What You Need to Know About Clinical Holds in Research
Recently, the FDA placed a “clinical hold” on two clinical trials. One was a Phase I/II trial of a gene therapy for a rare metabolic disorder. The second was on a Phase I dosing trial for an oncology drug. A clinical hold is an order issued by FDA to the sponsor of an IND application to delay a proposed clinical investigation or to suspend an ongoing investigation. Any clinical research site in the trial may be impacted when the FDA issues the clinical hold, and sometimes all involved clinical trial sites must cease the trial.
A clinical hold can occur for both commercial INDs and sponsor-investigator INDs.
The FDA can impose a clinical hold on a Phase I study for a variety of reasons, including, but not limited to:
- Unreasonable or significant risk to human subjects
- Clinical investigators are not sufficiently qualified to conduct the study
- Misconduct of the clinical investigator
- Investigator brochure is misleading or incomplete
Phase II and III trials can be halted if the FDA deems that the trial protocol design is deficient to meet its stated objectives or for any of the reasons described above for Phase 1 studies.
When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and the investigational drug may not be given; patients already in the study should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety.
Subjects enrolled in the study should be notified of any changes to their treatment schedule and/or follow-up study visits due to the clinical hold. The sponsor will provide the correspondence and guidance to follow. Be sure to have these communication and guidance documents reviewed by the IRB.
Subjects enrolled that received the investigational agent should continue to be monitored for adverse events. Monitoring of significant adverse events (SAEs) should be done in accordance with the protocol and promptly reported to the sponsor.
All study personnel involved in the study should be made aware of the clinical hold and the restrictions imposed.
Study records for subjects may need to be updated if there will be planned missed study treatment and visits.
A trial may resume only after the sponsor has been notified by FDA that the trial may proceed. This may occur once the regulatory agency is satisfied that the recommendations and concerns have been sufficiently addressed. Restarting a clinical trial after a hold may entail recruiting new participants. The IRB will need to review any modifications to the trial and to approve the institution’s participation. Research staff, such as clinical research coordinators, may require additional training to ensure appropriate ongoing monitoring.
Central to this process is clear and frequent communication among the sponsor, investigators, research staff, study subjects, the IRB, and the FDA.