Human Gene Therapy for Retinal Disorders: Guidance for Industry

Description

This guidance provides recommendations to sponsors developing human gene therapy (GT) products for retinal disorders affecting adult and pediatric patients. These disorders vary in etiology, prevalence, diagnosis, and management, and include genetic as well as age-related diseases. These disorders manifest with central or peripheral visual impairment and often with progressive visual loss. This 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. This guidance finalizes the draft guidance of the same title dated July 2018.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

2

Human Gene Therapy

Includes genetically modified cells

Gene Therapy

A type of ATMP involving recombinant nucleic acids or viral vectors.

Stakeholders

3

Sponsor

Entity responsible for submitting applications under section 524B

OTAT

Office of Tissues and Advanced Therapies in CBER

Pediatric patients

Known to have a lower risk of GVHD than adults; population with response profiles differing from adults; Pediatric patients may have response profiles that differ from adults; Population: ≥12 years old or ≥ 2 years old

Regulatory Context

Regulatory Activities

7

Early communication meetings

Meetings with FDA to discuss alternative testing approaches

Biologics license application

Type of application (BLA) whose applicants are subject to this guidance.; BLA for biological products containing synthetic fragments

Accelerated approval

eligible for one or more of FDA's expedited programs

Regenerative medicine advanced therapy designation

Expedited program for development and review

Breakthrough therapy designation

Expedited program for drugs showing substantial improvement

Investigational new drug application

IND phase of drug development

INTERACT meetings

Initial Targeted Engagement for Regulatory Advice on CBER products

Attributes

4

Patient experience data

Data providing information about patients' experiences with a disease

Endotoxin limit

The endotoxin limit for intraocular delivery should follow specifications

Benefit-risk profile

Assessment for both mother and child

Surrogate endpoint

Microbiological outcome reasonably likely to predict clinical benefit

Technical Details

Substances

4

Nucleic acids

Examples of gene therapy products include nucleic acids like plasmids

Transgene product

Expressed protein from the gene therapy vector

Corticosteroids

Example of a drug with age-specific safety concerns regarding growth velocity.

voretigene neparvovec-rzyl

Recombinant adeno-associated vector carrying the gene for human retinal pigment epithelium-specific 65 kDa protein

Testing Methods

6

Toxicology studies

Conducted in animal models to identify potential toxicities

Proof-of-concept studies

Preclinical in vitro and in vivo POC studies recommended to establish feasibility

In silico testing

Alternative approach to animal testing

Optical coherence tomography

Method to document choroidal neovascularization in trial patients.

Early Treatment of Diabetic Retinopathy Study chart

Used to measure best corrected distance visual acuity

Autofluorescence photography

Used to determine rate of photoreceptor loss

Processes

1

Manufacturing process

Information relating to production that may qualify as a trade secret.

Clinical Concepts

2

Retinal Disorders

Disorders affecting adult and pediatric patients including genetic and age-related diseases; Target disease category for the gene therapy guidance

Glaucoma

Safety monitoring via intraocular pressure

Standards & References

External Standards

2

USP <771>

Endotoxin limit for intraocular delivery should follow USP <771>

USP <789>

GT vector-based final products should be tested for particulate matter following USP <789>

Specifications

2

Potency assay

A potency assay to assess the biological activity of the final product

Visual acuity

Subjective efficacy and safety endpoint

ICH References (1)

ICH Q5E

Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process

Related CFR Sections (2)

21CFR211.165§ 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on sRead full regulation →
21CFR50.52§ 50.52 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.
Any clinical investigation within the scope described in §§ 50.1 and 56.101 of this chapter in which more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely tRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods

7

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch

4

Failure to establish adequate written procedures for production and process control

3

Failure to exercise appropriate controls over computer or related systems

2

Failure to establish the accuracy, sensitivity, specificity, and reproducibility of test methods

1

Failure to ensure returned drugs meet appropriate standards

1

Failure to establish an adequate quality control unit

1

Failure to exercise appropriate controls over computer systems

1

Failure to follow a written testing program designed to assess stability characteristics

1

Quality control unit failed to approve or reject all procedures or specifications

1