Accelerated Approval: Safe at Any Speed?

Drug regulatory authorities like the FDA have a mandate to protect public health by requiring and evaluating evidence of safety and efficacy before licensing new drugs for commercial sale. But for decades now, patient advocates have argued that FDA bureaucracy kills by keeping promising drugs from the IV's of terminal patients. In response to these criticisms, FDA and others have created new pathways for drug approval whereby drugs can be partially approved for sale on the basis of smaller, Phase 2 trials using surrogate endpoints (tumor shrinkage) instead of survival– provided drug companies confirm efficacy in subsequent trials.

This pathway, called "accelerated approval," is controversial because it allows companies to sell drugs whose efficacy and safety is not yet well established. True- the companies are obliged to run confirmatory studies, but a) how will confirmatory trials enroll enough subjects if patients know they might be randomized to standard, ineffective drugs, and they can get the drug outside a clinical trial? b) drug companies will not have sufficient incentive to run confirmatory studies once their drug is provisionally approved. c) drug companies stand to make lots of money selling unproven drugs to desperate patients in search of a cure.

In the most recent issue of Journal of Clinical Oncology, Elizabeth Richey and coauthors put these concerns to the test in an analysis "Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs." They find that:

• a very large percentage of new cancer drugs are initially approved under "accelerated approval." (37% approvals between 1995 and 2008)

• 63% of drugs receiving accelerated approval have their clinical benefit confirmed in subsequent studies

• drugs involving very rare cancers are often not subjected to confirmatory testing (42%); drugs for more common cancers are tested in confirmatory studies typically (71%-- though the percentage I calculated from their figures is actually higher- 86%)

• drugs receiving accelerated approval are twice as likely to receive black box warnings compared with drugs approved by the standard mechanism (21% vs. 10%)

• about half of non-orphan drugs approved under accelerated approval (47%) become first line treatment regimens in the National Comprehensive Cancer Network.

The authors see the glass half full on accelerated approval: to the title question of their article, the authors answer "Improved Access to Therapeutic Breakthroughs." (photo credit: Marxpix 2008)