Turn the page – electronic PROs

A frustrating psychological condition has been cropping up in clinical studies, misleading investigators and posing a threat to the reliability of pharmaceutical research for a number of years.

Some may refer to the state as mere absent-mindedness, but experts in the field will know it by a more colloquial, distinctly American, name. 'Parking lot syndrome' occurs when patients enrolled in studies fail to complete their symptom questionnaires at the times required. Instead, they retrospectively fill in days or weeks worth of diaries just prior to a clinic visit (the name arising from the idea that this might well be in the hospital car park).

This has grave repercussions for studies that depend on patients reporting how they're feeling at specific intervals. It's one of the main reasons some organisations are reconsidering the use of conventional questionnaires. Technology has revolutionised many other industries; is it time for the clinical trial world to follow suit?

Nadir Ammour, associate director of clinical science and operations at Sanofi, certainly thinks so. In recent years, he's seen a shift in focus for the pharmaceutical industry, moving away from marketing to clinicians and instead seeing subjects as the end consumer.

"What we have seen more recently is that the patient viewpoint is becoming more and more critical," he says. "We have to generate evidence from the volunteer's perspective and not only build their views into our development plan, but also report it."

Paper jam

Patient-reported outcomes (PROs) are now invaluable for measuring treatment efficacy and safety in some clinical trials. Traditionally recorded with paper diaries in the comfort of a subject's own home, they come directly from the volunteers and provide their insights throughout the course of a study, on aspects such as quality of life and pain management.

Ammour, who has a background in dental surgery, now spends much of his profession looking into whether patients reporting their symptoms electronically could transform clinical studies. Well aware of the problems paper poses to researchers, he explores the best way organisations can take full advantage of more modern systems.

"With paper, there is no way, absolutely no way, to know for sure that the patient has filled in the information according to protocol, or whether the data has been recorded on the day it says it has been recorded," he emphasises.

Galina Velikova, professor of psychosocial and medical oncology at the Leeds Institute of Cancer and Pathology, agrees that this phenomenon poses a large barrier to the dependability of such studies.

"They have to remember to complete the questionnaire," she says. "And even if they do, patients may still miss questions on the form."

Velikova's research focuses on monitoring the well-being of people diagnosed with cancer and undergoing treatment. She recalls a time she used a self-reporting quality-of-life survey for a study, where the questions were printed double-sided. When patients returned the form, many had accidentally completed only half the questionnaire.

"When that happens, I say: 'we are not saving the trees.' You come across all kinds of unexpected trouble with paper diaries," she says.

Electronic ease

The search for an alternative method of collecting PROs has been investigated since the late 1990s. And there are now a number of options available, from voice-interactive telephone systems to touch-screen devices. Several studies have indicated patient compliance is significantly higher when assessments are administered with such systems, called electronic patient-reported outcomes (ePROs), compared with paper.

In 2002, for example, Stone et al concluded in the British Medical Journal that concerns about compliance with paper diaries are justified. Adults with chronic pain were enrolled in a study, where half used pencil and paper, while the remainder filled in an electronic device three times daily, documenting their symptoms. Results showed 94% compliance with the e-diary, compared with the paper counterpart's paltry 11%.

Additionally, a 2007 paper in Pain Medicine Journal suggested patients actually found an electronic diary easier to use and would continue using it over paper if given the choice.

Benefits of such systems include reminders to volunteers sent in real time. Alerts can be transmitted to study staff if patient non-compliance is detected. Time-stamped data entry, which is immediately available for investigators, is produced. And there's no need to manually input the information into a computer system afterwards.

"You have the benefits of knowing exactly when the questionnaire is completed with ePRO," explains Velikova. "It's particularly handy for some studies which are time-sensitive. If you know the toxicity of a certain treatment is at its peak at day five, that's when you want the data, not three weeks later."

With funding from the National Institute for Health Research, Velikova is currently researching the use of an online system for patients to self-report adverse events during and after chemotherapy and radiotherapy for breast cancer treatment. She's also working on options for subjects who might not have access to the internet.

"We've developed a separate system giving patients the opportunity to use either phone or internet," she explains. "So, when volunteers respond, they can use internet one day, but if they go on holiday, they might want to do it over the phone. The data goes to the same place in the end."

Plenty of successful clinical trials have used ePRO in previous years, with the drug subsequently gaining regulatory approval. These include: ketorolac for ocular pain; eszoplicone for insomnia; and milnacipran for fibromyalgia.

But, despite the numerous benefits ePRO can bring to a study, several hurdles exist in its implementation. There's a significantly low uptake of the data collection method compared with studies with paper diaries.

In the age where everyone has a smartphone, why hasn't the technological leap translated to clinical studies?

Staff reluctance

"I think the number one point is simply the perceived complexity," reveals Ammour. "Of course, anyone would say it's much easier to just use paper."

Investigators often worry new methods won't seem palatable for patients, but Velikova believes the problem lies with staff, rather than the volunteers themselves. Electronic methods can actually empower subjects to be more compliant.

"I think patients are easier," she says. "As long as you explain to them why they need to do it, people are generally happy to help. It's all about being honest about what happens to the data and responding to their questions. And obviously making it clear that it's not part of their primary care."

For time-starved investigators, being faced with another system which will require further training, and another computer username and password, can be off-putting.

"All difficulties that apply to changing medical practice apply here too," Velikova acknowledges.

Aside from researchers wanting an easier life, decisions will also always come down to costs. Ammour reckons it can sometimes be difficult to put the case forward for ePRO, in light of rigid study budgets.

"What we've observed is it often depends who's sitting on a study. If someone has already used ePRO in the past, they know how to do it and what it takes to do it. They would therefore be in a better position to push for it," he reveals.

On the other hand, he says, while funds may be a key concern, electronic information capture also has the potential to actually decrease costs, by eliminating manual data input, hence reducing study timelines. And the vast selection of ePRO technologies affords investigators a choice they can match to their requirements.

Balancing act

For the best chance of ePRO success, both scientists agree user-friendly solutions which enhance patient satisfaction have to be designed. This means respecting the time it will take for the volunteer to complete the report and keeping the questionnaire as simple as possible.

"Because it is electronic, we can capture the opportunity to ask more information of the patients. But that's a common mistake," reveals Ammour. "To think of ePRO as a medical interview system is misleading. It's intended to report observations that are very important because you report them at a specific time."

He reveals that during the design phase of trials at Sanofi, a panel of volunteers are recruited to assess the level of feasibility for the suggested ePRO technology. It's all about balancing the data to be collected against the ease of use from a patient's perspective.

It is clear to Ammour that electronic self-reporting methods have a promising outlook.

"The FDA and EMA are really pushing for ePRO and strongly sending the signal that the revolution is happening right now. They're basically saying: 'we would probably question, if not reject, claims that are coming from paper diaries. We just won't accept that in the future, we're sorry'," he says.

He also suggests a big trend for the industry in coming years will be the concept of 'bring your own device' - where patients will be able to complete assessments at home using their personal gadgets.

Velkiova agrees that once the industry gets used to the new systems, there will be no looking back.

"Technology has influenced our lives hugely. We all have smartphones and depend on them. Health hasn't yet quite mirrored that use. It's only the beginning - but I'm sure it will progress and be the way to do things in the future," she says.