The agency asks ODAC whether sponsors should be required to conduct at least two trials post approval to verify clinical benefit.
Although the FDA appears to be suggesting that doing two confirmatory studies is a better path forward, following such a policy provides a sponsor with no guarantees. Such was the case with Avastin, where Genentech’s AVADO and RIBBON1 trials showed a significant improvement on progression-free survival but failed to verify the magnitude of benefit seen in the E2100 study.
The FDA also asks whether accelerated approval should be delayed until confirmatory trials are ongoing.
"Once a drug gains accelerated approval in a refractory disease stage, accrual to a confirmatory trial in the same setting is difficult," the agency says. "Pursuing a confirmatory clinical trial in a less refractory setting can potentially circumvent this problem. However, changes in science, accrual challenges, and other hurdles may lead to delays. The FDA believes that more timely completion of accelerated-approval confirmatory trials can be enhanced if accelerated approval is granted when the confirmatory trial is ongoing."
Examining the Role of Cooperative Groups
The fourth question posed focuses on the use of cooperative study groups to conduct confirmatory trials. Even when a postmarketing study is being conducted by a cooperative group, the ultimate responsibility for completing the trial with due diligence rests with the drug sponsor. This responsibility holds added importance since the FDA Amendments Act of 2007 allows for imposition of civil money penalties if sponsors fail to complete trials on a timely basis, the agency notes.
The FDA asks whether, in those cases where a cooperative group is used, an additional trial conducted under the sponsor’s direct supervision should be required to ensure timely satisfaction of postmarketing obligations.
The complexities encountered in using cooperative groups are exemplified in Novartis’s briefing materials for Gleevec. Three of the company’s postmarketing commitments for imatinib’s accelerated approval in the adjuvant treatment of GIST are encompassed in an ongoing study sponsored by the American College of Surgeons Oncology Group (ACOSOG) and the National Cancer Institute under a Cooperative Research and Development Agreement.
There was no specific provision in the original CRADA granting Novartis access to data from the primary analysis for regulatory purposes, thereby necessitating a contractual amendment. Four-year follow-up data on recurrence-free survival were due in November, but this submission has been delayed pending receipt of data from ACOSOG.
"For industry sponsors, collaborations with cooperative groups can add challenges to a study very different to those encountered with industry-sponsored studies requiring close collaboration between all parties involved," Novartis said. "Often, as is the case with ACOSOG Z9001, the conduct of the study is within the control of the cooperative group."
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.