Monday, March 18, 2019

Adjudication Committee (AC), Endpoint Adjudication Committee (EAC), Clinical Endpoint Committee (CEC)

The clinical trials are getting bigger and more complicated these days. For typical multi-national, multi-center pivotal clinical trials, there will be a lot of committees formed: steering committee (SC), data monitoring committee (DMC), central reader, and adjudication committee, each with specific responsibilities.

Adjudication committee (AC) may also be called endpoint adjudication committee (EAC) or clinical endpoint committee (CEC) and are usually needed when the study endpoints are subjective measures.

What is the Adjudication Committee?

Adjudication committee is an independent group of experts that reviews clinical trial data in order to give expert opinions about clinical safety or efficacy events of interest.

According to the FDA’s Guidance for Industry “Establishment and Operation of Clinical Trial Data Monitoring Committees “, the adjudication committee is mentioned the following:
3.3. Endpoint Assessment/Adjudication Committees Sponsors may also choose to establish an endpoint assessment/adjudication committee (these may also be known as clinical events committees) in certain trials to review important endpoints reported by trial investigators to determine whether the endpoints meet protocol-specified criteria. Information reviewed on each presumptive endpoint may include laboratory, pathology and/or imaging data, autopsy reports, physical descriptions, and any other data deemed relevant. These committees are typically masked to the assigned study arm when performing their assessments regardless of whether the trial itself is conducted in a blinded manner. Such committees are particularly valuable when endpoints are subjective and/or require the application of a complex definition, and when the intervention is not delivered in a blinded fashion. Although such committees do not share responsibility with DMCs for evaluating interim comparisons, their assessments (if performed at frequent intervals throughout the trial with results incorporated into the database in a timely manner) help to ensure that the data reviewed by DMCs are as accurate and free of bias as possible.
Which Clinical Trials Need a Clinical Endpoint Adjudication Committee?

Increasingly, regulatory authorities are placing significant focus on clinical trial processes that ensure consistent, standardized, objective and unbiased reporting of safety and efficacy results; given that the definitions for many endpoint events include subjective components, and investigator-to-investigator subjective assessments may differ. Moreover, an increasing number of trials are now conducted in multiple geographies, and clinical practices across these settings can vary substantially. The likelihood of discrepant interpretations of safety and efficacy endpoints by investigators is thus increased.

Throughout a clinical trial, therefore, it is expected by regulatory agencies that certain events that form safety or efficacy endpoints for the study undergo centralized adjudication by a clinical endpoint adjudication committee (CEC).

A CEC consists of a panel of independent experts who have the relevant therapeutic area expertise, are experienced in clinical trials and have been trained on the specific study protocol. The CEC centrally reviews subject/event data and classifies efficacy and/or safety endpoints in a blinded and unbiased manner. The centralized adjudication process should be designed to both preserve the independence of the CEC and prevent any undue bias that could impact its decision-making processes.

A CEC can be used in any therapeutic area where there is a need for an independent, accurate, consistent and standardized assessment of important study events. CECs are most commonly used in cardiovascular outcome / safety studies; however, they are also frequently used in peripheral vascular disease, neurovascular, respiratory and oncology studies.

In some disease areas, the adjudication of the clinical endpoint is expected or even required by the regulatory agencies.

The study endpoint adjudicated by a central committee will be more reliable and is viewed as more credible.

Examples of Clinical Endpoints that Requires Adjudication

In Cardiovascular outcomes studies, a Major Adverse Cardiac Events (MACE) composite endpoint is often used as the primary endpoint for evaluating the efficacy and/ or safety. MACE is comprised of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death. Once events are confirmed through centralised adjudication to meet protocol endpoint criteria, endpoint data is analysed for the number of occurrences of the composite endpoint in the respective treatment groups.

In the Cardio-Pulmonary field, the clinical trials in pulmonary arterial hypertension with composite morbidity/mortality endpoint will require the adjudication. European Medicines Agency (EMA) has a specific guideline “GUIDELINE ON THE CLINICAL INVESTIGATIONS OF MEDICINAL PRODUCTS FOR THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION” where a composite endpoint of clinical worsening can be used as a valid primary efficacy endpoint for establishing the efficacy.
The investigation of a composite primary endpoint that reflects, in addition to mortality, time to clinical worsening is encouraged. The composition of this composite endpoint may vary depending on the severity and the aetiology of the disease. The following components are suggested:
1. All-cause death.
2. Time to non-planned PAH-related hospitalization.
3. Time to PAH-related deterioration identified by at least one of the following parameters:
i. increase in WHO FC;
ii. deterioration in exercise testing
iii. signs or symptoms of right-sided heart failure
Any chosen parameter should be clinically relevant, adequately defined, well validated and centrally adjudicated by a blinded adjudication committee.
In oncology studies, the RECIST criteria are used to evaluate if the solid tumor has responded to the treatment. If the response rate is the primary efficacy endpoint, it is usually expected that a central reader facility will be used to review the images centrally to assess the treatment response. The central reader process is like the adjudication process. Here are some discussions about the adjudication in oncology trials.

Who are the Adjudicators in the Adjudication Committee?

Adjudication committee is an independent group of experts that reviews clinical trial data in order to give expert opinions about clinical safety or efficacy events of interest.

They are usually the expert in the academic setting. As an independent adjudicator, they cannot be the investigator for the study and cannot serve in other committees (such steering committee and data monitoring committee).

Will the Adjudication Committee be Blinded to the Treatment Assignment?

For double-blinded studies, the adjudication committee members are always blinded to the treatment assignment so that the adjudication is unbiased.

For open-label studies, the adjudication process can still be kept blinded.

What are the Regulatory Requirements for Adjudication Process?

For a study with endpoint adjudication committee, the source data for the primary efficacy endpoint analysis will be based on the adjudicated results – therefore, it is critical to ensure that the adjudication process is adequate, valid, and unbiased.

FDA emphases the importance of the adequate adjudication process in its document “The Use of Clinical Source Data in the Review of Marketing Applications”. In many cases, the adjudication process may be audited by the FDA.
Although many types of clinical source data require minimal or no interpretation after collection (e.g., blood pressure, cholesterol, or other discrete laboratory values), other clinical source data types require detailed interpretation by expert clinicians to assign endpoint values (i.e., endpoint adjudication (e.g., examination of radiographic images to measure tumor size, or examination of hospital records or accumulated data to determine whether a myocardial infarction has occurred)). How the applicant evaluates these source data can critically affect the reported results of the trial. In most cases, it would be expected that such interpretations are made blindly, whether conducted by investigators or special assessment groups (e.g., endpoint assessment committees (EACs)). It is equally critical that there be well-described, prospectively defined, evaluation criteria. In some cases, inspection of the clinical source data by clinical review staff may be necessary to establish the reliability of the data in the CRFs and CRTs for FDA review.
However, the processes used to inspect these source data can themselves pose challenges.
Evaluation of clinical source data is often subjective and, depending on the procedures used, susceptible to bias that could affect both the values of clinical endpoints and the results of efficacy and safety analyses. An FDA audit that reveals deficiencies in endpoint adjudication may trigger the need for additional evaluation of the clinical source data, but the audit itself could be biased. Therefore, just as an applicant’s methods of adjudicating endpoints should be well-defined a priori and free of bias, FDA inspection of such data also should use well-specified audit procedures, generally blinded as to treatment assignment, agreed to before the audit to minimize bias.
On-site inspections related to endpoint adjudication may be warranted under certain circumstances. For example, review of some NDAs may raise questions as to whether proper procedures were followed on endpoint adjudication. Other examples include when re-adjudication requires special equipment only available at the clinical site to access the clinical source data, or when on-site visits are necessary to retrieve clinical source data for re-adjudication. 
If the audit determines that the data in the CRFs and CRTs are not reliable enough for review because of deficiencies in the applicant’s endpoint adjudication process, or in the quality of the actual source data itself, clinical review staff may conclude that a re-adjudication of the endpoints is necessary. Clinical review staff should establish acceptable re-adjudication procedures with the applicant, and the applicant is, in most instances, expected to conduct the re-adjudication and the appropriate reanalysis. Instances in which clinical review staff conduct the re-adjudication itself, excluding the applicant, should be rare and well-justified

Adjudication Committee Charter

A critical document for the adjudication process is the adjudication committee charter. The charter will define the composition of the committee, responsibilities of the adjudication committee, the adjudication process/flowchart, the size of the adjudication committee, …

What is the Typical Adjudication Process?

A good whitepaper by Quintiles (now IQVIA) described the best practice for adjudication committee.

In the studies with the adjudication process that I was involved, a consensus adjudication process was employed. With a consensus adjudication process, the adjudicators must reach a consensus regarding the endpoint. Suppose we have three adjudicators; the case will be assigned to two independent adjudicators. If two independent adjudicators give the same assessment, the event is considered adjudicated. If two independent adjudicators disagree with the assessment, the event will be sent to the third adjudicator. The third adjudicator must agree with one of the initial adjudicators to close the case.

In some cases, the third adjudicator don’t agree with either of two adjudicators, a meeting may be needed to discuss the case and reach the consensus.

Will a Separate Electronic System be Needed for Adjudication Process?

Yes, usually a separate electronic system will be needed for the adjudication process. The adjudication system will be independent of the electronic data capture (EDC) system that is for collecting the clinical data.

Further Readings: