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Best Practices for Protecting Non-Participants in Human Gene Transfer Clinical Trials

Non-Participants in Clinical Trials

Emerging gene editing and viral engineering technologies used in clinical trials can pose risks to individuals not directly involved in the research (non-participants).1 Non-participants include healthcare professionals, research staff, caregivers, family members, and friends of the participant, and other members of the public who may encounter the participant and be exposed to research-related risks but do not meet the regulatory definition of a human participant. With few exceptions, current regulations do not address Institutional Review Board (IRB) responsibilities related to the identification and mitigation of risks to non-participants. This document outlines the best strategies for identifying and mitigating these risks based on real-word experience at WCG’s IRB.

WCG’s HGT Clinical Trials Experience

From January 2023 to December 2023, we identified human gene transfer (HGT) clinical trials reviewed by our IRB from an internal database. We classified trials based on the degree of risks posed to non-participants and documented if these risks were acknowledged and how risk mitigation instructions were communicated. We reviewed protocols, informed consent forms (ICFs), and participant-facing materials, including injection site care and hygiene instructions, for described risks and mitigation practices. Trials were stratified by risk level: higher-risk trials (e.g., replication-competent oncolytic viruses, in vivo gene editing) and lower-risk trials (e.g., Chimeric Antigen Receptor (CAR) T-cells, certain replication-defective viral vectors, and other products unlikely to be transmitted from the participant to others).

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-participants were described in 15% of protocols, 19.5% of ICFs, and in six percent of participant-facing materials. After analyzing the degree of risks posed to non-participants, we found trials testing lower-risk study agents (e.g. mRNA vaccines, CAR T-cells) described risks to non-participants only 11% of the time (four percent in protocols and seven percent in ICFs). Conversely, HGT trials testing higher-risk study agents (e.g. oncolytic viruses, in vivo genome editors) described risks to non-participants 100% of the time. Where these risks were described varied: 20% of higher-risk trials described risks to non-participants in the protocol, ICFs, and participant-facing materials; 50% in the protocol and ICFs; 10% in ICFs and participant-facing materials; 10% in ICFs alone; and 10% in participant-facing materials alone.

In general, instructions provided to non-participants on how to mitigate risks were diverse and based on a combination of study agent characteristics and handling procedures at the trial site. These mitigation instructions were often directed toward healthcare professionals, immunocompromised individuals, and pregnant women, as well as household contacts, caregivers, and sexual partners of the participants. At-risk non-participants were commonly instructed to wear protective gloves when assisting participants in applying or changing occlusive dressings; safely dispose of used dressings, gloves, and cleaning materials; and avoid contact with the study agent and participants altogether if the non-participants are at higher risk due to various conditions (e.g. immunosuppression, pregnancy).

Many HGT trials present unique risks to non-participants that are directly linked to the biological nature of the study agent itself. Although the Common Rule (45 CFR 46.108 (a) (4) Subpart A) alludes to protecting non-participants in the form of reporting ‘unanticipated problems involving risks to subjects or others’,2 and Subpart B requires IRBs to consider research risks to fetuses and neonates (who may not be participants),3 current regulations do not address IRB responsibilities related to the identification and mitigation of anticipated risks to non-participants. Following a recent Secretary’s Advisory Committee on Human Research Protections (SACHRP) subcommittee recommendation that IRBs identify and seek to minimize risks to non-participants in consultation with other institutional oversight bodies, we began requesting input on HGT trials from our Institutional Biosafety Committee (IBC) partners prior to IRB review.

Recommendations

Our experience indicates that a significant proportion of HGT trials reviewed by our IRB in 2023 posed research-related risks to non-participants. All higher-risk HGT trials acknowledged risks to non-participants, but mitigation instructions were communicated inconsistently through various documents. To address this issue, we recommend the following as best practices:

  1. Risks to non-participants should be noted in Informed Consent Forms (ICFs) signed by participants.
  2. 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.
  3. All participants should be provided with separate instructions designed to reduce risks to non-participants in a manner that is clear, realistic, and tailored to the research.

Finally, we urge IRBs, IBCs, and other appropriate institutional oversight bodies to develop defined criteria and formalized workflows aimed at identifying and mitigating risks posed to non-participants by HGT technologies. As trials testing oncolytic viruses and genome-editing technologies become more commonplace, timely implementation of such an approach will be critical to protect participants and non-participants alike.

If you have additional questions about how to identify and mitigate risks to non-participants in your HGT trials, or if you have other ethical and biosafety concerns, our team of experts is here to help. Submit a consultation request using the form below. Let’s work together to ensure your studies are both compliant and ethically sound.


References

  1. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html.
  2. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/common-rule-subpart-b/index.html#46.203.

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