Gene Therapy: BIO Comments on FDA Draft Guidance, Human Gene Therapy for Retinal Disorder and Hemophilia

November 14, 2018 

Re: Docket No. FDA–2018-D-2236: FDA Draft Guidance, Human Gene Therapy for Retinal Disorder

Re: Docket No. FDA–2018-D-2238: FDA Draft Guidance, Human Gene Therapy for Hemophilia

Dear Sir/Madam:

The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments regarding Draft Guidances titled: “Human Gene Therapy for Retinal Disorders” and “Human Gene Therapy for Hemophilia”.

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.

We applaud the FDA for putting forth this guidance to assist stakeholders developing human gene therapy (GT) products for the treatment rare diseases, including hemophilia and retinal disorders. The Draft Guidance is reflective of the Agency’s experience gathered over the past decade on the evaluation of safety of gene therapy products. Below we have provided general comments on both of these Draft Guidances.

  • In general, BIO supports the idea that preclinical in vitro and in vivo proof-of-concept studies and disease-specific animal models be developed when possible. However, preclinical models have limitations which should be recognized in the Draft Guidances. These include limited utility when informing assays for human use and practical as well as biological limitations in the collection of samples from animal models. Therefore, Sponsors should have the flexibility to use different clinical laboratory assays, where feasible, assays intended for human use, as well as discretionary use collection and use of samples.  
  • In addition, while animal models can be used broadly for testing GT products, they are not as broadly applicable to GT products in which the genetic sequence guides used for gene editing are specie-specific as well as nucleotide-specific. BIO suggest the FDA apply science-based regulatory flexibility when evaluating appropriateness of animal models for certain GT products.
  • The terminology “pharmacokinetics” is commonly associated with measures of exposure to drug (e.g., Cmax and AUC) as well as concepts such as clearance, volume of distribution, and half-life. As such, the terminology “pharmacokinetics” should not be used in the context of a GT product in order to avoid confusion and the calculation of PK parameters that may be meaningless or misleading.
  • It is unclear as to how the data from biodistribution studies can be used to design preclinical toxicology studies. Often the biodistribution studies and toxicology studies are performed in parallel rather than the biodistribution study being performed before the preclinical toxicology study is performed. This approach is taken in order to move rapidly into the clinic and bring these life-changing therapies to patients as soon as is feasible.  In this approach, a full set of tissues is taken for histopathology in the preclinical toxicology study.
  • Similarly, the data obtained from the biodistribution study may not impact the design of the clinical trial. In theory, the biodistribution study could help in the selection of the secreta/excreta to be collected in the clinical trial for the determination of “vector shedding”.  However, the clinical trial can be designed in the absence of the animal biodistribution data or a full set of secreta/excreta may be requested by the Health Authority regardless of the results of the animal biodistribution study. Consequently, the biodistribution study may be regarded as superfluous and it may not be necessary to conduct the study. BIO believes Sponsor should have the possibility to justify not conducting an animal biodistribution study at a pre-IND or IMPACT meeting. This will reduce the number of animals used as well as reduce the overall cost of drug development.
  • In general, considering that reproductive/developmental toxicity studies these may or not be conducted for an individual development program, FDA should acknowledge the consideration for need on a case by case basis, and clarify when and what kind of additional nonclinical studies may need to be considered to address the potential for reproductive/developmental toxicity. The Draft Guidances should discuss considerations for the type of GT and vector in determining the need and type of reproductive/developmental toxicity studies. For example, the considerations may vary depending on whether AAV or lentivirus is used.
  • In line with the ongoing efforts by the FDA to further modernize the regulatory review process, the Agency should recognize in its Draft Guidances that complex innovative designs might be fit-for-purpose to execute clinical trials of GT products for rare diseases. Consequently, BIO suggest the Agency include in its Draft Guidances discussion on the use of innovative clinical trial designs. In addition, the Agency should avoid using limiting language regarding clinical trial design such as that recommending specific number of treatment arms, utilizing different doses but the same product administration procedures, or the inclusion of a sham control group. Similarly, the Draft Guidances would benefit from further discussion on how FDA would consider use of natural history studies as a control for rare diseases. Overall, using of innovative clinical trial design can decrease unnecessary and unethical patient exposure to clinical procedures and experimental products while still advancing clinical development.
  • BIO generally agrees with the Agency in that complex GT delivery procedures should be performed by individuals experienced in the method of planned delivery. The Sponsor should ensure that investigators utilize the same device and that the product is delivered in a standardized, reproducible way.
  • Given that GT will generally have a long-lasting impact on the patient condition, FDA should consider discussing how Sponsors might assess long-term efficacy and safety in the presence of intercurrent events (for example, additional therapies to treat the same condition).
  • Regarding inclusion of patient experience, BIO believes additional guidance from the Agency would be helpful on what types of patient experience data may be the most useful or persuasive for a gene therapy. BIO also welcomes the opportunity to work with the Agency on incorporating the patient voice and provide additional thinking on this topic.

BIO appreciates this opportunity to submit comments regarding FDA’s Draft Guidance, Human Gene Therapy for Retinal Disorders” and “Human Gene Therapy for Hemophilia”. We would be pleased to provide further input or clarification of our comments, as needed.