1. Single Pivotal vs Two Replicated Studies. Zijiang Yang
Single Pivotal vs Two Replicated Studies Zijiang Yang Joint Statistical Meeting 2018

2. How to get a drug approved?
In 1960s, single center, loose blinding, no need to pre-specify.
In 2000s, AWCS (Adequate & Well-Controlled Study) is a must.
How are test & control selected (design), treated (conduct), observed or analyzed (analysis).
Usually replicated, unless ethically inappropriate (eg, multi-drug resistance bacteria).

3. Replications are important
Significant results need to be confirmed in a replicated experiment to achieve general acceptance
Although sounds like a low chance for false positives, the proportion of false positives among all positives may be much higher (selective inference)
FDA usually requires two independent studies, both showing statistical significance and clinically meaningful as a necessary condition for approval
EMA also recommends replication of findings, though not a requirement

4. The orientation of
It is usually referenced as “statistically persuasive” vs “statistically significant”.
If you achieve one-sided p < for study A and B, the type I error reduced to 0.025^2 = one-sided. Convert back to 2-sided and you have
It meant to provide the “same amount of evidence” as two replicated studies.
But do they always agree with each other?

5. Pop Quiz
Assume we have two replicated studies (Study X and Y) with clinical response as primary endpoint. We have treatment T and control C, 200 subjects per group and powered at 90% with 2-sided alpha of If we pool the data, what is the power for this single study (400 per group) to reach the significance level of ?
0-70%
71-81%
82-90%
91-95%
95%+
Given the above pooled data failed to achieve , what is the chance for BOTH of study X and Y to be significant at 0.05 level?
Don’t bother, it NEVER happens!
Must be extremely rare, like 1% or something?
I guess it has a decent chance, maybe about 10%?
It happens sometimes, 20% to 50%….
This is actually the more likely scenario, 50% or more.