Sr. Director, IBC Services WCG Gig Harbor, Washington, United States
Background: Clinical trials involving emerging gene editing and viral engineering technologies can pose risks to individuals not involved in the research itself (non-subjects). With few exceptions, current regulations do not address IRB responsibilities related to the identification and mitigation of risks to non-subjects.
Methods: Clinical trials involving human gene transfer (HGT) reviewed by our central IRB from January to December 2023 were manually identified from an internal database. Trials were classified based on whether study activities posed risks to non-subjects, including healthcare professionals and research staff, caregivers, family members, and friends of the subject, and other members of the public who may encounter the subject. For each trial, we determined whether risks to non-subjects were acknowledged, and if so, the format used to convey risk mitigation instructions to non-subjects. We reviewed protocols, informed consent forms (ICFs), and subject-facing materials, including injection site care and hygiene instructions for risks and mitigations practices described to protect non-subjects. Finally, we stratified HGT trials based on the relative degree of risk posed to non-subjects. Higher-risk trials included those testing replication-competent oncolytic viruses and gene editing products designed to work in vivo. Lower-risk trials included those testing CAR T cells, certain replication-defective viral vectors, and other products unlikely to be transmitted from the subject to others.
Results: In 2023, we reviewed 87 clinical trials involving HGT. Of these, 57 (66%) involved CAR-T cell and other engineered cell therapies; 12 (14%) used an oncolytic replication-competent virus, and 18 (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% in subject-facing materials. After analyzing degree of risks posed to non-subjects, we found trials testing lower-risk study agents (e.g. mRNA vaccines, CAR T cells) described risks to non-subjects only 11% (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%. Further analysis revealed that 20% described risks to non-subjects in the protocol, ICFs, and subject-facing materials; 50% in the protocol and ICFs; 10% in ICFs and subject-facing materials; 10% in ICFs alone; and 10% in subject-facing materials alone.
Limitations: We identified HGT studies from a database that relies on manual data entry. We employed algorithms in Excel to analyze data, rather than more sophisticated analysis software. Our approach acknowledges the practical constraints of analysis while still striving to capture a diverse range of relevant studies for examination. Risk mitigation instructions provided to study staff may be also under-represented, as such instructions are often conveyed in documents not reviewed by the IRB.
Discussion: In our experience, research-related risks to non-subjects were present in a significant proportion of HGT trials. All higher-risk HGT trials noted risks to non-subjects, but mitigation instructions were conveyed inconsistently using several different documents. As best practices, we recommend: i. Risks to non-subjects be noted in ICFs signed by subjects; ii. Risk information and mitigation strategies be conveyed to healthcare providers and research staff in the protocol, pharmacy manual, or similar document provided to study staff; and iii. Subjects be given instructions designed to reduce risks to non-subjects in a manner that is clear, realistic, and tailored to the research.
