By Stephen Mason, Greenleaf Health
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 (Ref. 1),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 On July 11, 2018, the FDA issued for public comment six draft guidance documents intended to serve as part of a modern, comprehensive framework for how the Center for Biological Evaluation and Research (CBER) will help advance the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This is the third article in a six-part series summarizing each of the draft guidance documents. In previous articles, we reviewed Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) and Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up. This article will discuss the draft guidance Long Term Follow-Up After Administration of Human Gene Therapy Products.
Since gene therapy (GT) products are designed to achieve therapeutic effect through permanent or long-acting changes in the human body, there may be an increased risk of delayed adverse events. As a result, subjects in GT trials may be monitored for a “long term follow-up” (LTFU) period lasting as long as 15 years. The guidance notes that LTFU observations are extended assessments that continue past the active follow-up period and are an integral portion of the study of some investigational GT products. Post-licensure LTFU may be needed, as well. The guidance outlines the risk assessment that a sponsor should perform to determine whether LTFU is needed.
The draft guidance, when finalized, will replace the 2006 guidance Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events. The new draft updates those recommendations in response to new clinical experience and the development of GT products using emerging technologies, such as genome-editing, which may be associated with an increased risk of delayed adverse events.
The draft guidance document provides recommendations regarding the design of LTFU observations with specific considerations for different gene therapy products and provides recommendations on patient monitoring for licensed GT products. The guidance also provides details related to product characteristics, patient-related factors, and the preclinical and clinical data that should be considered when assessing the need for LTFU observations for a GT product.
Assessing Whether LTFU Is Needed
The guidance recommends that sponsors answer these five questions in sequence to assess whether LTFU is needed:
1. Does your GT product utilize genome-editing technology?
If the answer is “no,” go to Question 2. If the answer is “yes,” all clinical protocols proposing administration of the GT product should include LTFU observations for appropriate human subject protections.
2. Is your vector used only for ex vivo modification of cells?
If the answer is “no,” go to Question 3. If the answer is “yes,” go to Question 4.
3. Do preclinical study results show persistence of the GT product?
If the answer is “no,” the risk of product-related delayed adverse events is low, and LTFU observations may not be needed. If the answer is “yes,” go to Question 4. The draft guidance recommends that the preclinical study design assess biodistribution and persistence of a GT product.
4. Are your vector sequences integrated or is the human genome otherwise genetically altered?
If the answer is “no,” go to Question 5. If you have evidence that suggests that the product may integrate, or if the product was intentionally designed to facilitate integration, the answer is “yes.” If the answer is “yes,” all clinical protocols proposing administration of the GT product should include LTFU observations for appropriate human subject protections. The draft guidance provides a table describing the propensity of commonly used GT products/vectors to modify the host genome.
5. Does the GT product have the potential for latency and reactivation?
If the answer is “no,” the risk of product-related delayed adverse events is low, and LTFU observations may not be needed. If the answer is “yes,” all clinical protocols with the GT product should include LTFU observations for appropriate human subject protections.
Recommendations For LTFU Protocols
The draft guidance recommends elements appropriate to the design and conduct of LTFU observations for delayed adverse events in study subjects receiving investigational GT products, including the appropriate populations and duration of the observations. The guidance outlines the requirements for informed consent for patients to ensure they are aware of the risks of participating in the clinical trial. The guidance also identifies special considerations regarding GT products that are integrating vectors and genome-editing products, which may require additional monitoring activities.
Post-Approval Monitoring Plans For GT Products
The continued safety monitoring of GT products is often essential even after product licensure. The draft guidance recommends that a biologics license application (BLA) sponsor for a product that is the subject of an ongoing LTFU study submit a pharmacovigilance plan (PVP) as part of their BLA.
The PVP is described in the FDA’s E2E Pharmacovigilance Planning guidance and should include:
- The LTFU protocol,
- The statistical analysis plan, and
- The projected schedule of anticipated study milestones for any proposed or required post-marketing observational studies or clinical trials in their BLA submission.
The FDA will accept comments on the draft guidance through October 10, 2018. You can submit comments electronically at https://www.regulations.gov/.
The next article summarizes the new draft guidance Human Gene Therapy for Rare Disease.
- 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:
Stephen Mason is senior VP of regulatory policy in the Drug and Biological Products group at Greenleaf Health, Inc. He has experience from FDA, Capitol Hill, and within the innovator and generic pharmaceutical industries. He specializes in regulatory and legislative policy development and analysis. You can reach Mason at email@example.com.