Comment from J. M.

I am commenting as an individual working in the clinical research industry, a Clinical Operations Lead at a global CRO, whose role includes providing guidance to Sponsors and Investigators on how to conduct the trial in compliance with the protocols, the CFR, and GCP. From my experience, I have found that the FDA would do well to clarify the following sections of this draft guidance, as I will explain further: III. B. 1. - lines 199 through 204 - which references 21 CFR 312.66 III. C. lines 365 through 369 - which references 21 CFR 312.30(b)(2)(ii) I request that the FDA provides additional detail to define "immediate hazards to human subjects." Specifically, I recommend that the FDA specifies that, in almost all circumstances, the following are not immediate hazards, as participation or continued participation in a clinical trial should not be assumed as necessary: 1. A hazard that will be incurred by starting the use of the Investigational Product (IP). 2. A hazard that will be incurred by re-starting the use of the Investigational Product (IP). 3. A hazard that will be incurred by continuing the use of the Investigational Product (IP). If the hazard can be prevented by stopping, pausing, or not initiating IP use, then it is not immediate. As a specific example, I have seen a Sponsor direct Investigators to require subjects to take new preventative concomitant medications (not previously required per the approved protocol) prior to starting/re-starting IP. This was done without first amending the protocol or informed consents, and without first getting either approved by the IRB. The justification given by the Sponsor was that this was to eliminate an immediate hazard to the subject (a serious adverse reaction expected for this IP). However, in my opinion, the subject does not have to start, restart, or continue IP. Therefore the hazard is not immediate - it is preventable. The Sponsor should have waited to enroll further subjects until the necessary safety precautions were included in an IRB approved protocol and informed consent form. Including this clarification in this guidance will allow people in my role to show Sponsors and Investigators this guidance, prevent situations like this from occurring, and therefore protect the rights and safety of clinical trial participants. Thank you for your attention to this matter and for the excellent work of the FDA.