Introduction
Our recent webinar, “Beyond the Trial: Ethical Oversight in Gene Therapy Long-Term Follow-Up,” sparked an engaging discussion on the complexities of monitoring and protecting participants in gene therapy studies. While the session covered critical topics, time constraints meant some audience questions went unanswered.
To keep the conversation going, we’ve compiled these remaining questions and invited our expert speakers to share their insights. From regulatory strategies to IRB considerations and evolving risk assessments, this Q&A dives deeper into the issues shaping the future of long-term follow-up (LTFU) in gene therapy research.
Questions
- Considering the long-term nature of gene therapy interventions, what specific regulatory or clinical monitoring strategies are being implemented to proactively mitigate potential delayed adverse events? Also, how will data collection ensure the robustness of long-term safety profiles?
The regulatory requirement for LTFU of gene therapy, post-clinical trial or in post-market settings, is dependent on risk associated with specific types of gene therapy products and directly addresses the concerns about the possibility of long-term adverse events. By collecting long-term follow-up data and monitoring patients, LTFU programs aim to proactively mitigate the impacts on individual patients and the relevant patient community (or communities) at large.
The clinical monitoring strategies to be aware of are specific to the product and the potential signs and symptoms of the adverse event. Common methods include data surveys. For example, the survey may ask, “Have you had any new medical events?” If yes, then the researcher may obtain details via standard lab work, imaging, genetic analysis, etc. that may detect an abnormality. Currently, we have not made great headway in developing new regulatory strategies. The robustness of long-term safety profiles would need to start first with the identification of related events.
- How can I gain access to the Multi-Regional Clinical Trials (MRCT) Toolkit for supporting LTFU studies for gene therapies?
The toolkit is available on the Multi-Regional Clinical Trials (MRCT) website Resources page. Directly access the Toolkit Release Webinar and toolkit here.
- Usually after a drug intervention trial, when all participants are off treatment and are only seen for LTFU, the risk is reduced to no more than minimal, with at least annual continuing reviews (CR). However, with gene therapy trials and potential for late effects, what risk level do you suggest after the gene therapy has been completed and the acute follow-up period has ended? Are there any regulations about this? Essentially, does the full board need to review the CR or if an expedited reviewer can review the CR based on the assigned risk during LTFU?
The regulations for the determination of risk and review requirements for LTFU are the same as any other. The difference is that unlike a drug intervention trial, which may have only data or minimal risk procedures, gene therapy trials may have more invasive testing, which would have more than minimal risk. However, if the procedures of the LTFU are only the collection of clinical information or testing of samples that have already been gathered for clinical purposes, the standard data collection, and routine lab work, it would still be minimal risk. Thus, it would not require review by the IRB committee. The fact that risks may be realized in the LTFU does not make them risks of the LTFU. They are risks of the administration of the drug, which happens outside of the LTFU component.
Beyond what is required from a regulatory basis, it is important to have mechanisms in place to ensure that safety issues or concerns are not missed during LTFU. In the MRCT Center Toolkit, it mentions that aggregate data should be monitored regularly to detect patterns or safety signals. Although not required, the inclusion of a Data Safety Monitoring Board (DSMB) or Observational Study Monitoring Board (OSMB) could be considered. Moreover, when selecting a DSMB or Data Monitoring Committee (DMC), it is critical to partner with a true independent expert to stay compliant with current FDA regulations. Consult WCG’s DMC experts today.
- How does the FDA approach participants wishing to participate in new trials who are actively in follow-up in another existing LTFU trial?
Currently, the FDA does not have any guidance regarding this topic. From an ethical perspective, participating in a LTFU study should not exclude a patient from participating in another trial or receiving another approved treatment.
As the MRCT Center Toolkit states,
Exclusion of patients from eligibility for either post-trial or post-approval
LTFU studies may introduce bias, preclude the collection of valuable data,
and deny patients their opportunities for ongoing surveillance and the ability
to contribute to furthering the science of gene therapies. Important
associations or findings may be missed…. It is unethical to prevent LTFU
participants from receiving additional treatments in the future if they feel it is in their best interests. If a subset of patients goes on to additional future treatments, excluding them from LTFU might cause bias if this subset is particularly vulnerable to adverse events that are associated with the gene therapy.
- How can the IRB ensure that participants are adequately consented to these studies?
FDA guidance notes that for gene therapy interventional trials, consent for LTFU should be included in the consent for the original parent trial. If the LTFU is run as a standalone study, there would be an additional consent. There are pros and cons for either design, which are reviewed in the MRCT Center Toolkit. From a consent perspective, it is important to convey to patients that they always have the right to withdraw, but the data from LTFU is important to understand the risk/benefit profile of these products. Also, it’s important to convey to patients what the benefits of LTFU participation would be to them (e.g., there may be enhanced monitoring, notification of any changes, etc.) and that there are limits to withdrawal in the sense that often gene therapies are long-lasting/permanent.
In brief, an IRB would follow its routine procedures for consent and documentation, including informing participants of new information, to ensure participants in LTFU are adequately consented. If the IRB requires additional specialized expertise to gather the information needed, it can use its collaboration with IBC experts. As LTFU studies gather new information that may affect a person’s willingness to participate, such information should be added to revised informed consent documents, throughout the course of the study.
- What recommendations do you have for documenting risk assessments for a study determining LTFU? Are the speakers seeing any changes in LTFU requirements following recent developments in gene therapy spaces?
Risk assessments for LTFU are recommended to document the appropriate risks to participants, including unknown risks and risks to close contacts throughout the duration of the LTFU. The advances in gene therapy technology are not outpacing recent changes mentioned in the talk, for example, to a more nuanced approach to determine adequacy of LTFU. One main leap forward in gene transfer technology has been in moving into those areas with solid safety information.
A recent collaborative white paper led by Catalyst with industry and patient advocacy representatives suggested that Chimeric Antigen Receptor (CAR) T LTFU duration should be reduced from 15 years to five years. While that is a proposed change to LTFU requirements, it has not yet been adopted by regulatory agencies.
- What are some concerns that IRBs have when it comes to the current landscape of gene therapy trials?
The informed consent process for gene therapy clinical trials is perhaps more ethically complex than for other types of clinical trials. For one, there are still significant uncertainties about gene therapies as a class or category. For example, their long-term benefit/risk profile is uncertain, and many gene therapies have only one dosing opportunity, which makes the decision about when to participate in a trial relatively high stakes. Most gene therapies are also long-lasting or permanent.
Additionally, patients and/or their care givers may be vulnerable and feel a sense of urgency for the decision if the disease is progressing rapidly, and there are no other therapeutic or research options. IRBs may also have concerns about the justifications for eligibility criteria for gene therapy trials. On the one hand, safety is a primary concern, but on the other hand, exclusions should be scientifically and ethically justified. IRBs might want to look carefully at the dosing choices and dose escalation plans in a gene therapy trial protocol as well. Additionally, the IRB may consider whether participation in a particular study may exclude participants from being eligible for future treatments, and whether treatment with the gene transfer agent involves exposure risks to family members or other close contacts. IRBs play an important and essential role in gene therapy trials.
Conclusion
Groundbreaking gene therapy studies continue to grow, bringing both promise and responsibility. Addressing long-term safety, ethical oversight, and participant protection requires collaboration across sponsors, CROs, investigators, and ethical review partners. We hope these experts’ responses provide clarity and practical guidance as you navigate this evolving landscape.
For more information, access the full webinar recording (hyperlink to https://www.wcgclinical.com/insights/beyond-the-trial-ethical-oversight-in-gene-therapy-long-term-follow-up/). If you’d like to get in touch with WCG’s experts, contact us today.