Description
We, FDA, are providing you, a sponsor who is developing a human gene therapy product (GT Product), recommendations regarding the design of long term follow-up studies (LTFU observations) for the collection of data on delayed adverse events following administration of a GT product. Often, GT products are designed to achieve therapeutic effect through permanent or long-acting changes in the human body. As a result of long term exposure to an investigational GT product, study subjects may be at increased risk of undesirable and unpredictable outcomes that may present as delayed adverse event(s). To understand and mitigate the risk of a delayed adverse event, subjects in gene therapy trials may be monitored for an extended period of time, which is commonly referred to as the “long term follow-up” (LTFU) period (of a clinical study). LTFU observations are extended assessments that continue some of the scheduled observations of a clinical trial past the active follow-up period, and are an integral portion of the study of some investigational GT products. LTFU observations are important to monitor long term safety of GT products. For GT products that present long term risks to subjects, LTFU/surveillance plan(s) should also be put in place post-licensure for monitoring of delayed adverse events (for details we refer you to section VI. of this document). Not all GT products will require LTFU observations; a risk assessment should be performed by a sponsor based on several factors as outlined in this guidance.
Scope & Applicability
Product Classes
6Specific category for CMC guidance
Definition of products that mediate effects by transcription or translation
Vectors that may persist and undergo reactivation
Products that introduce permanent changes to the host genome
A type of ATMP involving recombinant nucleic acids or viral vectors.
General term for gene therapy products discussed in the text
Stakeholders
3Entity responsible for submitting applications under section 524B
Healthcare professionals who reference labeling and public resources
Responsible for qualifications, training, and trial conduct; Individual responsible for trial conduct and data governance at a site.; May delegate tasks but retains overall responsibility; Person responsible for the conduct of the clinical trial at a trial site; Responsible for trial conduct and participant safety; Responsible for trial conduct, data integrity, and investigational product management.; Individual responsible for trial conduct at a site and informing the institution.; maintaining
Regulatory Context
Attributes
5Preclinical data used for assessment of delayed risks; Transgene positive results in subjects over 5 to 7 years
Increase in percent cells positive for a vector integration site
Criteria for vector integration monitoring
Recommended duration of LTFU for AAV vectors
Recommended duration of LTFU for integrating vectors
Identified Hazards
Hazards
7Risk from disruption of critical host genes or activation of proto-oncogenes
Replication Competent Retrovirus testing and risk assessment
testing required if a retroviral vector is used
Risk leading to aberrant gene expression or chromosomal translocation
Potential risk factor when comparing vectors
nonlinear dose response associated with the genotoxicity and carcinogenicity of acetaldehyde; Historical perception of aniline; Potential for a mutagenic mode of action
integrating vectors may increase the risk of delayed adverse events
Related CFR Sections (11)
- 21CFR600.80§ 600.80 Postmarketing reporting of adverse experiences.
(a) Definitions. The following definitions of terms apply to this section:Read full regulation →
- 21CFR50.20§ 50.20 General requirements for informed consent.
Except as provided in §§ 50.22 , 50.23 , and 50.24 , no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An invesRead full regulation →
- 21CFR50.25§ 50.25 Elements of informed consent.
(a) Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each subject:Read full regulation →
- 21CFR312.31§ 312.31 Information amendments.
(a) Requirement for information amendment. A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report. Examples of information requiring an information amendment include:Read full regulation →
- 21CFR312.33§ 312.33 Annual reports.
A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of the investigation that includes:Read full regulation →
- 21CFR312.30§ 312.30 Protocol amendments.
Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application. This section sets forth the provisions under which new protocols may be submitted and changes in previously submitted protocols maRead full regulation →
- 21CFR312.32§ 312.32 IND safety reporting.
(a) Definitions. The following definitions of terms apply to this section:Read full regulation →
- 21CFR312.64§ 312.64 Investigator reports.
(a) Progress reports. The investigator shall furnish all reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained. The sponsor is required under § 312.33 to submit annual reports to FDA on the progress of the clinical investigations.Read full regulation →
- 21CFR312.62§ 312.62 Investigator recordkeeping and record retention.
(a) Disposition of drug. An investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. If the investigation is terminated, suspended, discontinued, or completed, the investigator shall return the unused supplies of the drug tRead 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 →
- 21CFR312.42§ 312.42 Clinical holds and requests for modification.
(a) General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. When a proposed study is placed on clinical hold, subjectRead full regulation →
Related Warning Letters (10)
- 2025-09-09
Clinical Investigator
Shirish M. Gadgeel, M.D.
- 2025-07-15
Clinical Investigator
Mark J. Savant, M.D
- 2025-05-20
Bioresearch Monitoring Program/Institutional Review Board (IRB)
United Health Products, Inc.
- 2025-03-25
Clinical Investigator
Americo F. Padilla, M.D.
- 2024-11-05
Institutional Review Board (IRB)
Armstrong County Memorial Hospital
- 2024-10-22
Clinical Investigator
Namita A. Goyal, M.D.
- 2024-10-08
Institutional Review Board (IRB)
Louisiana State University Health Science Center IRB
- 2024-08-13
Bioresearch Monitoring Program/IRB
Konrad Rejdak, M.D., Ph.D.
- 2024-07-16
Bioresearch Monitoring Program/IRB
Massachusetts Institute of Technology MIT
- 2024-06-18
Clinical Investigator (Sponsor)
Angela D. Ritter, M.D.
See Also (8)
- Development and Licensure of Vaccines to Prevent COVID-19: Guidance for Industry (Status: Final)
- Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report (Status: Final)
- How to Complete the Vaccine Adverse Event Reporting System Form (VAERS-1): Guidance for Industry (Status: Final)
- Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines: Draft Guidance for Industry (Status: Draft)
- Evaluating the Risks of Drug Exposure in Human Pregnancies (Status: Final)
- Biological Product Deviation Reporting for Licensed Manufacturers of Biological Products Other than Blood and Blood Components (Status: Final)
- Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed Without an Approved Application (Status: Final)
- Safety Reporting Requirements for INDs (Investigational New Drug Applications) and BA/BE (Bioavailability/Bioequivalence) Studies: Guidance for Industry and Investigators (Status: Final)