Human Gene Therapy for Rare Diseases: Guidance for Industry | Guideline Explorer

Description

This guidance provides recommendations to sponsors developing human gene therapy (GT) products intended to treat a rare disease in adult and/or pediatric patients regarding the manufacturing, preclinical, and clinical trial design issues for all phases of the clinical development program. Such information is intended to assist sponsors in designing clinical development programs for such products, where there may be limited study population size and potential feasibility and safety issues, as well as issues relating to the interpretability of bioactivity/efficacy outcomes that may be unique to rare diseases or to the nature of the GT product itself. This guidance finalizes the draft guidance of the same title dated July 2018.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

3

Human Gene Therapy

Includes genetically modified cells

Regenerative Medicine Therapies

Scope of the standards recognition program

Gene Therapy

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

Stakeholders

4

Sponsor

Entity responsible for submitting applications under section 524B

Applicants

Entities submitting supplements to BLAs

Regulatory Context

Regulatory Activities

9

IND

Investigational New Drug submissions

Formal Meetings

Formal Meetings Between the FDA and Sponsors or Applicants

Expedited Programs for Serious Conditions

Guidance for Industry: Expedited Programs for Serious Conditions - Drugs and Biologics

Clinical Outcome Assessment Qualification Program

Drug development tool qualification programs

Biologics license application

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

INTERACT

Initial Targeted Engagement for Regulatory Advice on CBER Products meeting type.; INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs

Priority Review

Expedited review goal of 6 months for marketing applications

Breakthrough Therapy Designation

Expedited program for serious conditions; Designation for products demonstrating substantial improvement over available therapies

Regenerative Medicine Advanced Therapy Designation

Designation under section 506(g) of the FD&C Act

Document Types

1

Informed consent document

must describe reasonably foreseeable risks

Attributes

4

Critical Quality Attributes

Physical, chemical, biological, or microbiological properties

Patient Experience Data

Information about patients' experiences with a disease or condition

Critical Process Parameters

identify any critical process parameters that should be monitored or controlled

Minimal risk

regulatory threshold for involving children in clinical investigations

Technical Details

Substances

2

Viral Vectors

Used in gene therapy products to modify cells.; Used to modify cells ex vivo

Vector

Example of a platform technology delivery method

Testing Methods

4

Allometric Scaling

Used in dose exploration and kinetics characterization

Immunogenicity Assessment

Critical in the setting of repeat administration

Potency Assays

quantitative analysis for potency assays should be accompanied by a qualitative comparison

Genetic test

performed to ensure correct diagnosis of the disorder of interest

Processes

4

Comparability Assessment

Needed when changes to the manufacturing process are necessary.

Biodistribution studies

Conducted to assess distribution, persistence, and clearance of the vector

Toxicology studies

should incorporate elements of the planned clinical trial

Manufacturing process

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

Clinical Concepts

5

Rare Disease

Impact of expanded access on rare disease drug development.

Clinical Outcome Assessment

Measures used to evaluate the drug's effectiveness based on patient or caregiver input.

Rare diseases

Diseases with low prevalence in certain regions

Natural history study

provides critical information to guide drug development stages

Adverse events

Safety findings including deaths and post-mortem examinations

Identified Hazards

Hazards

1

Viral Shedding

Potential for shedding should be addressed early

Standards & References

Specifications

2

Surrogate Endpoint

Marker used as a substitute for a direct measure of clinical benefit

Study Stopping Rules

Criteria for halting the study based on adverse events

ICH References (1)

ICH E2E

Pharmacovigilance Planning

Related CFR Sections (4)

21CFR601.2§ 601.2 Applications for biologics licenses; procedures for filing.
(a) General. To obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing aRead full regulation →
21CFR601.20§ 601.20 Biologics licenses; issuance and conditions.
(a) Examination—compliance with requirements. A biologics license application shall be approved only upon examination of the product and upon a determination that the product complies with the standards established in the biologics license application and the requirements prescribed in the regulatioRead full regulation →
21CFR312.23§ 312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational New Drug Application” (IND) including, in the following order:Read 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 obtain informed consent

5

Failure to ensure that the investigation was conducted according to the investigational plan

3

Failure to submit an Investigational New Drug application (IND)

2

Failure to prepare, maintain, and follow written procedures governing the functions and operations of the IRB

1

Failure to ensure proper monitoring of the investigation

1

Failure to secure clinical investigator's compliance

1

Failure to submit an IDE application and obtain FDA approval

1

Failure to immediately conduct an evaluation of unanticipated adverse device effects

1

Failure to review proposed research at convened meetings with a majority of members present

1

Failure to prepare and maintain adequate documentation of IRB activities, including minutes of IRB meetings

1

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics

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