You can't have an informed risk assessment without clinical trials because you don't have the data to inform assumptions about risk / benefit. The models currently used to predict risk / benefit are really poor predictors of whether something is safe and effective. If you don't do phase 3 RCTs you'll just end up w a bunch of people gaming the risk assessments and getting drugs that don't work approved
Statistics and study powering are designed to address the issue you cite about marginal benefits "smoothing out" as the population gets bigger. That's why you have to do big phase 3 studies with __predefined__ endpoints and statistical analysis plans powered by estimated effect sizes
Saying that phase 3 study "clearly worked" is not true. It didn't do better than sham. Yes it could be true that there is some drug related benefit in the nontreated eye, but another interpretation is the sham injection itself could cause the observed improvement. Or the study design was wonky, endpoints inconsistently measured, etc
Statistics and study powering are designed to address the issue you cite about marginal benefits "smoothing out" as the population gets bigger. That's why you have to do big phase 3 studies with __predefined__ endpoints and statistical analysis plans powered by estimated effect sizes
Saying that phase 3 study "clearly worked" is not true. It didn't do better than sham. Yes it could be true that there is some drug related benefit in the nontreated eye, but another interpretation is the sham injection itself could cause the observed improvement. Or the study design was wonky, endpoints inconsistently measured, etc