Using a novel trial design, GlaxoSmithKline (GSK) has conducted a study in Salford, U.K., using real-world data in patients with chronic obstructive pulmonary disease (COPD). The study used an electronic data-monitoring system to notify physicians immediately of any adverse events. The phase IIIb, open-label, randomized controlled trial (RCT) of Relvar lasted four years and enrolled almost any patient with COPD who wanted to participate, without the limitations on age and health status commonly placed on medication trials. Indeed, over one-half of the patients in Salford with COPD were recruited into the trial, which included 2,800 patients across 80 general practices.

Relvar is a combination of an inhaled glucocorticoid and a long-acting beta-2 agonist (fluticasone furoate and vilanterol). The medication, with its Ellipta delivery system, was approved by the FDA in 2013 for the treatment of COPD and in 2015 for asthma. It is sold in the U.S. under the trade name Breo.

“This recruitment rate allows conclusions to be drawn for the ‘real life’ situation,” said Janos Porszasz, M.D., Ph.D., director of the Pulmonary and Exercise Physiology Laboratory, Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.

“The fact that the study was initiated pre-license is one of the many factors that makes the Salford Lung Study (SLS) unique,” said David Leather, M.D., medical vice president of GSK Respiratory Franchise.

In the SLS, patients were followed under everyday conditions, even if they discontinued Relvar mid-trial. If a physician determined that another medication would better serve the patient, they were able to make the switch without dropping the patient from the study. In a departure from the typical clinical trial protocol, patients were not monitored to determine whether they took the drug exactly as prescribed. Rather, they were allowed to forget doses and fail to follow instructions. They were allowed to have comorbidities, and their preferences were taken into account, hence the “real life” moniker.

Only 7% of patients dropped out, versus the 20% to 30% typically seen in a more traditional double-blind, randomized trial. Relvar was tested against the patient’s usual care, rather than a placebo or a standardized treatment, and patients were treated by their own physicians. Acute symptoms were reduced by approximately 8%, a result that GSK attributes to the more patient-friendly, once-daily dosing of Relvar. However, there was no reduction in the number of hospital or physician visits.

The significance of this trial, however, is not so much the improvement in patient symptoms as the structure of the trial itself. The electronic database linked patients’ primary- and secondary-care records and was updated every 24 hours. If a patient saw their general practitioner or was seen in the emergency department or hospitalized, the study researchers were notified and were able to review the records right away to determine whether the activity represented a COPD exacerbation. Prescription and blood test results were also incorporated into the database. Dr. Leather emphasized, “The safety alerting system was more robust than that of a standard RCT because every serious adverse event was reported in real time with study-team access to the patient’s entire medical record.”

Dr. Porszasz did note that “this type of ‘population’-based clinical trial falls short of specific physiological outcomes. ... Importantly, these trials are again not mechanistic or even efficiency trials, but ‘patient-centered outcomes’.”

As exciting as the pioneering study design is, implementing this type of trial in the U.S. may also be problematic. Dr. Porszasz said, “I think that the approach can and could be used in the U.S.; however, I see certain problems. One of these is the general availability of electronic medical records (EMR) and the potential incompatibilities that could pose information technology barriers. ... Such a population-based trial would require full compatibility among the different EMR platforms. Secondly, the regulations may not allow access to these hospital-based—or even medical practice-based—EMRs simply because of the very strong regulations about HIPAA.” Another question is how this might fit into the recent congressional act aiming to make the data requirements less rigid for new indications for drugs already approved in the U.S.

According to Dr. Leather, “The study would seem to be generally aligned with the broad principles of the 21st Century Cures Act, but there are no specifics to date.”

Dr. Leather said, “GSK is the only company to have carried out a study of this kind, which has been done in response to the external world’s request [prescribers, payers and regulators] to see meaningful evidence of effectiveness and benefit/risk as early as possible.

The study aims to provide relevant and important information for clinicians, healthcare providers, payers and patients on the effectiveness and the true value of a medicine in an everyday clinical setting. We hope that the data generated by effectiveness studies, like SLS, will add to the existing data sets generated by the traditional clinical trials. There will always be a need for both types of trials to understand the efficacy of a medicine in a controlled environment, but then to also understand the effectiveness of the medicine in the real world with real patients that general practitioners see every day.”

Dr. Leather continued, “The need for data in a more representative population that reproduces everyday clinical practice is increasingly being recognized as an important complement to the traditional efficacy RCTs in order to further inform the benefit/risk profile and therefore the value of a medicine.”

Dr. Porszasz concurred. He said, “I feel strongly that the classical trial designs (phase I-III) are needed; maybe phase IV trials could be targeted by this approach. Even more so, any new medication or therapeutic approach/procedure should be supported by the results gained from this type of ‘population-based’ trial.

“The SLS by GSK is a pioneering approach in clinical trials. ... All in all, I see a potential in the U.S. of conducting ‘population-based’ studies with a rather restricted—but important—outcome arsenal.”

This article was reprinted from Volume 21, Issue 09, of CWWeekly, a leading clinical research industry newsletter providing expanded analysis on breaking news, study leads, trial results and more. Subscribe »