Randomized Trials and Regulatory Decision Making

This segment will discuss how the U.S. Food and Drug Administration’s (FDA’s) criteria for drug approval have changed over decades, starting with the “two trials” rule in the 1970’s and evolving into a more flexible set of criteria to accommodate situations of great need with few therapeutic options, rare diseases where large randomized controlled trials are not possible, or when therapeutics appear to use specific mechanisms with dramatic effects. This situation has evolved in tandem with a variety of new “approval pathways” to accelerate decision making, with non-randomized evidence assuming a more prominent role. Although the FDA has stated that its decisions are always based on the statutory requirement of “substantial evidence” of effectiveness, recent examples show that the strength of evidence underlying this descriptor is highly variable, contextual, and without formal structures that would enforce consistency of standards across therapies or disease areas.