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FDA’s Guideline on Human Gene Therapy for Retinal Disorders

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Today from Revio we are sharing with you an overview on the FDA’s Guidance for Industry “Human Gene Therapy for Retinal Disorders”. This document focuses on issues specific to gene therapy (GT) products for retinal disorders, offering recommendations related to product development, preclinical testing, and clinical trial design. These disorders vary in etiology, prevalence, diagnosis, and management, encompassing genetic and age-related diseases.


GT products are typically administered via medical delivery systems, with intravitreal or subretinal injections being common methods. In some cases, the GT products are encapsulated in a device to be implanted intravitreally.

Sponsors of GT products for retinal disorders should consider general GT considerations as well as CMC considerations specific to these products, including:

  • Consideration of the final product formulation and concentration for the expected dose and volume.
  • Endotoxin limits for intraocular delivery following USP <771> specifications.
  • Testing of vector-based products for particulate matter, following USP <789>.
  • Product testing and release should include testing of the final product configuration.
  • Evaluation of compatibility between the GT product and the delivery system.


In the development of a preclinical program for an investigational GT product intended for treatment of retinal disorders the following elements should be considered.

  • Preclinical proof-of-concept studies should establish feasibility and support the scientific rationale for administration of the investigational product in clinical trials.
  • Biodistribution studies should be conducted to assess the distribution, persistence and clearance of the vector and possibly the expressed transgene product in vivo from the site of administration.
  • Toxicology studies should incorporate elements of the planned clinical trial (dose range, ROA, dosing schedule, endpoints, etc.).
  • Animal models of retinal disorders are frequently developed in rat or mouse strains. Animal models with more “human-like” eyes, such as rabbits, pigs or nonhuman primates may also provide applicable safety information.


The guideline discusses key elements to consider during the development of clinical programs for investigational GT products for retinal disorders:

  1. Natural History Studies: A thorough understanding of the natural history of a disease is an important element in all clinical development programs.
  2. Study Design: To facilitate interpretation of clinical data, inclusion of a randomized, concurrent parallel control group is recommended for clinical trials whenever possible.
  3. Study Population: For clinical trials of GT products providing gene replacement, the correct genetic diagnosis is essential for identifying potential participants.
  4. Study Use: For early-phase trials, dose-ranging study designs are recommended and comparing a range of doses can identify potential therapeutic doses for a wider group of patients.
  5. Safety Considerations: Intraocular administration (e.g., intravitreal or subretinal injection) may be the most efficient method to deliver GT products intended for treatment of retinal disorders.
  6. Study Endpoints: To guide further clinical development, FDA encourages sponsors to explore a wide spectrum of potential clinical endpoints and other clinical effects in early phase trials.
  7. Follow-Up Duration: The length of follow-up to provide additional information regarding the safety and efficacy of the GT product depends on many aspects of a GT product, including vector persistence, genome integration, and transgene activity, and the goal of the follow-up.
  8. Patient Experience: Patient experience data may provide important additional information about the clinical benefit of a GT product.


Sponsors of GTs aimed at addressing unmet medical needs in the treatment of severe or life-threatening conditions may have access to various programs. These programs (regenerative medicine advanced therapy designation, breakthrough therapy designation, fast track designation, accelerated approval and priority review) are intended to facilitate and expedite development of these therapies.


The FDA recommends early communication with the Office of Therapeutic Products (OTP), previously known as the Office of Tissues and Advanced Therapies (OTAT), before submitting an investigational new drug application (IND). Various types of meetings are available for these discussions, depending on the product’s development stage and specific matters to be addressed.

This is some information provided in FDA’s Guidance for Industry on Human Gene Therapy for Retinal Disorders, for more information you can check the official guideline here!

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