These criteria are made restrictive to increase the() of the results to produce an accurate and unbiased estimate of efficacy. However, the tradeoff is that RCTs have low (); this means the results cannot be generalized to the heterogeneous population that will actually end up using the drug including patients with several concomitant medications, complex medical histories, and increased severity of illness and pregnant women, children, and the elderly.3– 5 The safety profile might then change once the drug is approved, which may require a reevaluation of the benefit–risk profile for the product.