disorder Draft Guidance). Since repeated administration of the GT product that has limited persistence may result in a prolonged duration of exposure to a GT product, it does not seem appropriate to emphasize the persistence of the GT product after a single administration. With respect to safety risk, there may be safety concerns related to the presence of the viral vector, whether the vector contains a genome (i.e., full capsids) or does not contain a genome (i.e., empty capsids) through immune-mediated mechanisms. Since GT products often utilize naturally occurring viruses (e.g., AAV), it is possible that safety concerns can arise as a result of an infection with a naturally occurring viral infection. It is likely that the long-term safety risks of the presence of the GT viral vector/capsid are no greater than the safety risks of a naturally occurring infection with the source vector.

• In general, BIO welcomes the updated change in the Draft Guidance on LTFU periods of 5 to 15 year follow up, which affords flexibility upon clinical experience and are based on product type. BIO notes that LTFU periods can present unique logistical challenges for sponsors. For example, patients can choose not to participate in the LTFU, drop out of a program, or relocate geographically without giving notice to the gene therapy manufacturer. Similar concerns exist for the health professionals treating patients, for example, a study investigator or a patient’s personal physician may retire from practice during a 15-year period. BIO encourages FDA to work along with Sponsors to explore and develop best practices to ensure that the maximum number of patients can be effectively tracked and engaged over the course of lengthy follow-up timeframes.

• The Draft Guidance discusses the conduct of the biodistribution study for the purpose of designing the LTFU study. However, the Draft Guidance on Human Gene Therapy for Retinal Disorders indicates that the biodistribution study is conducted in order to design the toxicology study. Additionally, the biodistribution study is often taken into consideration as part of the environmental impact assessment. Acknowledgement of all uses of the biodistribution study should be included in this and other relevant Draft Guidances. In addition, BIO believes the Agency should consider partner with multiple stakeholders to evaluate key biodistribution questions including whether a quantitative approach is required, if studies using in vivo imaging may be acceptable, or whether studies evaluating the distribution of the viral vector without a transgene (i.e., evaluating the distribution of empty capsids) may be acceptable. 

• BIO encourages the Agency to continue its initiative to promote global harmonization across multilateral organization in this field. As new GT are developed, harmonization become increasingly critical to support efficient development of safe and effective therapies for patients. Harmonization efforts should include organizations such as the International Conference on Harmonisation (ICH), or the International Pharmaceutical Regulators Programme (IPRP).

BIO appreciates this opportunity to submit comments regarding FDA’s draft guidance titled “Long Term Follow-Up After Administration of Human Gene Therapy Products”. We would be pleased to provide further input or clarification of our comments, as needed.