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P104: Protection of Non-subjects in Clinical Trials Involving Human Gene Transfer: Data and Best Practices from a Central IRB

Poster Presenter

Christopher Doyle

Senior Director, IBC Services
WCG
United States

Objectives

Use of emerging gene editing and viral engineering technologies in clinical trials can pose risks to individuals not involved in the research itself (non-subjects). Here, we outline best practices for identifying and mitigating these risks based on real-word experience at a central IRB.

Method

Clinical trials involving human gene transfer (HGT) reviewed by our central IRB during 2023 were identified. Trials were classified based on whether study activities posed risks to non-subjects, whether risks were acknowledged, and the format used to convey mitigation instructions to non-subjects.

Results

During 2023, our IRB reviewed 87 clinical trials involving HGT. Of these, 66% involved CAR-T cell and other engineered cell therapies; 14% used an oncolytic replication-competent virus, and 20% used other modalities. Across all HGT trials, risks to non-subjects were described in 15% of protocols, 19.5% of informed consent forms (ICFs), and 6% of other subject-facing materials. After stratifying trials based on the degree of risk posed to non-subjects, we found that trials testing lower-risk study agents (e.g. mRNA vaccines, CAR T cells) described risks to non-subjects only 11% of the time (4% in protocols and 7% in ICFs). Conversely, HGT trials testing higher-risk study agents (e.g. oncolytic viruses, in vivo genome editors) described risks to non-subjects 100% of the time. Closer examination of these trials revealed that 20% described risks to non-subjects in the protocol, ICFs, and other subject-facing materials; 50% in the protocol and ICFs; 10% in ICFs and other subject-facing materials; 10% in ICFs alone; and 10% in other subject-facing materials alone. Instructions provided to non-subjects on how to mitigate risks posed to non-subjects were diverse and based on a combination of study agent characteristics and handling procedures at the trial site. Mitigation instructions provided to non-subjects were often oriented toward healthcare professionals, immunocompromised individuals, and pregnant women, as well as household contacts, caregivers, and sexual partners of subjects. At-risk non-subjects were commonly instructed to wear protective gloves when assisting subjects in applying or changing occlusive dressings; safely dispose of used dressings, gloves, and cleaning materials; and avoid contact with the study agent and subjects altogether if they are at higher risk due to various conditions (e.g. immunosuppression, pregnancy).

Conclusion

Non-subjects are individuals who are likely to be exposed to research-related risks but do not meet the regulatory definition of a human subject. Many HGT trials present unique risks to non-subjects that are directly linked to the biological nature of the study agent itself. In such trials, non-subjects include healthcare professionals and research staff caring for the subject, caregivers, family members, and friends of the subject, and other members of the public who may come into contact with the subject. Although the Common Rule (45 CFR 46 Subpart A) alludes to protecting non-subjects, and Subpart B requires IRBs to consider risks to fetuses and neonates, current regulations do not otherwise address IRB responsibilities related to the identification and mitigation of risks to non-subjects. Following a recent SACHRP subcommittee recommendation that IRBs identify and seek to minimize risks to non-subjects in consultation with other institutional oversight bodies, we began requesting input from our Institutional Biosafety Committee for HGT trials prior to IRB review. Our data show that research-related risks to non-subjects were present in a significant proportion of HGT trials reviewed by our IRB in 2023. While all higher-risk HGT trials we reviewed included some information regarding risks to non-subjects, the information was conveyed inconsistently using several different documents. Based on our experience, we recommend the following as best practices: i. Risks to non-subjects should be noted in ICFs signed by subjects; ii. Risk information and mitigation strategies should be conveyed to healthcare providers and research staff in the trial protocol, pharmacy manual, or similar document provided to study staff; and iii. All subjects should be provided separate instructions designed to reduce risks to non-subjects in a manner that is clear, realistic, and tailored to the research.