Current Issues in Clinical Trial Design: Superiority versus Equivalency Studies

HISTORICALLY, the gold standard for drug approval by positive for the human immunodeficiency virus were the US Food and Drug Administration (FDA) has been randomized to the placebo group at a time when it was convincing evidence of efficacy in double-blind, placeknown that azidothymidine (AZT) prevented fetal trans bo-controlled, clinical trials. Because a placebo-conmission of the virus. On February 18, 1998, the placebo trolled superiority trial provides the most straightforarm of these trials was suspended after Public Citizen‘ ward opportunity for demonstrating efficacy, it is the and members of the medical and public health commumost widely used regulatory benchmark in the drug nities denounced the trials as unethical. approval process. One alternative to a placebo-controlled superiority trial In some settings, a study to determine whether a drug is an equivalency tria1.t Here, the focus is a comparison is more efficacious than placebo may be inappropriate. of the test drug with standard therapy (active control), The clearest example is a case in which withholding treatment or administering placebo would cause serious or irreversible harm to subjects enrolled in a clinical trial. Although no Investigational Review Board in the United States today would sanction a placebo-controlled superiority trial in men with syphilis when effective treatment is available (as occurred in the infamous Tuskegee Institute study), the National Institutes of Health recently funded studies that exposed human subjects to serious injury. In Africa and Asia, pregnant women who tested not efficacy of the test drugper se. The primary outcome variable may be an effectiveness end point or a safety end point, e.g., an adverse event, clinical laboratory variable, electrocardiographic measure, or pharmacodynamic variable.2 Ethical considerations aside, selecting an appropriate study design is largely dependent on the trial’s objective. Because their role is to prevent ineffective or potentially harmful products from entering the marketplace, regulators primarily want to know whether an investigational drug is effective. Hence, the majority of protocols submitted to the FDA by the pharmaceutical industry are * Instructor of Anesthesiology, Harvard Medical School, Boston Massachusetts; Former position: Medical Officer and acting Team Leader, Anesthetic and Critical Care Drugs, Food and Drug Administration, Rockville. Maryland. p~acebo-contro~~ed superiority trials. on the other hand, clinicians want to know not only whether a new drug is effective, but how much more effective it is for their