Screening Pressure in a Phase I Healthy Volunteer Cohort
A Phase I first-in-human study in healthy volunteers is enrolling a cohort of 12. On Thursday, a 29-year-old applicant presents for screening. His ALT is 72 U/L (ULN 40; 1.8× ULN), AST 45 U/L, bilirubin normal. He reports taking St John's wort 300 mg daily for low mood until 10 days ago and levothyroxine 75 mcg daily for hypothyroidism for 3 years. His BMI is 31.4 kg/m²; the protocol excludes BMI >30. The inclusion criteria require ALT ≤1.5× ULN and a 28-day washout of herbal supplements. The exclusion criteria list clinically significant thyroid disease unless stable for 6 months. The PI is out of town; the sub-investigator says, 'He's basically healthy; repeat the ALT tomorrow and if it's better, enroll him, because we need two more by Friday.' The applicant says he can stop the herbal product and asks whether he can still join.
1. Assess the applicant against the protocol criteria and explain whether he can be enrolled.
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He does not meet the protocol as written. The ALT is 1.8× ULN, above the inclusion limit of 1.5× ULN. A repeat test may be permitted only if the protocol defines repeat or rescreening rules; even a normal repeat does not automatically erase the original abnormal result unless the protocol says the last value is used. More importantly, BMI 31.4 exceeds the exclusion threshold of >30, and that is not a value that will change by Friday. The St John's wort washout is only 10 days against a required 28 days; his offer to stop now does not retroactively create a 28-day washout. His levothyroxine for 3 years with normal bilirubin and no reported thyroid instability may satisfy the stable thyroid criterion, but that does not fix the other failures.
The correct decision is screen failure for this cohort. He could be considered for a future cohort only if the protocol criteria differ and he completes the required washout; the BMI criterion may still exclude him. The coordinator should not reserve a slot or imply he will be enrolled.
2. How should the coordinator respond to the sub-investigator's instruction, and what documentation and communication are required?
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The coordinator should state clearly that enrollment cannot proceed because three protocol criteria are not met, and that repeating the ALT tomorrow would not resolve the BMI or washout failures. The sub-investigator may not grant a protocol exception; only the sponsor and IRB can approve a protocol amendment, and that cannot be done retroactively for this applicant. Escalate to the PI by phone or email, document the conversation, and ask the PI to confirm the screen-failure decision in writing. If the sub-investigator insists, escalate to the sponsor monitor and IRB; do not enter the applicant into the randomization system.
Document the screening visit with the actual ALT, BMI, supplement history, washout dates, thyroid history, and the reason for screen failure. Notify the applicant promptly and neutrally: he does not qualify for this cohort, and no study procedures or study drug will be given. If the protocol allows rescreening, explain the 28-day washout and any BMI requirement; do not promise a future slot. Complete the screening log and do not create an enrollment record. This protects the applicant, the site, and the integrity of the cohort.