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Data disruption: Navigating cardiovascular clinical trial adjudication during a respiratory pandemic

The COVID-19 pandemic disrupted clinical trials across all indications. For trials that persevered, COVID-19 impacted patient enrollment, participation, and data collection. Clinical endpoint adjudication (CEA) and safety monitoring of trial participants were forced to mitigate and account for the influence of COVID-19 on clinical trial endpoints.

CEA is performed by a blinded, independent Clinical Event Committee (CEC), and is used to reduce variability in the interpretation of clinical trial results. Blinded adjudication controls bias when a clinical trial’s safety and efficacy endpoints are made up of clinical events — such as admittance to a hospital due to heart attack. Adjudication also informs safety oversight by the independent data monitoring committee (IDMC), with real-time adjudication of clinical events ensuring the highest quality of safety oversight.

At ICON, the IDMC and Endpoint Adjudication (IDEA) team facilitates both adjudication and safety monitoring for clinical trials. The IDEA team coordinates adjudication for trials overseen by ICON, but it also serves as a standalone partner that collaborates with academic research organisations, other contract research organisations and clinical trial sponsors.

CEA of cardiovascular and respiratory clinical trials were disproportionately impacted by the pandemic, because symptoms associated with participants' underlying cardiovascular or respiratory conditions were difficult or impossible to discern from those of COVID-19. Appropriate adjudication is especially important for the success of cardiovascular and respiratory trials, because their endpoints are frequently clinical events.

Despite the challenges to CEA introduced by COVID-19, ICON has been well-positioned to continue coordinating and managing adjudication of cardiovascular and respiratory clinical trials. The IDEA team of over sixty members has many decades of adjudication experience and 20 clinically trained nurses are specialised in a range of therapeutic areas. In addition, IDEA has established relationships with key opinion and thought leaders around the world. ICON partners with an electronic adjudication vendor to provide an intuitive, end-to-end electronic adjudication system that facilitates real-time reporting, centralised data collection, and an audit trail. In addition, ICON’s experience running 350 studies with home health services prepared them to continue adjudication of clinical trials with a remote, decentralised and hybrid model.

This blog will provide an overview of the disruptions COVID-19 has introduced into cardiovascular clinical trials, and will highlight some of the successful strategies that ICON and collaborators have adopted to mitigate disruptions to endpoint adjudication.

More bias, less data

Study sponsors and sites were forced to navigate myriad disruptions to CEA in order to persevere during the COVID-19 pandemic.

Drops in enrollment, participation and even study closure due to the pandemic affected most clinical trials. Mandatory regional lockdowns and participants’ concern of spreading or contracting COVID-19 contributed to abnormally low enrollment across nearly all clinical trials. In response, some clinical trial sponsors pulled their funding and either temporarily halted or completely shut down their trials. In addition, sites were forced to close because coronary care units were converted into COVID-19 care centres, especially in the US and Brazil. Regardless of whether trials shut down or were ongoing, the clinical research organisation’s obligation to follow up with patients for CEA and safety oversight remained.

COVID-19 made adjudication of clinical events more challenging because the number of cardiovascular and respiratory clinical events rose due to COVID-19, but the cause of those events were less certain, and the proportion of patients who sought care for clinical events declined. As a consequence, both the sensitivity and specificity of adjudication for respiratory and cardiovascular endpoints suffered.

For example, in cases where hospitalisation for a heart attack was a clinical trial endpoint, source documentation needed to be modified to include COVID-19 relevant information and CECs needed to be retrained to identify COVID-19 characteristic heart attacks. Even with the appropriate training and documentation, it was often impossible to determine whether the cause of a heart attack was due to COVID, an underlying condition, or the experimental treatment, an issue which created noise in the study results. Additionally, it is estimated that participants were 20 percent less likely to seek medical care following a heart attack, which contributed to underestimation of total events. At the same time, a 15% mortality rate among trial participants hospitalised with COVID drove up the mortality event rate when the cause of death — COVID-19 or an underlying condition — was unclear.

Missing patients and missing patient data due to COVID-19 further interfered with CEA. Changes in participant behaviour during the pandemic generally made it more difficult to track participants and follow up with those who discontinued treatment. Oftentimes, hospital closures or restrictions prevented staff from accessing source documents and prevented patients from going to the hospital for continued treatment or testing. Missing data points lowered the quality and quantity of data used in CEA. Smaller sample sizes compromised the significance of findings. If data or patients did not go missing at random, it introduced more bias into the analysis. For example, if a disproportionate number of treatment intolerant participants discontinued the study, the existing data would overestimate treatment tolerance during the trial.

To be confident in the findings of a clinical trial conducted during the pandemic, players involved in endpoint adjudication management and continuation had the difficult task of accounting for changing event rates, shifts in participant behaviour, missing data and missing patients due to the pandemic.

With experienced oversight, clinical trials persevered

Conducting cardiovascular clinical trials in COVID-19 conditions required coordinated and intentional efforts to reduce trial bias, increase trial accessibility and increase accommodation of hybrid trials and remote adjudication. ICON relied upon its extensive expertise in clinical trial adjudication, close collaboration with trial sponsors and partners, decentralised electronic adjudication system and digital software to proceed with cardiovascular and respiratory clinical trials during COVID-19.

Improving data quantity and quality

Efforts to prevent or minimise missing data and missing people from clinical trials benefited from flexible study sites and robust communication between the ICON team, partners and clinical research associates. Patients were educated about the importance of follow-up even after discontinuation of the study drug. After initial education during the informed consent process, this information was reinforced during every patient visit.

Impact on CEA during COVID-19 was further reduced by successful efforts to prevent missed visits and follow-up. Barriers to patient participation, such as an inflexible follow-up schedule, limited mobility or local quarantine measures, were proactively identified and resolved wherever possible.

When missing data could not be avoided, it remained crucial to classify the data by the level of bias it introduced into the study. Contact was re-established with participants as early as possible to avoid recall bias. And in scenarios where participants were unreachable, public records, medical records and death records were used to identify the participant and establish vital status.

Post-hoc strategies for addressing missing data during adjudication included demonstrating that information was not censored, ensuring that patients with unknown outcomes were unlikely to have had additional events, and conducting a sensitivity analysis to show that the event rates of patients with missing data could be inflated, while preserving statistical significance of the study.

Improving accessibility and flexibility

The 21 CFR part 11-compliant electronic adjudication system (EAS) utilised by ICON provided decentralised and streamlined access to clinical data, facilitating real-time adjudication despite lockdowns and restricted access to trial sites.

In addition, in-home health services were critical in sustaining clinical trials through COVID-19. ICON’s experience conducting more than 350 decentralised and hybrid clinical trials with Accellacare In Home Services and telemedicine visits allowed for the transition of over 20 in-person studies to hybrid models in response to the pandemic. This strategy was key to retaining participants, which was backed up by the findings of one cardiovascular study: Here, the drop-out rate for onsite patients during COVID-19 was 67 percent, while the dropout rate for home care patients was only 3 percent.

Along with real-time CEA and in-home services, digital health technology helped to streamline data collection and analysis in hybrid clinical trials. Wearables were selected and managed using an end-to-end approach that ensured patient engagement and regulatory compliance. FIRECREST, a digital solution that hosts clinical trial protocol training online, was used to train patients about wearable use. And finally, the ICONIK system which integrates data from multiple sources can generate a compliance dashboard indicating if expected wearable data is present and allowing near real time initiation of corrective action through our direct-to-patient contact unit.

Conclusion

To adapt to the COVID-19 pandemic, endpoint adjudication of cardiovascular and respiratory clinical trials needed to identify and proactively address the impacts of COVID-19 on data collection and analysis. ICON’s combined four decades of experience in adjudication and close collaboration with partners helped cardiovascular and respiratory clinical trial operations to adapt to unprecedented and challenging circumstances. Successful cardiovascular clinical trials that occurred concurrently with COVID-19 also benefited from a decentralised 21 CFR part 11-compliant electronic adjudication system, in-home health services, and the adoption of digital health technologies.  

Watch the webinar to learn more about these strategies or contact us to discuss how we can support your cardiovascular clinical trial.

Webinar: Cardiovascular event adjudication during COVID-19 and beyond

This webinar will discuss best practices for cardiovascular event adjudication across drug and device clinical trials, including advances in connected devices.

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