Accelerated FDA Approval of Drugs Used To Treat Hematologic Malignancies: Are Policy Changes Needed?.

Background: In 1992, the FDA extended the accelerated approval program from HIV and AIDs, to include drugs for other diseases that are serious or life-threatening, appear to provide benefit over available therapy, or for which no other therapy is available. Approval is based on a surrogate endpoint, and pharmaceutical companies are required to confirm safety and efficacy by conducting clinical trials with clinically relevant outcomes. Since 1995, eight drugs used to treat hematologic malignancies have received accelerated approval.

Methods: Information available to the public under the Freedom of Information Act was surveyed for new drug applications and supplements for new uses approved by the Division of Oncology Products from January 1, 1995 to August 31, 2003. The package insert and corresponding published literature for the approval of each drug were reviewed for indication, time from drug submission to approval, surrogate endpoint, number of patients in trial, percent response and status of full approval.

Results: Of the eight drugs which received accelerated FDA approval, approval was granted within 6 months for three (these also received priority review), 1 was approved within 6–12 months; and 4 were approved after 1 year of FDA review. Approvals were based on the surrogate clinical outcome of response rate. Pivotal studies were often small, with < 100 patients (n=3) and 100–250 patients (n=4). The overall response rate was < 33% for four drugs. Only one of the approvals has been converted to full approval (imatinib). Post-marketing studies have identified three potentially fatal adverse drug reactions related to two drugs (gemtuzumab associated veno-occlusive diesease, gemtuzumab associated severe infusion reactions and imatinib associated upper GI bleeds).

Conclusion: To date, accelerated FDA approval for eight hematologic oncology drugs has been granted based on pivotal trials with small sample sizes and low response rates (with the exception of imatinib). Conversion to full approval has rarely occurred (N=1) and post-marketing identification of severe adverse drug reactions, in what were initially off-label settings, has occurred for two of the drugs. Modification of the accelerated approval process for hematologic oncology drugs should be considered.

FDA approval information for accelerated approval drugs used to treat hematologic malignancies.