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Reviewing FDA’s New Gene Therapy Guidances on LTFU

In the past few years, gene therapy has turned from concept into reality. The first gene therapy clinical trial was conducted in 1990. However, the FDA only approved the first gene therapy product in August 2017.

In January, the FDA released a new guidance for gene therapy products. These guidances primarily revolve around the long term follow-up after the administration of the products. With gene therapy products, they are designed for permanent or long term affects within the human body. Because of this, subjects in gene therapy trials may need to be monitored long-term.

Is Long-Term Follow-Up (LTFU) Needed?

The FDA uses the following five questions in order to determine whether long term follow up is needed:

1) Does your gene therapy product utilize genome-editing technology?

Genome editing-based gene therapy products transmit biological activity through site specific changes in the human genome. With this, genome editing may produce undesired changes in the genome. This may lead to impairment of gene function and has the risk of malignant tumor which may require long term follow up for the subject. If the answer to this question is no, head to question number two.

2) Is your vector used only for ex vivo modification of cells?

If the answer to this question is “no”, head on to question 3, but if you’ve answered “yes”, skip down to question 4 and keep reading.

3) Do preclinical study results show persistence of the gene therapy product?

If you answered no to the question, LTFU may not be needed because the risk of delayed adverse effects is low. However, if you answered yes move on to the next question. If you are unsure if your pre-clinical study shows persistence, the FDA recommends you assume the gene therapy product does persist.

Product persistence of the gene therapy product very much heightens the risk of delayed adverse events following exposure or implementation of the gene therapy product. As the product persistence persists, the duration and degree of risk of delayed adverse events rises.

4) Are your vector sequences integrated or is the human genome otherwise genetically altered?

If no, head to question five. If yes, if there is evidence the product may integrate or if the product was designed to facilitate integration the FDA recommends LTFU.

5) Does the gene therapy product have the potential for latency and reactivation?

With the potential for latency, there is a potential for reactivation from latency. If the answer to is no, LTFU may not be needed. If yes, LTFU should be included for appropriate human subject protections.

FDA’s Recommendations for LTFU Observations

The goal of LTFU observations are to identify and reduce the long term risks attributed to patients who received a gene therapy product. The protocols are designed to collect information about the persistence of gene therapy products.

FDA’s recommendations for duration for LTFU Observations are:

  • 15 years for integrating vectors such as gammaretroviral and lentiviral vectors and transposon elements
  • Up to 15 years for herpes virus vectors (or oncolytics) that are capable of establishing latency
  • Up to 15 years for microbial vectors that are known to establish persistent infection
  • Up to 15 years for genome editing products
  • Up to 5 years for AAV vectors

A few key components of LTFU Observations are an established, dedicated clinical LTFU protocol, maintaining adequate and accurate case histories, establishing methods for investigators when recording new medical records, designing health care professional visit plans and having investigators contact subjects at least once per year.


Our expert blogger is Dr. Khanh Ngo Courtney, Avomeen’s Project Director of Biologics. She provides clients with unparalleled expertise and tactical knowledge of protein biochemistry and molecular biology. Her experience extends from R&D to analytical method development, validation, implementation, method transfer, and optimization of test methods for the cGMP setting per USP and ICH guidelines. This understanding of the entire process helps guide successful and productive collaborations across different laboratories, sites, and functions.

Learn more about Khanh’s expertise and experience.