Randomized clinical trials (RCTs) are the definitive contributors to evidence-based medicine. RCTs assessing serious outcomes in cardiovascular disease have grown, with 'megatrials' becoming more common with the realization that wrong conclusions resulted from random error in inadequately sized trials. Simple design and a heterogeneous patient population were early features, but multinational trials have increased in scientific, logistical, bureaucratic, regulatory, and legal complexity. These studies now exceed the financial means of academia or medical charities. Governments have left the bill with the pharmaceutical industry, encouraging a symbiosis with academics, who contribute medical and scientific expertise, and access to patients. Industry provides pharmacological, pharmaceutical, technical and regulatory know-how, good clinical practice expertise, and legal assistance during the trial. Study supervision is then in the hands of an independent steering committee and associated subcommittees, until appropriate dissemination of results. Prospectively defined interaction with the sponsor facilitates unbiased design and conduct, but arrangements need careful implementation to avoid conflicts of interest. The patient is protected by a strong data safety monitoring board that is wholly independent. Megatrials are under threat from over-regulation, increasing costs, and difficulties in execution. These issues merit urgent public and political education and debate.