Reviewing FDA's Gene Therapy Guidances on LTFU

Gene therapy has moved from concept to reality in the past few years, and the biologics market is quickly expanding and becoming more competitive. While the first gene therapy clinical trial was conducted in 1990, the first gene therapy product was approved by the US Food and Drug Administration (FDA) in August 2017.

In January 2020, new guidance for gene therapies was released by the Agency, which primarily concerns the long-term follow-up with patients after gene therapy products are administered. As gene therapy products are specifically designed to produce permanent or long-term affects within the human body, subjects who participate in gene therapy trials may require long-term monitoring.

Evaluating the need for long-term follow-up (LTFU) for gene therapies

The FDA uses the following 5 questions to determine whether long term follow-up is needed for specific gene therapy products:

1) Is genome-editing technology used within the gene therapy product?

Genome editing-based gene therapy products transmit biological activity through site-specific changes in the human genome. As such, undesired changes in the genome may be produced as a result of genome editing. These undesired changes may lead to the impairment of gene function, along with a risk of developing malignant tumors, which may necessitate long-term follow-up with the subject. If the response to this question is negative, skip to question 2.

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

If the answer is “no,” advance to question 3. However, if the question has been answered affirmatively, proceed to question 4 for further information.

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

If the answer to this query is “no,” LTFU may not be needed, as there is a low risk of delayed adverse effects. Nevertheless, if the response to this question is yes, question 4 will provide more information regarding next steps. If you are unsure if the pre-clinical study shows persistence, the FDA recommends an assumption should be made that the gene therapy product does persist.

The risk of delayed adverse events following exposure to, or implementation of, the gene therapy product is heightened significantly with product persistence. As product persistence continues, both the duration and degree of risk associated with delayed adverse events increases.

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

Head to question 5 if the reply to this question is negative. If the response is affirmative, the FDA recommends long-term follow-up if evidence demonstrates the product may integrate, or if the product was designed to facilitate integration.

Does the gene therapy present a potential for latency and reactivation?

With the potential for latency, there is a potential for reactivation from latency. If the answer to this inquiry is no, long-term follow-up with the patient may not be needed. If yes, LTFU should be included for appropriate human subject protections.

The FDA’s recommendations for LTFU observations

LTFU observations are carried out with the goal of identifying and reducing the long-term risks attributed to patients receiving treatment by means of gene therapy products, and LTFU protocols have been specifically and purposefully designed to collect valuable information and data about the persistence of gene therapy products. The FDA’s recommendations for the duration of LTFU observations are as follows:

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

Some of the key components of LTFU observations include an established, dedicated clinical LTFU protocol, the maintenance of adequate and accurate case histories, the establishment of methods for investigators when recording new medical records, and the design of visit plans by health care professionals, as well as establishing contact with subjects at least once per year.