Table 2. Possible approaches for estimating HIV incidence in hypothetical placebo group or effectiveness of the control drug in an active-control trial.

Unobserved parameter	Approach	Validity
HIV incidence in hypothetical placebo group	Run-in period without active treatment or Trial within a Cohort (TwiC) i.e. establish a cohort of individuals potentially interested in PrEP before trial drug becomes available.(7, 24)	Potential interest does not equate to agreement to be randomised. Number of infections usually small and estimates therefore imprecise. Potentially inaccurate if long period of follow-up and change in HIV incidence over time.
	Recent HIV prevention studies in the same geographic region in population with similar characteristics	Potentially unreliable if HIV incidence changing rapidly
	Estimates from epidemiological surveillance systems(4)	Likely to under-estimate incidence as diluted by low-risk individuals testing largely for reassurance
	Infer incidence from tests for recent infection on baseline samples(8)	Number of recent infections usually small and estimates therefore imprecise. Incidence just prior to trial entry may not reflect incidence over whole follow-up period.
	Measure STI incidence within trial, and calibrate from ecological association between incidence of HIV and other STIs	Ecological association not strong. HIV incidence possibly less stable than that of common STIs such as gonorrhoea.
Effectiveness of active control drug (versus placebo)	Meta-analysis of previous trials comparing active control to placebo(1)	Hinges on “constancy” assumption i.e. that effectiveness can be validly extrapolated from meta-analysis (but studies often highly heterogeneous)
	Measure adherence within trial and infer effectiveness from meta-regression or PK/PD models(7, 25)	Elicited adherence often inaccurate. Drug levels more reliable but expensive to collect samples.