When experts disagree, it is not always easy to know who is right or even if anyone is right. In the academic world debate and disagreement feed the science and many times new ideas emerge from debate and break barriers that seemed solid up to that point. But in a clinical trial there is little room for “constructive debate”.
Imagine that you are working on a complex global clinical trial on a heavy life-threatening disease with a lot of expected adverse events, complicated dosing procedures, different therapeutic options in order to preserve patients’ survival and quality of life and set to go on for several years.
In addition to the usual interactive voice randomization system (IVRS), electronic data capture (EDC), clinical trial tracking system (CTMS), risk-based monitoring (RBM) system, central laboratory services (CLS) and electronic trial master file (eTMF), the company was asked by the regulators to establish a data safety monitoring committee (DSMB) and to adjudicate the most complex endpoints by an independent adjudication committee (CEC) of experts.
You have struggled for months to prepare the protocol, write the committee charters, the patient information and consent forms (ICF), translated in several languages most of which you do not speak and adapted to the legislation of many countries, obtain ethics committee (EC)/ independent review board (IRB) approvals, identify sites, sign contracts, train investigators and staff, train DSMB and EA committee members, obtain the necessary blinded supply of investigational drug, write and submit for approval one or two amendments to the protocol and at last the first patients were enrolled and data starts to poor in. Does that sound familiar so far?
As the adjudication coordinator you must oversee the extraction of source data from the sites, ensure translation and blinding and follow up on the assessment by some highly specialized experts. And now you start seeing an unusually high rate of disagreements.
Are these due to insufficient information, unclear instructions, inadequate training, changing medical knowledge or just the personality of the reviewers?
Depending on the root cause you may be able to correct the origin of the disagreements or not. A good knowledge of the intra-variability may prove valuable for understanding the origins of the issue.
If a particular reviewer is showing a high variability in his or her judgment then they may need to refresh their training, if on the other hand the discrepancy is repeatedly among the same two reviewers maybe a consensus meeting is the best approach.
Most of the time, a high rate of disagreement indicates an underlying cause that can be easily corrected and in all cases the disagreement must be quickly resolved either with help from the chairperson or via a consensus meeting.
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