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Leveraging RWD can lessen the strain normally put on investigators and sites.
Extension studies, or ‘rollover studies’ conducted after RCTs, allow clinical trial patients to ‘roll-over’ into a longer term follow-up study, where researchers continue to observe and measure long term safety, tolerability, and/or effectiveness.Extension studies provide insight into the long-term benefits and risks associated with products, though they can be difficult to develop and costly to carry out. However, the growing use of real-world data (RWD) has helped to offer lighter touch approaches to follow up. By designing extension studies that leverage RWD and/or direct to patient follow-up, it is possible to measure outcomes with less burden on investigators and sites.
The key to generating real-world evidence (RWE) on long-term safety and effectiveness in extension studies is to ensure that critical information from the parent study is captured and integrated with the study data for the extension study and approaches to minimize burden on investigators and sites are employed. Some methodologies include:
To design an extension study to measure long-term safety and effectiveness, researchers should start by defining objectives and stakeholder requirements. From there, they can outline steps to follow, such as:
For an extension study to deliver accurate analysis, it must reflect a clear timeline starting with the date a patient is randomized into the parent clinical trial and then following the patient throughout extension follow-up. Other key data points that need to be captured from the clinical trial and used for the extension study include the date of diagnosis, treatment assignment, baseline demographic and clinical information, and outcomes of interest throughout the clinical trial. Changes in the treatment regime or discontinuation should also be on the record, as well as patient death or the end of the study period and the reason for it.
To gather meaningful follow-up data, all trial patients should be eligible to rollover into the extension study. Avoid including only patients who responded positively during the parent trial. This selection bias leads to skewed results that favor the product and are not necessarily reflective of the true longer term outcomes. Researchers can provide information on the absolute number of clinical trial patients enrolling in the extension study compared to the number who participated in the parent trials. They can also include descriptions and response outcomes of those who did and did not enroll to understand the extent to which this bias may be a concern.
To generate comparable results from the data collected in an extension study, include a control group for the comparison. An internal control arm may not always be possible, and can be challenging when the extension study includes more than one parent trial. In some instances, researchers might benefit from using external (or historical) controls based on RWD.
Researchers should measure objective, hard outcomes that can be easily measured over longer periods of time and verified using health records. Often, trial outcomes may be measured or recorded differently from the post-trial outcomes recorded in RWD, such as hospital or clinic charts, insurance billing records, or EHRs.
There are many reasons why researchers lose access to patients during follow-up extension studies, including dropout because of a lack of response to the treatment or a change in insurance companies. A high dropout rate can compromise the findings of the study. One way to combat this is with a hybrid approach, linking data sources such as the National Death Index with other health databases, and combining this with annual check-ins via telehealth or digital communications.
Extension studies are complex and take a concerted effort to design and implement. Start planning early to ensure a smoother transition to the extension study after the trial ends and obtain advanced consent from trial participants on issues such as:
Since most RCTs have a global focus, it is vital to use simple, standardized data collection methods to account for different time zones.
The use of RWD ultimately offers a solution to the many barriers that have historically arisen in the execution of extension studies, such as time, cost, and access to patients. As these challenges are diminished, RWD simultaneously allows researchers to garner more comprehensive understanding of long term risks and benefits. By developing a hybrid approach to data collection that optimizes use of related studies, researchers can ultimately support improved delivery of safe and high-performing medical products that drive better patient health outcomes.
Jennifer Christian, PharmD, PhD, VP of Clinical Evidence and Epidemiology, IQVIA