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International Clinical Trials

Easier with ePRO

Protocol compliance is vital to the success of clinical trials. Having spent considerable time and money planning who can participate and what metrics will be tracked, sponsors can ill afford for poor compliance to affect data quality. Simply telling patients and sites to comply is not enough – it needs to be made easy, which is where mobile technology can help.

Sponsors can only feel confident that a trial has generated data of the highest quality when their protocols are followed precisely. If a study falls short of this ideal, the sponsor risks having data that fails to meet the needs of regulatory authorities. At best, such an outcome necessitates the running of further trials, adding to the development budget and moving back the date on which the product can begin to deliver a return on investment. At worst, it can see a project abandoned. Yet, despite its importance, ever more complex designs have made protocol compliance harder in recent years.

Protocol Complexity

Tufts Center for the Study of Drug Development (CSDD) found that, during 2000-2003, the median number of unique procedures per protocol across all therapeutic areas and phases of development was 20.5. By 2008-2011, the figure had increased by almost 50% to 30.4. Comparable increases were seen in the total number of procedures, which jumped by 57% over the decade to reach 166.6 by 2008-2011. The surge in protocol complexity had a knock-on effect on total investigative site work burden. Tufts CSDD calculated that the median units of work rose by 64% over the analysed period.

This picture is inversely correlated to some worrying figures for sponsors. According to Tufts CSDD, the screen-to-complete ratio was 52% during 1999-2002. Over the next three years, up to 2006, the ratio fell to 28%. The rise in complexity of protocols and number of eligibility criteria is one explanation for the increase in the proportion of people who wanted to take part in clinical research but were unable to. Similarly, the US Institute of Medicine thinks the burdens faced by research sites contribute to many investigators dropping out after just one trial.

Ultimately, it is in everyone’s interest to remove unnecessary barriers to patient and investigator participation in research, and ensure both groups remain motivated and compliant once involved in a study. Sponsors – a group that stands to benefit immeasurably if the efficiency and quality of research improves – need something to offset protocol complexity and tip the balance in favour of compliance. Mobile electronic patient-reported outcomes (ePRO) can be that something.

Patient Compliance

The benefits of mobile ePRO for all stakeholders start with the interaction between patients and the devices. Compliance issues arise, in part because trials impose new tasks onto existing routines. While all patients enter a trial with the intention of performing these tasks and complying with the protocol, as the weeks pass the likelihood of remembering to do so in a timely manner diminishes. A paper co-authored by Phil Skolnick of the US National Institutes of Health and published in the journal Molecular Interventions in 2011 cited data from two studies to illustrate the rate of non-compliance.

In the first, a Phase 1b trial of the antidepressant, amitifadine, 30% of subjects failed to meet the threshold for compliance. The threshold was the detection of any level of the drug or its metabolite in at least three out of the four blood tests taken over an eight-week period. Compliance in the second, a Phase 3 study of bicifadine, fell from 67.5% at its peak to 53.6% by week 12. As such, the final datasets in the trials were skewed by the fact that only a subset of patients in each study were taking the medication as dictated by the protocol.

Mobile ePRO is proven to help in this regard. A paper published in the International Journal of Medical Informatics in 2011 found that diabetics who received a daily reminder via SMS text message failed to take their medication 15% of the time, compared to 19% for the control arm. The difference was even more pronounced when the timeliness of the dosing was considered, with significantly more patients who received reminders taking their treatment within a predefined one-hour window. The opportunity to build educational content and reminders through SMS or in-app notifications enables mobile ePRO to encourage such compliance, while keeping patients motivated to stay in the trial.

Reminders are also effective in ensuring participants complete patient-reported outcomes (PRO) forms on time and attend site visits. In a post-marketing cardiovascular outcomes study, the use of mobile ePRO saw site visit compliance rise by 5% and the drop-out rate fall by 4.5% for the subset using this approach. When scaled across the full 13,000-person study, the improvements would have cut four months and $14 million from the trial. Similarly, reminders can increase the likelihood of a PRO form being completed on time. Importantly, time-stamping of the PRO means the sponsor and site know the patient is compliant.

Removing Burdens

The time-stamping of PRO forms is one of the ways in which mobile devices can help investigators to monitor compliance with the protocol. Mobile ePRO can give investigators access to this information in real-time. If a patient is non-compliant with PRO aspects of the protocol, the technology will alert the investigator. Having access to such real-time data allows investigators to adopt a targeted, risk-based approach to their attempts to keep patients in the trial and compliant with the protocol. Consequently, they can allocate their finite amounts of time and resources more efficiently.

With mobile ePRO driving improved compliance among patients, a smaller proportion of participants require such attention. This is just one of the ways in which the patient-focused benefits of mobile ePRO resonate with sites and investigators. For example, the use of mobile ePRO to alert patients about upcoming site visits, and how they should prepare, frees investigators from the burden of sending reminders and helps ensure patients attend during their allotted appointment time, having completed any preparation appropriately.

Mobile ePRO can take on other patient-support tasks as well. Instead of site staff going through the diary completion process with each patient, the app itself can include training features and prompts to give instructions on what they need to do and when. Freed from this education task, site staff can focus on the humanistic aspects of their jobs, such as building relationships with patients.

Why Sponsors Need ePRO

All of the benefits realised by patients and investigators are felt by sponsors. Compliant patients and sites generate high-quality data in which sponsors and regulators can have confidence. In the field of PRO, such confidence is new. Traditionally, paper diaries enabled patients to complete forms in the car park just before their site visit, but claim they filled it in at the time. The entry of erroneous data and illegibility of handwriting are problems, too. In moving from paper diaries to mobile ePRO, sponsors gain built-in safeguards against these shortcomings that reduce confidence in the data.

Real-time data also offers advantages. Just as mobile ePRO helps investigators to support the patients who need it most, the technology allows sponsors to focus their resources on sites that require extra help. Clinical research associates (CRAs) have access to real-time data on the activities of site staff, giving them an overview of whether they are complying with their contracts. When CRAs identify a site that appears to be struggling to comply, they can step in to offer extra training and support – potentially preventing an adherence issue before it arises.

Responsive Designs

Furthermore, the real-time data supports more flexible, responsive study designs. In a flu trial, for example, a sponsor can triage patients from weekly to daily diary entries when they record certain symptoms. Being able to make this switch immediately, instead of after the patient visits the site, means the sponsor starts gathering daily data as soon as it becomes of interest. With paper forms, sponsors would miss out on all the daily data between a patient recording the symptom and visiting the site. Equally, such remote oversight reduces the burden on patients by cutting the number of site visits.

In doing so, sponsors can make it even easier for patients to comply with the protocol and reduce the burden on investigative sites. Equipped with mobile ePRO and the real-time data it generates, the burdens and compliance challenges that were, until recently, viewed as an inherent problem in clinical trials can be diminished. There is always a need to be vigilant about protocol compliance – mobile ePRO is making such vigilance easier.

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As Vice President of Operations, Laurence Burke leads the global operations teams at Exco InTouch and is responsible for ensuring the effective delivery of all customer-driven projects. With almost 25 years of experience in clinical research and IT service provision, he is able to utilise a background in project management and Lean Six Sigma to direct an operations strategy for the business that supports the needs of patients and sponsors in clinical studies. Email:
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