Clinical adjudication—also known as endpoint or event adjudication—has become a critical part of the clinical research ecosystem. By now, many trials involve outside adjudicators, typically physicians, to validate the sponsor’s interpretation of data and provide an additional layer of unbiased confirmation that regulators may need to approve novel therapies.
FDA is paying close attention to medical devices and employing a premarket approval (PMA) process that is much more rigorous than the traditional 510(k) when a predicate device is not available. For manufacturers of novel and potentially high-risk devices, that means general controls will be insufficient to prove their safety and effectiveness, and stringent scientific documentation will be required to get them to market. This rigor is motivating sponsors of Class III medical device trials to engage experienced, independent third parties to help ensure the meticulous clinical investigation requirements of the PMA application are fulfilled properly and mitigate the risk of delays.
The Clinical Investigations section of the PMA application includes study protocols, safety and effectiveness data, adverse reactions and complications, device failures and replacements, patient information, patient complaints, tabulations of data from all individual subjects, and results of statistical analyses, among other detailed information.
These are all important parameters to assess the impact of a device on disease progression, though clinical endpoints that measure the effect on morbidity and mortality represent the highest standard for patients, providers, and regulatory authorities. The focus on endpoints is the driving force behind the growing engagement of independent adjudicators in these carefully supervised trials.
Benefits of Clinical Adjudication
Compared to drug trials, device trials are typically smaller; difficult to blind, randomize, and control; and depend heavily on physician technique. Perhaps most importantly, the endpoints are highly diverse. Clinical adjudication provides value to these trials by tapping unbiased, highly specialized experts to evaluate a device against preestablished criteria to determine patient safety and clinical efficacy.
Specific issues that frequently arise in device trials that can be addressed by clinical adjudication include:
- Study bias. The study team can be inherently biased because they truly believe in the safety of the device being studied. Despite best intentions, there may also be bias derived from a lack of clinical equipoise among investigators, pressures from institutional quality assurance programs, and financial implications from up-coding events. Engaging independent parties that are not invested in the device or connected to the sponsor eliminate these concerns.
- Inconsistent event definitions. Clinical event/endpoint definitions often don’t match among sites around the world, creating potential discrepancies in how the events are classified and reported. For example, what constitutes a myocardial infarction varies from country to country. This problem is only magnified in large multicenter and increasingly global trials but can be addressed by centralized adjudication, which pre-establishes consistent event definitions.
- Lack of scientific rigor. Clinical event/endpoint adjudication by an independent group of adjudicators ensures the process is carried out with a rigor that can withstand review by various study stakeholders from regulatory bodies to patients.
Manufacturers of medical devices would be wise to adopt independent clinical adjudication sooner rather than later as safety standards are likely to become even more rigorous over time. As the scientific community continues to advance medical device capabilities and inventions, there will only be increasing pressure to get the devices on the market faster. Proving efficacy without causing harm can be guaranteed by a thoughtful and independent clinical adjudication process.