Waiting for Godot: Thirty-Six Month Follow-Up on Accelerated FDA Approval of Drugs To Treat Hematologic Malignancies.

Background: At ASH 2005, we reported that 9 drugs had received accelerated approval (AA) for 11 hematologic indications since 1992, and that only 2 of these drugs had fulfilled post-marketing requirements for conversion to regular approval. Following our original report in 2004, only 1 drug had converted to regular approval by 2005. At that time, we suggested that the FDA establish stricter post-marketing milestones, a suggestion echoed in Congressman Ed Markey’s report “Conspiracy of Silence.” Two years later, we update the experience with AA for hematologic indications and reevaluate the FDA’s post-marketing approval process.

Methods: Information on approval status and the clinical trials which form the basis of AA was obtained from the FDA website, product inserts, and medical literature reviews.

Results: Since 1992, 11 drugs have received AA for 14 hematologic indications. Post-marketing requirements have been fulfilled for only 2 indications (14%), and none have converted to regular approval since 2005. The median time since AA for the 12 indications with pending post-marketing commitments is 5.5 years. For solid tumors and supportive oncology, by contrast, 15 drugs have received AA for 15 indications; Subpart H requirements have been fulfilled for 9 indications (56%). The median time to completion of post-marketing commitments for oncologic and supportive indications is 8 years, and the median time since AA for indications with pending commitments is 3 years. The mean number of patients in clinical trials for AA is 155 for hematologic indications and 1567 for solid tumor and supportive indications.

Conclusions: The rate of conversion to regular approval for drugs with hematologic indications remains low. Our prior recommendation for stricter post-marketing milestones seems to be an untenable solution given the stagnancy of the approval process since our last report. Completion of Subpart H commitments may simply be unachievable, due to small numbers of patients and slow accrual to clinical trials following AA, in part due to violation of equipoise. We therefore revise our approach to AA. Surrogate endpoints are typically predictive of clinical benefit, while safety signals are often missed in early trials; the FDA should concentrate on preventing harm by mandating drug companies to keep safety registries after AA is granted, while still encouraging the emergence of new drugs for rare diseases through AA.

Drug AA Indication/Date Years since AA # pts in trials on which AA based Date Subpart H commitment fulfilled (P=Pending) BORTEZOMIB MYELOMA-5/13/03 4.25 193 3/25/05 IMATINIB CML, INITIAL TX-5/10/01 6.25 864 12/8/03 Nelarabine T Cell ALL-10/28/05 1.8 68 P Clofarabine Pediatric ALL-12/28/04 3.33 74 P Tositumomab Rituxan-naive follicular NHL (expanded indication)-12/22/04 3.33 130 P Tositumomab Rituxan-refractory NHL-6/27/03 4.1 100 P Imatinib Pediatric CML-5/20/03 4.25 39 P Imatinib GIST-2/1/02 5.5 147 P Ibritumomab NHL-2/19/02 5.5 157 P Alemtuzumab CLL-5/7/01 6.25 93 P Gemtuzumab CD33+ AML-5/17/00 7.25 42 P Cytarabine liposomal Lymphomatous meningitis-4/1/99 8.33 14 P Denileukin Diftitox Cutaneous T cell lymphoma-2/5/99 8.5 71 P Doxorubicin liposomal AIDS-related Kaposi’s sarcoma-11/17/95 11.75 77 P