Table 4.

Stopping rules for first-in-human trials

Individual subject	•Coding adverse events and laboratory abnormalities according to e.g. CTCAE criteria/grades may facilitate definition of stopping rules, even though CTCAE not really suitable for healthy subjects • 1 adverse event of severe intensity (Grade 3*) *Some stakeholders apply this stopping rule only in case of a causal relationship with the IMP • 1 serious adverse event • Relevant signs or symptoms affecting subject safety • Decision always taken by the investigator
Dose group/cohort (stop of further dose escalation)	•≥50% of subjects of the preceding dose step experienced adverse events of moderate (Grade 2, safety alert, ‘warning signal?’) or severe (Grade 3) intensity considered to be drug-related (selective unblinding) • 1 serious adverse event suspected to be drug-related (unblinding advised) = 1 serious adverse drug reaction • In case trial to be continued following safety consultation between all stakeholders, substantial amendment required
Termination of entire trial	• Decision taken by mutual agreement between investigator and sponsor

IMP investigational medicinal product, CTCAE Common Terminology Criteria for grading of Adverse Events developed by the National Cancer Institute (1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death), version current at the time of publication of this consensus paper: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf