The FDA Outlook of Events Reporting after Ticagrelor or Clopidogrel in the PLATO Trial: Impact of Sponsor Censoring Dates, Drug Discontinuation, and Withdrawal of Consent

Abstract

Background: Censoring by the study sponsor of clinical endpoint events in indication-seeking randomized trials represents a controversial approach since the reported data may be biased in favor of experimental agents due to the obvious conflict of interest. The frequency of drug discontinuation and rates of consent withdrawal may also impact the trial outcomes. Purpose: To assess patterns of event reporting dependent on sponsor censoring dates, drug discontinuation and consent withdrawal in the PLATO trial. Methods: Analysis of theFood and Drug Administration Complete Response Review for ticagrelor. Results: Excluding adjudicated deaths, the distribution for clopidogrel appears more uniform while that for ticagrelor was skewed to the right, suggesting more events were reported after the sponsor censoring end date. PLATO investigators reported 16 unmatched primary endpoint events for ticagrelor immediately following the sponsor censoring date. Twenty-six out of 30 unreported events following early drug discontinuation occurred amongst patients using ticagrelor. More ticagrelor patients withdrew consent (Δ = 47), or were ‘not willing’ to complete the study (Δ = 87) when compared to clopidogrel. Conclusions: Site-reported primary endpoints were unequally distributed for clopidogrel and ticagrelor in the PLATO trial. This pattern suggests the importance of questioning the impact of sponsor-mediated censoring on event reporting by investigators in indication-seeking trials. In PLATO, this pattern seems to have favored the experimental drug and may require further assessment.

Bleeding Complications in Percutaneous Coronary Interventions

“…A possible explanation is that the true incidence of retroperitoneal bleeding was underreported, which is often the case in such retrospectively analyzed studies. Even in prospective trials, the true incidence of retroperitoneal hemorrhage is probably underdetected; only systematic postprocedural imaging and independent event adjudication could reveal the true incidence [3]. …”