The randomized controlled trial (RCT) forms the basis for drug approval by regulatory agencies. Observational studies using existing data from healthcare databases now also provide real‐world evidence (RWE) in regulatory decision‐making. Several initiatives are assessing the value of RWE by conducting observational studies that emulate published RCTs. While many RCTs are straightforward to emulate, others are challenging. We describe three RCT design aspects that pose challenges for observational studies. First are trials that enrol already treated subjects who must discontinue these treatments at the time of randomization, which can distort the comparison with observational studies. Second is the inclusion of a run‐in phase, especially to exclude non‐compliant subjects from the trial. Third are trials that evaluate the effect of weaning off treatment. In conclusion, future randomized trials that aim to be emulated by observational studies could consider study designs that allow emulation and thus provide valid and complementary RWE.