Event adjudication clinical trials

Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers round 1. If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus round 2. Among 16, participants, 48, adverse events were reported, among which were reviewed by the Clinical Endpoint Committee.

After triage, were adjudicated in round 1; required committee consensus in round 2, yielding myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Since definitions for nonfatal events are generally heterogeneous and subjective, one reason for a central process of adjudication is to assist in assuring systematic application of the definition used in the trial. In open-label trials, assuring that the adjudication is done blinded to treatment assignment may provide protection against differential misclassification.

Regulatory authorities, including the FDA, derive confidence in the validity of results when central adjudication is performed. When total mortality is included, subcategories such as CV death and non-CV death infection, cancer, or other organ-specific endpoints are often being evaluated.

Despite the fact that clinical endpoint adjudication has been applied for several decades, the evidence is surprisingly scarce on what endpoint definitions should be used and how to capture the information. Updates and revisions are necessary since the diagnostic tools such as biomarkers and new technology with highly sensitive methods develop with time. The CEA process is believed to enhance the validity of clinical trial CV outcome measures through independent, systematic, and standardized identification, processing, and review of CV events.

However, little is published that critically and consistently reports on the specifics of CEA organization and the process methodology, and there is no gold standard. The CEA charter is the document that regulates all aspects of the study specifics regarding CEA and to which there should be a reference in the study protocol.

The endpoint office EPO collects clinically relevant documents, such as hospital notes, relevant ECGs, lab reports, CT reports, and angiography documentation. The coordinator leads the daily work together with the CEA chair or co-chair. Collection of predefined source documents has always been challenging in large studies with a high number of endpoints.

It used to be paper or fax documents, but with modern technology commercial software is now available that enables the CEA to be carried out completely electronically. The EPO creates PDF files with the relevant endpoint information and submits the package to the reviewers after careful review for completeness Figure 1.

There is no evidence-based scientific evidence on how the flow of events and review process should be handled. However, the most common strategy used in the large global CEA centers is that two independent reviewers evaluate each potential event.

If there is agreement on all aspects, the event is complete. In case of disagreement, a process of resolving this is initiated. Depending on the level of disagreement, it may be a committee meeting with several senior specialists coming to a consensus decision or that the two initial reviewers come to a mutual agreement. Collection of the required source documents should be specified for each type of endpoint.

This should be handled by a query process at each site in the study. When this is completed a package of all documents is created as a PDF file. This also often includes some pre-selected relevant data from the eCRF often called patient profile. During the last few years, registry-based randomized controlled studies RRCT in cardiology have become a new exciting concept in clinical research, using quality improvement registries for prospective randomized trials Such studies are characterized by pragmatism, simple design, and non-complex outcome measures, such as total mortality.

Endpoint detection through the use of public registries as used in RRCTs can be employed in randomized clinical trials instead of the more traditional approach with active screening and central adjudication 10— There are several advantages with endpoint detection through public registries, including a rapid inclusion rate, a more representative all-comer population, as well as substantially lower costs compared to a traditional randomized clinical trial RCT Furthermore, official healthcare registries collect a much larger array of possible outcomes.

However, registry follow-up is largely based on ICD codes that are dependent on the judgement of the local hospital physician and not on a systematic review of study-specific event definitions. ICD codes are often fairly crude and do not catch granularities around an event, such as sub-categories of a death or an MI. The second is the ability to enable process controls and oversight that provide for early warnings about process, CRO and adjudication performance.

Whatever the system, it needs to allow CROs and sponsors alike to trace every aspect of process evolution, from collection, de-identification, dossier aggregation and adjudicator voting to CEC management.

When a single integrated system follows the data from cradle to final outcome, it enables the types of metrics sponsors and regulators have been expecting for years: the ability to evaluate site performance, the capacity to run QC on the adjudication process, and the means to compare individual adjudicators to their peer group within and across protocols.

Finally, with advanced system capabilities enabling fully auditable communications between stakeholders e. This in turn can have enormous benefits not only to patients but sponsors alike. The CEC charter describes all the key activities of the endpoint process. It should include standard operating procedures for the entire process including endpoint definitions, data capture overview, committee workflow and decision-making rules, dossier compilation responsibilities, key stakeholder roles and responsibilities, and in the case of the CEC, a description of CEC member requirements.

It is a critical document that needs input from all stakeholders involved in the process. Endpoint workflow can be complex and involve multiple stakeholders: site investigators; site research personnel; CEC coordinators; translators; adjudicators; site monitors; project managers. Each project may have variations on these key roles. Key personnel should be identified early, and roles specified in the charter.

Careful consideration needs to be given to event definitions. Ideally these need to be as clinically meaningful and also as objective as possible.

With cardiovascular endpoints there are standardized definition documents that can be used as outlines for event definitions. If there are no standardized event definitions,the definitions need carefully drafted to ensure they are not too ambiguous. If an event definition is too ambiguous and open to interpretation it can introduce further variability into the results. Similarly, the components of any definition utilized for a trial should be obtainable for review by the CEC.

For example, since cardiac biomarkers particularly Troponin are central to the FDA-recommended definition of an acute myocardial infarction event, then for trials where acute myocardial infarction AMI is an endpoint of interest, there should be a reasonable expectation that, for most suspected AMI events,relevant biomarker measurements will be available to the adjudicators. Prospective endpoint adjudication is now considered the gold standard in assessing trial progress.

When done correctly, tried and true workflows and event definitions ensure consistency and reproducibility and thus the reliability of final results in clinical trials.

Process matters in endpoint adjudication.