Guest Column | August 2, 2018

FDA's New Guidance On Gene Therapy For Retinal Disorders — A Primer

By Katie McCarthy, Greenleaf Health

FDA’s New Guidance On Gene Therapy For Retinal Disorders — A Primer

The FDA defines human gene therapy products as all products that mediate their effects by transcription or translation of transferred genetic material or by specifically altering host (human) genetic sequences. Some examples of gene therapy products include nucleic acids, genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells. Gene therapy products meet the definition of “biological product” in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262(i)) when such products are applicable to the prevention, treatment, or cure of a disease or condition of human beings.

Although the journal Science reports that the first gene therapy clinical trial was conducted in 1990,1 the FDA only approved the first gene therapy product on August 30, 2017. Two more approvals quickly followed, reflecting a suddenly rapid advancement in this field. On July 11, 2018, the FDA issued for public comment six draft guidance documents intended to serve as part of a modern, comprehensive framework for how the Center for Biological Evaluation and Research (CBER) will help advance the field of gene therapy.

This is the fifth article in a six-part series summarizing each of the draft guidance documents. In previous articles, we reviewed:

This article will discuss the draft guidance Human Gene Therapy for Retinal Disorders.


The FDA reports in this draft guidance that there are multiple gene therapy (GT) products being studied in clinical trials in the United States for retinal disorders. The draft guidance focuses on issues specific to GT products for retinal disorders and provides recommendations related to product development, preclinical testing, and clinical trial design for such GT products.

The guidance provides examples of established endpoints to evaluate the clinical benefit of GT products intended for the treatment of retinal disorders. However, the FDA encourages sponsors to develop and propose novel endpoints to measure clinically meaningful effects in patients with retinal disorders. The agency notes that this can be especially pertinent to rare retinal disorders for which the established efficacy endpoints may not be appropriate to assess clinically meaningful effect of an investigational product. The draft guidance references other guidances that address clinical development programs more broadly and should be understood as a supplement to those guidances, not a replacement for them.

FDA encourages sponsors to contact the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biological Evaluation and Research (CBER) before the sponsor’s investigational new drug application (IND) is filed. The agency also encourages sponsors to engage FDA early in the process to develop acceptable endpoints. The draft guidance notes the meeting types that may be used for discussion, including pre-IND meetings and the Initial Targeted Engagement for Regulatory Advice on CBER products (INTERACT), for early, nonbinding regulatory advice.

Considerations for Product Development

Sponsors should take into account general chemistry, manufacturing, and control (CMC) considerations. The draft guidance also provides CMC specific considerations for retinal disorder products, including the design of proof of concept studies, biodistribution studies to assess the pharmacokinetic profile of a GT product, toxicology studies, and animal models of disease.

Considerations for Preclinical Studies

The FDA notes that the overall objectives of a preclinical program for a GT product should include: 1) identification of a biologically active dose range; 2) recommendations for an initial clinical dose level, dose-escalation schedule, and dosing regimen; 3) establishment of feasibility and reasonable safety of the proposed clinical route of administration; 4) support of patient eligibility criteria; and, 5) identification of potential toxicities and physiologic parameters to guide clinical monitoring for a particular investigational product.

Considerations for Clinical Trials

The FDA recommends the following elements for consideration during development of clinical programs.

Natural History Studies

A thorough understanding of the natural history of a disease is an important element in all clinical development programs. The FDA recommends that a sponsor perform a careful natural history study to facilitate the product development program, lthough it is not required.

Study Design

The agency recommends having at least two treatment arms, utilizing different doses but the same product administration procedures, to minimize patients’ ability to identify their treatment arm, while also having a sham control group. In addition to facilitating masking, the second treatment arm has value as a dose-ranging control. Although use of the contralateral eye to which the GT product is not administered as a control may potentially be considered, it is generally not recommended.

Study Population

The correct genetic diagnosis is essential for identifying potential participants. Thus, confirmation of the genetic mutation prior to enrollment is recommended as an important element of the clinical trial. In general, first-in-human GT trials should enroll patients with severities of visual impairment that offer a favorable benefit-risk profile. If preliminary safety data supports further clinical development, sponsors may consider a broader patient population in future trials. For diseases that affect both adults and children, trials in adult patients should be conducted prior to trials in pediatric patients, whenever feasible.

Study Use

For early-phase trials, dose-ranging study designs are recommended. Most retinal indications for which GT products are studied involve bilateral disease, and the FDA advises consideration of the planned administration of the GT product in both eyes. While the eye with more advanced disease often receives the GT product initially, a rationale should be developed for deciding which eye will receive the GT product first. Finally, the agency notes that a single administration of a GT product may not always be sufficient for a variety of reasons.

Safety Considerations

Risks from administration of the GT product include intraocular infection, elevated intraocular pressure, media opacities, and retinal damage. Local or systemic immune responses to GT products may pose important safety risks. The draft guidance provides recommendations to reduce these risks.

Study Endpoints

The FDA encourages sponsors to explore a wide spectrum of potential clinical endpoints and other clinical effects in early-phase trials, and the draft guidance identifies endpoints for consideration. For later-phase trials intended to provide substantial evidence of effectiveness to support a marketing application, primary efficacy endpoints should reflect clinical benefit, such as improvement in function or symptoms. Examples of established efficacy endpoints include: 1) best corrected distance visual acuity, measured with the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart or other visual acuity charts with an equal number of letters per line and equivalent spacing between lines; and 2) rate of photoreceptor loss, determined by measures such as optical coherence tomography or autofluorescence photography. The agency encourages sponsors to develop and propose novel endpoints to measure clinically meaningful effects in patients with retinal disorders.

Patient Experience Data

The FDA also encourages sponsors to collect patient experience data during product development, and to submit such data in the marketing application.

The FDA will accept comments on the draft guidance through October 10, 2018. You can submit comments electronically at

The next and final article in this series summarizes the draft guidance Human Gene Therapy for Hemophilia.


  1. Blaese et al. T Lymphocyte-Directed Gene Therapy for ADA− SCID: Initial Trial Results After 4 Years, Science 20 Oct 1995: Vol. 270, Issue 5235, pp. 475-480 DOI: 10.1126/science.270.5235.475

About The Author:

Katie McCarthy is VP of regulatory affairs in the Drug and Biological Products group at Greenleaf Health, Inc. She specializes in scientific and regulatory issues affecting pharmaceutical and biotechnology companies. You can reach her at