Sutent: Yes, this was one major ODAC issue regarding unplanned looks at efficacy and subsequent termination before planned interim analysis.
"The first issue is the early closure of the trial. The primary efficacy endpoint was investigator-determined PFS. The Data Monitoring Committee (DMC) took several unplanned looks at the efficacy data and recommended closure after 73 PFS events, representing 28% of the 260 planned PFS events. The study was terminated after 81 PFS events, or 31% of planned events. This is well before the pre-specified interim analysis of 130 PFS events. The early signal of improved PFS with sunitinib did not cross a pre- specified efficacy boundary. Stopping trials prematurely for efficacy may overestimate the magnitude of the observed treatment effect."
"There was no End of Phase 2 meeting or Special Protocol Assessment with the FDA for the sunitinib PNET development program. The Phase 3 PNET study was conducted from June 2007 to April 2009. The supplemental NDA was initially submitted in December 2009.
In May 2010, the FDA issued the sponsor a Complete Response letter for the sunitinib PNET efficacy supplement. The FDA was concerned that the study was prematurely terminated as a result of unplanned interim analyses after only 28% of the planned PFS events were observed. In addition, there was concern about un-blinding due to differences in frequency of adverse events between the sunitinib and placebo arms, which could have introduced bias in investigator determination of PFS. Finally, an FDA analysis of the data showed a reduced magnitude of effect on PFS when strictly applying RECIST criteria and appropriately censoring for missing and incomplete assessments.
Given these concerns, the FDA requested: (1) a post-hoc blinded independent central radiologic review of PFS events for all 171 subjects enrolled in the Phase 3 trial, and (2) a recalculation of investigator determined PFS applying strict RECIST criteria and appropriate censoring for missing data according to the 2007 FDA “Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.”
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