There are a number of reasons why problems can slip through clinical trials, even with proper clinical trials design. Some side effects are extremely rare, so

There are a number of reasons why problems can slip through clinical trials, even with proper clinical trials design. Some side effects are extremely rare, so rare that even with “large” clinical trials groups the problems don’t occur. Or they might occur, but at rates no greater than what the placebo group experiences. Some side effects only show up with repeated long-term use of a drug. That’s why there exists “post approval monitoring” to watch for these problems. Some side effects only show up when a drug is taken concomitantly with other drugs. Some side effects only show up when users have certain diets. Some side effects (and some efficacies) only show up for certain ethnicities and sub-populations. Some side effects only show up when patients take much larger doses than were tested in clinical trials. Larger statistical samples would help to reduce these problems, but it’s often not as easy as you might think to recruit large numbers of people for your study. First, it is quite expensive to put a large test group together. Some diseases / conditions are quite rare, so it can be difficult to even find enough people with the condition. As the test runs through, some fraction of the participants will drop out for one reason or another. Some people will just stop taking the medication for one reason or another. How you treat these “dropouts” is not a simple question and can have a huge impact on your clinical trials conclusions. Some test measures are highly subjective and experts will disagree on how efficacious / dangerous a drug is when presented with the same exact data. The bottom line is that drug approval is extremely complicated. Better test design and monitoring helps but it will not catch all problems. Regulators have to balance safety with benefits in the face of uncertainty.