In late March, I participated in several discussions at the 6^th Annual Gene Therapy for Rare Disorders (GTRD) Summit about how we continue to further gene therapy development. In 2022 we saw the most gene therapies approved in the U.S. and Europe in one year – five. There are hundreds of active trials for new gene therapies today and dozens in late-stage trials. As the momentum behind gene therapy grows, these programs have the potential to help thousands of patients and families.

But at the same time, we have seen headlines around unexpected side effects and, unfortunately, patient deaths. In the past few years, the U.S. Food and Drug Administration (FDA) has worked hard to understand the safety issues associated with gene therapy. Therefore, one of the questions we discussed at the Summit was how do we as an industry elevate safety across gene therapy development? I believe that while there is no one-size fits-all approach, there are four major variables emerging across gene therapy approaches that can influence key safety considerations and impact regulatory requirements.

1. Nature of disease
   First off, key factors about the disease itself will influence safety considerations and clinical trial design. The severity of the disease, its rate of progression, current unmet medical needs, as well as concomitant conditions and medications, are all key factors to consider when assessing the potential risk/benefit profile of a particular gene therapy approach. For example, diseases that involve the central nervous system (CNS) require a gene therapy approach that can cross the blood-brain barrier, which comes with distinct safety implications and methods of evaluation.
2. Mechanism of action
   Whether you take an in vivo or an ex vivo approach, for example, determines the method of evaluation needed to evaluate potential off-target effects. With an ex vivo approach, you can characterize the transduced stem cell population prior to introducing the drug product back into patients. With an in vivo approach, more cell types may have to be considered and evaluated preclinically.
   Similarly, different safety considerations are required depending on the type of vector selected. One of the safety considerations of the adeno-associated virus (AAV) gene therapy approach is immunogenicity against the AAV capsid antigens and the transgene. In contrast, a safety consideration for the lentiviral (LV) gene therapy approach is potential vector integration near a proto-oncogene, and thus LV-based gene therapy approaches should be accompanied with insertion site analysis to understand the likelihood of insertional oncogenesis.
3. Clinical patient population characteristics
   Many cell and gene therapy trials are for small patient populations that have rare, life-limiting genetic diseases, which can make clinical trial enrollment challenging. Certain FDA flexibility in trial design enables trials to be patient-sparing and yet still allows thorough evaluation of patient safety.
   Just as population size can vary, so can patient age. It is particularly important to mitigate concerns and address safety in pediatric trials. Considerations may include creation of an Independent Data Monitoring Committee (IDMC) to enhance scientific integrity and ensure that the interests of patients are being well-served. Additional approaches such as sentinel dosing and staggering of patient cohorts also can reduce risk by phasing dosing
4. Route of administration
   Additionally, the route of administration may have implications that need to be considered. Vectors might be injected intravenously or intracranially, for example, and different routes have different rationales and different levels of risk.

All of these components need to be worked out within the broad gene therapy community and with regulators across geographies. I am sure you have heard this before, but it bears repeating – engage with regulators early and often so you can get their feedback along the way. It is critical to prioritize safety at every step, from the very beginning.

I’ll add two additional long-term safety considerations that I believe are very important areas for us as an industry to address, especially as gene therapy treatment in pediatric populations becomes more common.

1. FDA last issued guidance on long-term follow-up (LTFU) for gene therapies in early 2020. The recommendation was 15 years of safety follow-up for gene therapies using LV vectors and five years for gene therapies using AAV vectors. All LTFU studies have a dedicated clinical protocol that specifies patient-visitation schedules, a schedule of assessments for both safety and efficacy, the methodology that will be used to assess integration sites and immunogenicity against the protein expressed and a means for collecting accurate case histories.
   In designing the LTFU study, it’s important to think through how you will actually obtain these data from patients over a five- or 15-year time period. The basic promise of gene therapy is that a one-time treatment potentially cures the genetic disease. How do you keep a patient coming back frequently in a LTFU study to go through a battery of tests – including sometimes uncomfortable or invasive tests – who in some cases may no longer be considered a patient living with a particular genetic disease? Consider how geography, time commitment as well as assessment frequency may impact your LTFU protocol, and how leveraging digital technology as well as local advocacy groups, foundations and hospitals, may improve the patient experience.
2. Finally, and this point is sadly timelier now than ever before, keep in mind that guidelines emphasize that pharmacovigilance plans must detail how LTFU of treated patients will be conducted even in the event that drug development is halted, or the sponsor or marketing authorization holder (MAH) ceases to exist.

There is no one holy grail for ensuring gene therapy safety. Individual approaches must be customized based on the specific disease, technology, patient population and mode of administration. Taking these variables into consideration while keeping abreast of the larger issues surrounding gene therapy patient safety will allow the industry to take the necessary steps to respond to regulators. While the gene therapy industry has made steady progress, we still have a long way to go – there are still far too many patients who have tremendous unmet need and no solutions in sight. Holding conversations with leaders throughout the industry, as we did at the GTRD Summit, is critical to promoting innovation, enhancing safety and ultimately advancing therapeutics to improve patients’ lives.