Key Learnings from Running an Extension Study to a Real-World Effectiveness Trial: The Extended Salford Lung Study

The Ext-SLS study promised to deliver a unique dataset for the understanding of chronic respiratory disease. Ultimately, 53% of GP sites from the original SLS agreed to participate, representing 64% (4158) of the patients who completed the original SLS. The final cohort included 1147 patients (798 asthma, 349 COPD)—approximately 40% of invited patients, but only 18% of patients completing the SLS.

Although the Ext-SLS research cohort comprises only 18% of the patients who completed the SLS, the longitudinal dataset is unique, with historic and ongoing data collection. The dataset combines trial data, primary and secondary care EHRs with self-reported questionnaire data, to provide researchers with a tool to better understand patient disease journeys with asthma and COPD and the effects of treatment in a real-world setting.

Here, we discuss the key challenges we encountered during the set-up of the Ext-SLS and share learnings for future pragmatic trials and extension studies (Table 1).

One of the biggest obstacles we faced was the introduction of new data protection legislation during study set-up; ultimately affecting GP site recruitment, delaying patient recruitment by months and complicating the application for secondary care EHRs from NHS Digital. The European General Data Protection Regulation (GDPR) was widely publicised in the time leading up to its introduction and GPs were concerned about the implications that this had for their participation in studies using patient data. There was uncertainty around how to comply with the new regulations and for many GPs, the safest option was not to take part in this study. Although not all of the 35 GP sites declined to participate in the Ext-SLS for this reason, future extension studies should consider upcoming legislation that might affect participation in a trial during the design of the study.

An unanticipated consequence of the new legislation was the need to alter key study documents, including patient consent forms and information leaflets, once GDPR had come into effect. This led to significant delays negotiating the required changes with the sponsor, the Ethics Committee and the Health Research Authority. Compounded by the fact that the extension study had not been planned as part of the original SLS, these delays meant there was at least 12 months between the SLS ending and Ext-SLS site recruitment, and 18–24 months between GPs receiving invitations to participate in the Ext-SLS and consent packs being mailed out. These extended periods of time may have contributed to the attrition of GP practices. Had an extension study been planned as part of the original SLS, some of these delays could have been avoided; however, GDPR was a notable factor hampering the distribution of invitations.

The arrival of GDPR also complicated the already extensive process of applying for data from NHS Digital. Obtaining linked secondary care data was a lengthy process, further hampered by the prioritisation of COVID-19-related data requests above others. HES data were approved for use in the Ext-SLS in January 2021 and are expected to be available in May 2021, following the application process begun in 2017. In general, we would not recommend direct data procurement of secondary care data in this way under the current application process.

A second challenge we faced with site recruitment potentially stemmed from perceptions of the GP workload associated with the Ext-SLS. During the original SLS, GPs received support from the research nurse network which was crucial in allowing them to participate while minimising the impact on their usual work [17]. However, by the time invitations for the Ext-SLS were sent, the SLS support team had been largely de-mobilised and this may have impacted whether GPs decided to participate. GPs are known to have a high workload of NHS tasks [18] and the additional work of research may have been too much for many practices. To mitigate this, the Ext-SLS was designed to be ‘light-touch’ from the perspective of GPs, utilising third-party assistance and EHRs for data collection and patient identification; successfully demonstrating this approach was key to recruitment.

Another hurdle during the set-up of the Ext-SLS was in providing lists of potentially eligible patients for GPs to triage. The primary difficulty in identifying patients was that after completion of the SLS, flags in patient EHRs held by GP sites that identified individuals as SLS participants were removed, making it impossible to generate patient lists from the local integrated Digital Care Records alone. A total of 1055 patients (16% of the original SLS cohort) were excluded from the lists because they could not be positively identified as SLS patients, either because the patients did not have sufficient trial data available for matching or because they had died or moved to a new GP practice. Whilst eligible patients could have been identified if GPs were asked to search their archived paper records, this would have been very labour-intensive and against the ‘light-touch’ nature of the study. To overcome this hurdle, we developed a ‘key’ that could link SLS identifiers to individual patients using non-sensitive data from the SLS, an approach that was validated with the pilot study conducted at two GP sites. Nonetheless, failure of patient identification (including for death) remained a point of attrition and this highlights the need to consider extension studies when planning RCTs. This is particularly relevant when the subjects in the ‘parent’ study are elderly and at increased risk of death, e.g. mortality rate among patients with COPD is high (with estimates from one Dutch population-based study ranging from 41.9 to 249.9 per 1000 patient years depending on disease severity [19]). Movement of patients from their original GP practice also presented a challenge to patient identification as their record did not match that of the SLS.

An additional technical difficulty, related to the investigation of an initially unlicensed product in the SLS, was that the patient records did not necessarily contain details of the prescription of FF/VI. These prescriptions were entered as free text which was not included in data collection as it may have contained sensitive information. As such, patients from the FF/VI arm of the SLS could not be identified by their prescription record.

Beyond the challenges of recruiting participants to the study, the collection and handling of data from EHRs also proved difficult. By their very nature, real-world data are designed to record routine care and are hard to standardise for the purposes of research, even with schemes in place such as the Quality Outcomes Framework, which incentivises GPs to provide improved care, measured by consistent recording of clinical data in EHRs [20]. Additionally, GP practices are not research-ready organisations and data are not always entered with research in mind. Using a small sample in a PoC study, we were able to assess and refine our approach and this streamlined the remainder of the study. We strongly recommend including a PoC step in future studies. New systems are being implemented that will make data entry easier for GPs through the use of artificial intelligence to assign coding structures to free-text inputs, which should help improve the availability of data to research [21].

At first glance, extending a community-based pragmatic trial seems a relatively easy and straightforward task; however, setting up the Ext-SLS was challenging and technically difficult. The early decision to limit the access of data in the SLS to 4 years was a decision taken to drive success in the SLS. Future investigators undertaking pragmatic randomised trials using routinely available EHR data should carefully assess the benefits and risks of continued data collection beyond the interventional period. Nonetheless, developing an EHR-based trial extension to the SLS was achieved and consent rates were reasonable. We found that implementing EHR technology to reduce the burden on busy GPs may have helped to facilitate their participation. Direct collection of primary care data to avoid electronic case report forms was possible, but secondary care data could not be accessed in a timely manner. In future, initiation of extension studies prior to ‘parent’ study close-out may help in reducing patient attrition.

In summary, studies like the Ext-SLS are not without their challenges. However, with careful design, they can be a valuable source of patient-level, disease-specific data. The Ext-SLS comprises an extremely well-characterised cohort which includes data from a randomised clinical trial in its timeline. Furthermore, the Ext-SLS captured data not routinely collected in healthcare records alongside data from primary care; the coming addition of prospective data will further enhance the dataset and cement the Ext-SLS as an important source of patient-level information on chronic respiratory disease.