BICR Adjudication and EMA: Regulators, what do they think?

Those of us who manage clinical trials with complex endpoints have elaborated a certain way of thinking. We jump to create charters, define processes, contact experts as soon as the study outline is agreed. But let’s not forget why we do all this. In the vast majority of cases, the studies are intended for a regulatory submission seeking marketing authorization for our drugs. So, what do EMA regulators think about endpoint adjudication?

The EMA represents 28 countries with a total population of 513 million people.

The European Medicines Agency's scientific guidelines on the quality of human medicines help applicants prepare marketing authorization applications. Guidelines reflect a harmonized approach of the EU Member States and the Agency on how to interpret and apply the requirements for the demonstration of quality, safety and efficacy set out in the Community directives.

The EMA tends to employ more direct language than the US FDA: “The Agency strongly encourages applicants and marketing authorization holders to follow these guidelines. Applicants need to justify deviations from guidelines fully in their applications at the time of submission. Before that, they should seek scientific advice, to discuss any proposed deviations during medicine development.”

Several guidelines discuss the use of event adjudication, in particular in cardiovascular diseases, diabetes and cancer:

In particular the diagnosis of refractory angina pectoris but also that of myocardial infarction are subject to considerable inter-individual variability of the treating physicians/investigators. Since the key issue is to get unbiased event documentation, it is strongly recommended to establish blinded event adjudication committees for the additional verification of these events in the pivotal clinical trials (1). 

In clinical studies where endpoints are complex to assess and/or include subjective components or the study cannot be blinded, an Endpoint Adjudication Committee, consisting of clinical experts in a specific clinical area, might be set up to harmonize and standardize endpoint assessment. In order to allow for an unbiased endpoint assessment, the members of such a committee should be blinded to treatment assignment. Event Adjudication Committees are, for example, widely used in the assessment of radiological endpoints.(2) 

The safety evaluation should include a prospective definition of adverse events, particularly cardiovascular safety outcomes of interest that is common for all phase II-III studies, facilitating pooled analysis strategies. Furthermore, applicants should foresee a consistent central adjudication system for blinded assessment of all predefined CV and other adverse events of interest during the phase II-III program. A detailed statistical analysis plan for the pooled CV safety data should be prospectively designed. 

One strategy to try to detect and reduce ... bias is to conduct a complete Blinded independent central review (BICR) of all relevant data for all patients. This strategy is recommended when important investigator bias is expected or in case of moderate expected treatment size of effect. BICR will be more meaningful in situations where the majority of events will be captured based on imaging as opposed to clinical progression. 

In conclusion the EMA strongly recommends the establishment and use if independent adjudication committees for complex endpoint assessment.

Read Also this Blog Article: CEC Adjudication: Regulators, what do they think? #1: FDA and our Endpoint Adjudication Regulatory summary page

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