Accelerated Approval of Oncology Drugs: Can We Do Better?

The modification of Food and Drug Administration (FDA) investigational new drug regulations to provide for “accelerated approval” of promising new drugs was put in place in 1992 (1), motivated largely by the emergence of HIV/AIDS. The increasing rigor of FDA review, beginning with the 1962 passage of the Kefauver– Harris amendments to the Federal Food, Drug and Cosmetic Act, and the resulting changes to the FDA regulations regarding evaluation of investigational drugs, were perceived as intolerable obstacles to making potentially life-saving therapy available in the most rapid way possible to those suffering from a deadly disease with very limited therapeutic options. Accelerated approval was to be based on positive results for surrogate endpoints that were considered likely predictors of clinical benefit, as typically measured for oncological drugs by an improvement in survival. The application of this less restrictive pathway to drug approval was quickly used in other medical areas; among the first eight drugs to receive accelerated approval, four were for HIV/AIDS indications, two were for cancer treatment (one was for Kaposi sarcoma, an AIDS-related malignancy), one was for multiple sclerosis, and one was for bacterial infection. The article by Johnson et al. (2) in this issue of the Journal updates the FDA experience with accelerated approval of oncological drugs and biologics that first appeared in 2004 (3). Over 18 years, from the initiation of the accelerated approval process in 1992 through 2010, 35 products for 47 indications have been approved in accelerated fashion; 20 of these products have so far received regular approval for one or more indications. In only three cases has a product that received accelerated approval clearly failed to have clinical benefit confirmed (although it appeared that for one of these—gefitinib —the drug was, in fact, effective in a small subset of patients with certain tumor characteristics). The final status of many products that have received accelerated approval is as yet undefined because the clinical trials that were mounted to confirm clinical benefit of these products have either not yet been completed or remain under FDA review. Of the 47 accelerated approvals, 28 were based on single-arm trials and 19 were based on randomized trials. The proportion based on randomized trials has increased somewhat in recent years. Since 2005, half of accelerated approvals for oncology drugs were based on data from randomized trials; before 2005, the proportion was about 2:1 in favor of single-arm studies. Most of the accelerated approvals for a first-line or adjuvant treatment indication have been based on data from randomized studies. Only imatinib gained approval for first-line indications (for gastrointestinal stromal tumor and pediatric Philadelphia chromosome–positive chronic myeloid leukemia) based on data from single-arm studies. An important question related to accelerated approvals for oncology products that is not fully addressed by these data is the extent to which accelerated approval actually speeds the availability of products that offer an important advance in cancer treatment. In