International central adjudication committee in the PLATO trial: independent body of experts or friendly family picnic?

Abstract

The International Central Adjudication Committee (ICAC) is responsible for blinded independent assessment of complex clinical events in randomized trials. In this study, we analyze the constituence and impact of the ICAC in the PLATO trial. The PLATO ICAC was entirely governed by two academic institutions, Duke Clinical Research Institute (DCRI) and Uppsala Clinical Research Center (UCRC). Both co-chairman, all coordinators and half of the adjudicators in the PLATO ICAC belonged to either DCRI or UCRC. Among the other adjudicators representing USA, Canada and Australia, majority had DCRI ties, including at least five former Duke cardiology fellows. Furthermore, both co-chairmen are listed as adjudicators, representing obvious conflict. In the PLATO trial, the sponsor representatives were involved in selecting the ICAC members. Finally, 21 out of the 50 adjudicators represented Sweden, the homeland of the PLATO sponsor and primary investigator. Heavy selection bias in the ICAC constituence, lack of independence and potential control of the ICAC by the study sponsor may influence PLATO outcomes, and should be avoided in the future.

Keywords:

• clinical trials
• event adjudication
• myocardial infarction
• ticagrelor

Central adjudication of clinical events in randomized controlled trials is commonly used in multicenter international outcome-driven studies. This critical final assessment of trial results is entrusted to the International Central Adjudicating Committee (ICAC) to combat a potential variability of endpoint definitions, contribute to comprehending and resolving complicated clinical scenarios, and remove scientific ‘noise’ and potential bias from the totality of evidence [1–3]. However, it is not entirely clear whether or not the uniform use of this central adjudication is always justified. The clinical validity of event adjudication has often been challenged since – as a rule of thumb – the adjudicated data usually match well with the investigator-reported event rates, but with substantially increased affiliated costs [2,4]. In contrast to this formerly universal rule, recent analyses show unexpected discrepancies between the number of site-reported myocardial infarctions (MIs) and centrally adjudicated events in at least three major trials, TRITON (prasugrel), RECORD (rosiglitazone), and PLATO (ticagrelor) [5]. Central adjudication in these recent trials provided a critical advantage to study outcome, which interestingly favored the study sponsor in all three cases [5,6]. In fact, compared with site-reported events, the ICAC generated numbers differed by more than a factor of 2: from 72 to 145 events in TRITON, favoring prasugrel, and from 44 to 89 events in PLATO, favoring ticagrelor. Similar adjudication advantage occurred in the RECORD trial where data representing cardiovascular hazards diminished from 24 to 8 events, favoring rosiglitazone [5]. These alarming discrepancies generated much debate and placed adjudication techniques under public scope [5,6]. Our current report focuses on the ICAC membership and their role in the PLATO trial. The summary of PLATO is outlined below.

The PLATelet Inhibition and Clinical Outcomes (PLATO) trial was a Phase III, randomized, double-blind, parallel-group, multinational clinical study, comparing the efficacy of ticagrelor versus standard care treatment with clopidogrel. Patients (n = 18,624) with moderate- to high-risk acute coronary syndromes undergoing coronary intervention or medically managed were randomized to ticagrelor 180 mg loading dose followed by 90 mg twice daily or clopidogrel 300–600 mg loading dose followed by 75 mg once daily, for up to 12 months [7]. The primary endpoint was the time of the first event of death from vascular causes, MI or stroke, and occurred in 11.7% of patients treated with clopidogrel, versus 9.8% of patients randomized to ticagrelor, representing a significant benefit (HR = 0.84; CI = 0.77–0.92; p < 0.001) [7]. These initially optimistic findings of the published trial results were clouded by the FDA’s Secondary Review [8] and especially damaging Review of Complete Response [9]. Most importantly, these independent data analyses revealed a major disagreement between site-reported and ICAC-adjudicated MI, where 45 MIs were exclusively added to the clopidogrel PLATO arm. Indeed, central adjudication changed the primary endpoint outcomes in PLATO. Without the ICAC activities, the combined primary endpoint benefit of ticagrelor versus clopidogrel in the PLATO study was not significant despite a remarkable and still unexplained ticagrelor mortality benefit (hazard ratio = 0.92; p = 0.095) even by liberal log rank statistics [9]. The probability that all 45 MIs would exclusively belong to clopidogrel arm in PLATO is 0.0000000000002, a virtual impossibility [5]. In addition, significantly more cardiac events submitted for clopidogrel were counted in the primary analysis as MIs compared with those submitted for ticagrelor (p < 0.0001). Likewise, significantly more ticagrelor subjects that were hospitalized after an index event/hospitalization were deemed to have had no primary event compared with similar instances with clopidogrel (p = 0.002 in favor of ticagrelor) [10]. The PLATO trial ICAC structure is publically available in the initial trial publication supplemental materials [7], and summarized in Table 1.

Table 1. International central adjudication committee in PLATO.

ICAC role	DCRI	TIMI	UCRC	Sweden^†	Others
Co-chairmen	1	–	1	–	–
Coordinators	2	–	1	–	–
Adjudicators	14	4	11	10	11^‡
Study sponsor	–	–	–	1	4^§

^†Except UCRC, Uppsala, Sweden.

^‡Including at least five former Duke cardiology fellows.

^§From sponsor headquarters, Wilmington, Delaware, USA.

DCRI: Duke Clinical Research Institute; TIMI: Thrombolysis in myovardial infarction; UCRC: Uppsala Clinical Research Center.

The data in Table 1 may indicate a heavy selective bias in PLATO ICAC constitution and governing. Importantly, ICAC for PLATO was primarily pre-planned and was not created per a FDA suggestion due to unclear results from the enrolling sites [9]. Moreover, representatives from the sponsor along with the Duke Clinical Research Institute (DCRI) clinical events classification director selected ICAC committee members. Importantly, the details on how this selection occurred were not stated, and the ICAC Charter per se was also ‘silent on the matter’ [9]. In addition, ‘the FDA field investigator was not able to find any records that documented how the sponsor actively participated with DCRI co-chairman in the selection of the ICAC members. However, the sponsor stated in the response letter dated 10 April 2010 that they did have ongoing communications with the DCRI ICAC Chair. Evidence of sponsor awareness and, at the least, passive participation in selection of ICAC members were demonstrated in an email from DCRI ICAC Chairman dated 28 January 2008, which included an invitation list for the PLATO ICAC membership where two future ICAC members from PLATO sponsor were copied. The FDA complete response review also stated that the ‘selection process’ used by DCRI was approved by the PLATO study sponsor [9]. For a sponsor to approve the selection process of the ICAC committee in a trial it was directly monitoring is also a serious concern. In addition, despite disparities in the efficacy of ticagrelor versus clopidogrel in North America (harm with ticagrelor) and outside of North America (extreme benefit with ticagrelor), the FDA did not institute its own ICAC [9], which would certainly be reasonable considering the geographic discrepancies in outcomes.

There are a number of additional considerations that may pertain to the ICAC controversy in PLATO. First, ICAC was exclusively governed by two academic research institutions, DCRI, and Uppsala Clinical Research Center (UCRC), and there is proof that at least DCRI directly worked with the study sponsor in selecting the ICAC members. This makes for concern since both co-chairman, all coordinators, and half of the adjudicators belong to these prominent academic institutions. Similarly, among other presumably ‘independent’ adjudicators representing USA, Canada and Australia, majority had heavy DCRI research ties, including at least five former Duke cardiology fellows. Second, it seems entirely inappropriate for the study sponsors to have any potential influence in ICAC activities, which was not assured in PLATO. This is especially alarming since the PLATO sponsor self-monitored enrolling sites [11] and was most likely engaged in double control, first filtering the primary evidence generated by sites [8,9] and then selecting which cases underwent adjudication. Typically, this would not be of grave concern, but the fact that 45 additional events in PLATO were disfavorably adjudicated only in the clopidogrel arm lacks any reasonable explanation and cannot be explained by chance. Third, both co-chairmen of the PLATO ICAC were also listed as adjudicators, representing an obvious conflict. Finally, the fact that 42% of all adjudicators (21 out of 50) in the international trial represented Sweden, the homeland of the PLATO sponsor and principal investigator, seems quite odd.

Albeit the ICAC for PLATO was indisputably composed of some of the finest and most honorable cardiology experts in the world of science, it is difficult to deny that the results of the aforementioned adjudication are controversial and formally favored the study sponsor. This may lead to the bewildering thought that although the ICAC was meant to assure quality control of outcome data, it actually contributed to what may be perceived as a problematical influence. We are not proposing to defy ICACs. If appropriately created and used, central adjudication represents an important tool, as data delivered by study sites are often questionable. We sincerely hope that this article will generate a continuation of healthy debate [5,6,11–13] as an ‘illustrative case example’ that emphasizes appropriate central adjudication procedures in modern clinical trials. As a proposed improvement of clinical trial methodology quality and balanced presentation, trial publications ought to include site reported major efficacy and safety endpoints, thus contributing to transparency and data integrity. The regulatory authorities should continue to demand independent audits when there is a major discrepancy between centrally adjudicated and site-reported events influencing the overall results of a major clinical trial. It is entirely unclear whether or not ICAC controversy spread beyond PLATO, and impacts other major trials, since most FDA documents lack detailed ICAC descriptions. However, the evidence from PLATO, TRITON and RECORD trials is alarming. Composition of future ICAC should be subjected to public scrutiny, also the differences between site-reported and adjudicated primary events should be mandatory reported for every trial.

We conclude that by adding 45 MIs exclusively to the clopidogrel arm, ICAC turned around the PLATO trial results from neutral to highly significant in favor of ticagrelor. Heavy selection bias in ICAC constituence, lack of independence and the potential involvement of the study sponsor impacted the PLATO outcomes and influenced the regulatory approval of ticagrelor.

Financial & competing interests disclosure

VLS is listed as an inventor, and received compensation for the U.S. Patent Application “Treating Cardiac Arrhythmias, heart failure, peripheral artery disease and stroke with CYCLOPENTYL-TRIAZOLO-PYRIMIDINE or derivative thereof” (USN 61/253,829) assigned to HeartDrug™ Research. He received funding for research studies with clopidogrel, and consultant fees from the clopidogrel and ticagrelor manufacturers. SDF has nothing to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.