A perspective on the regulation of the evaluation of new antithrombotic drugs.

We have entered a period of great possibility for improving clinical outcomes for patients with arterial thrombotic disorders using new antithrombotic agents. A variety of new therapies are now in clinical trials, while several others have just received regulatory approval for use in clinical practice. Because of the increasing complexity of the clinical environment and improvements in our ability to manipulate biology for potential therapeutic benefit, a host of new therapeutic agents will be available for testing in the next decade, and it will become increasingly difficult to determine when a true benefit has occurred. In this therapeutic field, regulatory approval requires a substantial level of evidence from randomized controlled trials. "Superiority" trials are relatively easy to understand, but placebo-controlled trials are becoming increasingly difficult to justify when at least one effective therapy already exists for a disease. Proving superiority over an active control can be difficult and may require a large sample size. Positive-control trials are aimed at equivalence or noninferiority in an effort to prove that a significant difference in clinical outcomes can be excluded. Another approach to demonstrating that the experimental therapy is superior to a putative placebo has been called "sufficiency." A review of recent regulatory decisions demonstrates the need for carefully constructed clinical trial programs that take into account previous experience, interactions, and the current therapeutic environment.