Central event adjudication in randomized controlled trials is common for multicenter international outcome-driven studies. Delegating such a critical mission for the final assessment of the site-reported events should fix the variability of definitions, contribute to comprehending and resolving complicated clinical scenarios, remove “noise” and potential bias from the totality of evidence [1, 2, 3]. However, whether or not the uniform use of central adjudication is always justified and unbiased is unclear. The PLATelet Inhibition and Clinical Outcomes (PLATO) trial enrolled 18,624 patients with unstable angina or myocardial infarction (MI) treated coronary stenting or managed medically. The patients were randomized to receive ticagrelor 180 mg loading followed by 90 mg twice daily or clopidogrel 300–600 mg loading followed by 75 mg once daily, for up to one year [4]. The primary endpoint was defined as a combination of vascular death including bleeding fatalities, MI, and stroke. These events occurred in 11.7% of patients from clopidogrel arm, compared to 9.8% of ticagrelor treated patients (HR = 0.84; 95% confidence intervals (CI): 0.77–0.92; p 0.001) [4]. These favorable findings of the published trial results were challenged by the Food and Drug Administration’s (FDA) Secondary Review [5] and a Review of Complete Response [6].

Lately, the alleged clinical benefit of ticagrelor has been challenged further by mortality timing, causes, and vanished fatalities [7, 8], “friendly” pool of central adjudicators and International Central Adjudication Committee (ICAC) leadership [9], and involvement of sponsor representatives in the adjudicator selection [5, 6, 10]. Moreover, ticagrelor benefit based on site-reporting was not significant in PLATO [5, 6], while the disagreement in MI counts favoring ticagrelor was concerning [11, 12]. The latest comprehensive BMJ investigation confirmed the adjudication bias in PLATO [13]. However, several critical pieces with regard to the timing of final adjudication and primary endpoint data analyses were still unclear. We gained access to the FDA-issued adjudication dataset and analyzed the evidence focusing on geography, timing of final adjudication, disagreements, and trends for drug favoritisms in crosstabulation including primary trial endpoint components.

The FDA-issued database spreadsheet contains 10,704 events that occurred across 7171 patients. There were 938 deaths, 2751 MI’s, 359 strokes/TIAs, 2680 cardiac ischemia’s, 130 arterial thromboses, and 3782 bleeds.

Geography: The comparison of the FDA-reported and their matches with the site-reported events in different countries is shown in Table 2.

3.6 Primary Endpoint

There were 864 events in the ticagrelor arm and 1014 events in the clopidogrel arm constituting PLATO’s main efficacy result. Table 8 indicates favors of central adjudication exclusively for the events constituting the trial primary endpoint.

Table 8. Impact of central adjudication favoring over site-reported events on PLATO primary endpoint components.

			Endpoint			Total
			Death-vascular	MI	Stroke
Group assignment	Ticagrelor	Count	59	73	7	139
		% within adjudication	72.0%	61.9%	63.6%	65.9%
	Clopidogrel	Count	23	45	4	72
		% within adjudication	28.0%	38.1%	36.4%	34.1%
Total		Count	82	118	11	211
		% within adjudication	100.0%	100.0%	100.0%	100.0%

With regard to favoring, there was a consistent shift towards ticagrelor advantage for all 3 primary endpoint trial components. There was relatively equal dispersion of ticagrelor “favoring” for vascular death (72.0%), MI (61.9%), and stroke (63.6%). Overall, the central decisions differed from sites in only 211 out of 1878 primary endpoint events (11.2%). However, an extra 67 endpoint events (36 vascular deaths, 28 MI’s, and 3 strokes) were adjudicated in favor of ticagrelor. Hazard Ratios for the Primary Endpoint Adjudicated Results favoring Ticagrelor in PLATO are presented in Fig. 1.

Fig. 1.

Adjudicated primary end point results favor Ticagrelor in the PLATO study.

With regard to the exclusive primary endpoint events there was highly significant disagreement favoring ticagrelor for vascular death (HR = 2.02; 95% CI: 1.1–3.64; p = 0.019); MI (HR = 2.31 95% CI: 2.79–43.94; p = 0.034); stroke (HR = 1.37; 95% CI: 2.66–63.28; p = 0.036; and total events (HR = 2.51, 95% CI: 1.86–3.39; p = 0.01). Considering that 211/1878 Primary events were found to have disagreements, an extra 67/211 (31.8%) endpoint events were adjudicated in favor of ticagrelor. Given that there were 67 extra events this will happen by chance in 1 of approximately 485 trillion trials.

The clinical validity of central event adjudication has often been a challenge since adjudicated data usually match well with the local sites, but are substantially costly [1, 2, 3, 14, 15] and adding extra bureaucratic organizational burden [2, 15]. Historically, the balance of adjudication results and severity of disagreements were kept secretive and submitted only to the regulatory authorities, especially for the landmark indication-seeking trials. The current analyses became possible because we gained access to the full adjudication database after being awarded of the Joined Status Report by the US Federal Court Order agreement with the FDA and Department of Justice.

The main finding of this report suggests that central adjudication played a pivotal role in escalating ticagrelor benefits far beyond previously described misreported deaths [7, 8]. Without ICAC activities the benefit will remain non-significant [5, 6] making regulatory approval of ticagrelor impossible. In fairness, the ICAC in PLATO was extremely busy adjudicating over 10,000 events in a short-duration megatrial. Such massive tasks were substantiated by two main reasons: the introduction of the unique trial bleeding classification and questionable inclusion of enzymatic or “triggered” MIs. The exact definitions of these two categories were somewhat unclear to the local enrolling sites but subjected to the mandatory central adjudication accounted for about half of all adjudications and disagreements in PLATO. Also, most events were adjudicated fairly including bleedings, arterial thrombosis. and cardiac ischemic events. To make it crystal clear, most deaths, MIs and strokes were also adjudicated properly, but not all of them [7, 13]. For 1878 events constituting the primary endpoint the odds of favoring ticagrelor were 2.51 times higher (95% CI: 1.86–3.39) versus clopidogrel. Importantly, all 3 components of the primary endpoint were adjudicated favoring ticagrelor potentially challenging the treatment arm blindness of ICAC leadership. Importantly, issues with unfair adjudication rendered the PLATO results do not explain the rate of death from any cause which were reported in PLATO being lower after ticagrelor (4.5% vs. 5.9% with clopidogrel; p 0.001). Until the detailed exploration of the primary database entries and their corrections are being conducted, there are certain reservations about the clinical validity of ticagrelor approval. Another shortcoming of the trial central adjudication was a massive unaccounted delay when most events that occurred in 2008 were kept unadjudicated till the very end of the trial in 2009. The PLATO ICAC reserved a huge pool of events to be adjudicated later in 2009, and this delay was significant (HR = 0.84; 95% CI: 0.75–0.95; p = 0.004). Importantly, ticagrelor was significantly less favored in 2009 in comparison to 2007–2008 (HR = 1.19; 95% CI: 1.05–1.34; p = 0.005). These data corresponds well with the earlier FDA concern that there was a lack of early benefit for ticagrelor in the largest post-stenting PLATO cohort [5, 6], while the immediate spread of Kaplan-Meier (K-M) efficacy curves was so critical to achieve. However, the exact explanation of such adjudication delay is still lacking pending further investigation.

The geographical distribution of the central adjudication patterns was remarkably consistent in PLATO. About half of the enrolled patients experienced an event, with the matches and disagreements among 43 enrolling countries being similar as well. Importantly, such massive double-digit disagreements were well-balanced between treatment arms. They were mostly due to the introduction of novel PLATO bleeding scale classifying hemorrhages into 4 categories and the controversial inclusion of “enzymatic” or “triggered” MIs into the equation. It seems most investigators were not well aware of such novelties causing massive disagreements easier to comprehend. In contrast to stroke when most disagreements were minor the severity of mismatched decisions for vascular death and MI was either moderate or major. In fact, the average of major disagreements hovered around 30% for all adjudicated results. There was a heavy selective bias in PLATO ICAC constitution and governing. Importantly, ICAC for PLATO was primarily pre-planned and was not created per the FDA suggestion [5, 6, 9]. In fact, sponsor was definitely informed and potentially involved in ICAC members/reviewers selection although the details on how such communications occurred was hard to comprehend, and the ICAC regulations charter was also ‘silent on the matter’ [6]. Importantly, the FDA inspector did not find any records that explain how the ICAC selections occurred. In short, the FDA’ confirmed that the ICAC constitution was approved by the PLATO study sponsor [5, 6] what is obviously concerning. It is unclear whether any specific procedures were in place during the PLATO trial to ensure consistency and fairness in central event adjudication. That particular issue was also the FDA reviewers concern since the sponsor refused to provide any communication records among ICAC leadership, members and sponsor. In fairness, despite the friendly pool of adjudicators, we have no proof that they were unblinded or biased. Also surprising that despite outcome disparities in the United States, Russia, Georgia, Israel, and part of Ukraine (harm with ticagrelor when Clinical Research Organization (CRO) monitoring) and the other 39 countries (extreme benefit with ticagrelor when sponsor monitoring), the FDA did not institute its own independent ICAC [6], which would be reasonable considering inversed outcomes within the same trial. What matters the most is the fact that, central adjudication changed the PLATO primary endpoint results. Without the ICAC activities, the combined primary endpoint benefit of ticagrelor versus clopidogrel in PLATO was not significant (HR = 0.92; p = 0.095) even by applying liberal log-rank statistics [5, 6]. Importantly, these findings obviously may be extrapolated or confined to the specific context of the PLATO trial and may not be generalizable to other clinical trials or patient populations.

Central event adjudication in PLATO was unaccountably delayed while the primary endpoint shifted towards inflated ticagrelor benefit resulting in drug approval. The regulatory authorities should consider independent audits when there is a major disagreement between event assessments changing the results of the indication-seeking clinical trials.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

VLS, TM — conception; VLS, WZ, HACF designed the research study; HACF, BP, IH performed the research; WZ, HACF, BP, IH analyzed and interpreted the data; VLS, TM drafted the paper; VLS, WZ, HACF, BP, IH, TM critically revised the manuscript for intellectual content. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The original PLATO adjudication dataset was provided by the FDA based on the Federal Court Order and Joined Status Report with the Department of Justice (Washington, DC USA). CONSORT checklist or ethical approval is not applicable since we do not report here the results of the clinical trial.

This study was funded by HeartDrug Research, which covered affiliated legal fees to obtain FDA evidence and conduct statistical analyses.

VLS, BP and IH are from HeartDrug Research LLC, but have no conflict of interest. The authors declare that HeartDrug Research LLC had no role in the decision-making and conduct of this study. VLS is listed as an inventor and received compensation for the U.S. Patent Application P-17232 “Method for treating vascular diseases with prasugrel” assigned to Lilly; and “Treating Cardiac Arrhythmias, heart failure, peripheral artery disease and stroke with CYCLOPENTYLTRIAZOLO- PYRIMIDINE or derivative thereof” (USN 61/253,829) assigned to HeartDrug™ Research. He received funding for research studies with prasugrel, and clopidogrel, and consultant fees from the clopidogrel and ticagrelor manufacturers. WZ receives funds from the NIH. TM was the Medical Team leader for the FDA PLATO clinical reviews. HeartDrug Research LLC (Wilmington, Delaware, USA) paid the legal fees to obtain the FDA-issued documents, covered travel and statistical expences. Dr. Serebruany is an solo owner of HeartDrug Rssearch. Prof. Victor L. Serebruany is serving as one of the Editorial Board members and Guest editors of this journal. We declare that Prof. Victor L. Serebruany had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Dr. Lihua Sun and Dr. Leonardo De Luca.