23 CONDITON - Designed for life

Cardiovascular outcomes trials (CVOTs) have become a critical tool in drug development, particularly for blockbuster drugs like GLP-1 receptor agonists.

As long-term trials, CVOTs are essential for assessing a drug’s impact on cardiovascular (CV) health, ensuring safety and meeting regulatory requirements. The withdrawal of drugs like Merck’s Vioxx, approved without specific CV safety studies, highlights their importance.

Beyond safety, CVOTs can support regulatory approval when other endpoints are lacking and can be used to secure reimbursement. However, their cost and complexity demand a strategic approach to design and execution in a landscape that is continuously evolving.

A thoughtful and agile study design is the first step to a successful CVOT. Key considerations include the use of enrichment criteria to select a higher-risk patient population, which can reduce study duration and resource commitment. Emerging tools like polygenic risk scoring may further guide this selection.

Sponsors should consider adaptive designs, which allow for prespecified changes to an ongoing trial, such as adjusting sample size or eligibility criteria, to increase efficiency and save time and money. When a placebo is unethical, such as with established effective treatments, an active control group is essential.

For example: ‘The SURPASS CVOT for tirzepatide in type 2 diabetes with established cardiovascular disease used dulaglutide as an active control.’

For a CVOT to have valid and trustworthy findings, it must be conducted consistently, especially across international sites. Discrepancies, as seen in the TOPCAT study where conflicting regional results cast doubt on the trial’s validity, can compromise the entire study.

It is vital to ensure consistent diagnostic criteria and similar local treatment standards to enable a more direct assessment of the trial drug’s effect. Sponsors must also be aware that long-term studies can suffer from changes in standard of care during the trial, as seen in the SELECT study with semaglutide.

Effective endpoint capture is critical for a CVOT’s success. An independent data monitoring committee and endpoint adjudication committee must be established before the trial begins.

Technology like wearables, ECG patches and digital tools can be used to capture non-traditional data and patient-reported outcomes without overburdening participants.

For specific secondary endpoints like cardiovascular imaging, local validation of onsite facilities, equipment and procedures through a core lab is necessary to ensure data consistency.

Executing a CVOT is a complex logistical challenge with many moving parts. Partnering with an experienced contract research organisation (CRO) can be a strategic move to avoid a costly learning curve, especially with its therapeutic area expertise and pre-established global investigator relationships.

A CRO’s value also lies in supporting agile study teams that can monitor and clean large volumes of data in real time, preventing delays. Patient retention is another key factor for long-term trials. An overly burdensome schedule can lead to drop outs, especially with drugs that have significant side effects.

Sponsors should design flexible and realistic assessment schedules and proactively mitigate logistical barriers to trial participation via leveraging technology like hybrid decentralised models, video calls and home healthcare to reduce site and patient burden.

CVOTs are complex but essential for drug safety, regulatory compliance and demonstrating clinical value. By leveraging strategic study design, ensuring internal consistency and integrating modern technologies, sponsors can optimise their investment, maximise the value of their CVOTs and lay the groundwork for long-term success.

Designed for life

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