The Secret eDiary of Adrian's

eDiaries and other ePRO solutions are changing the face of clinical trials. They increase compliance and decrease false data - and they're the definition of discrete.

“The line between IT and drug discovery will continue to blur,” said Life Science Insights’ Jim Golden in one of his 2005 predictions. Golden could have been thinking of any number of things, but none more accurate than the field of patient data capture.

Although the exact figures vary – writing in European Pharmaceutical Executive, Medidata Solutions’ Steve Heath says a conservative “25 percent of all clinical trials programmes” use a paper-based process for gathering patient reported outcome (PRO) data; Christine Lys of etrials Worldwide claims it’s “roughly 90 percent” – the end result does not: patient self-report data capture is becoming increasingly important in the conduct of clinical trial programmes.

Symlin is the prime example. A replica of a natural hormone that slows the passage of food through the stomach and curbs the urge to eat after meals, clinical trials showed Symlin might be responsible for hypoglycemia and FDA approval was refused. In a final throw of the dice, Symlin’s developer, Amlyin Pharmaceuticals, launched one last trial, using only diabetic patients equipped with electronic diaries. It paid off – Symlin was approved in March 2005.

Why ePRO?

Capturing data from patients electronically is not a new process, the medical profession was an early adopter of computers, but advances in technology have given electronic patient reported outcome (ePRO) tools a much-needed kick up the bum. Electronic patient diaries (or eDiaries, normally PDAs), desktop computers and interactive voice response systems (IVRS) provide the means for change, but the impetus has come from elsewhere.

Steve Heath: “A seminal study published in the British Medical Journal by Dr Arthur Stone and his colleagues at the Department of Psychiatry and Behavioral Science at Stony Brook University, New York (USA), in collaboration with researchers at the University of Pittsburgh and invivodata, compared paper and electronic diary methods.

“The study confirmed what had long been suspected: patient compliance with paper diaries is very low (as low as 11%) and subjects frequently complete their paper diary cards retrospectively. Far more disturbingly, one third of the patients forward-filled their diary entries, thereby entering false or erroneous data. By contrast, patients using the eDiary were 93% compliant with the study protocol and entered their data in real-time.”

It doesn’t take a genius to see that by capturing PRO data in real-time, eDiaries reduced recall bias and increased the validity and accuracy of the data. But that’s not all.

Monitoring compliance

A 2004 study by R.B. Webber and Company estimated that, globally, the pharmaceutical industry spent more than US$650 million collecting, managing and analysing patient self-report data in 2000. This year, that amount is projected to have grown to US$3 billion. Data is getting more and more valuable – and to get it right, you need checks and balances.

“Over the course of nearly four decades of research,” says Christine Lys, “the most compelling benefit observed using ePRO tools over paper has been the ability to track and control patient compliance. ePRO tools allow for built-in audit trails (time and date stamps). These audit trails are particularly important in studies that are long term and/or require frequent or scheduled assessments.”

Non-judgemental

ePRO solutions can also help prevent other factors from contributing to failed trials. “For example, these tools can help reduce dropout rates by engaging patients in clinical trials through two-way communication, dynamic reminders and incentives,” says Lys. “Furthermore, patients report that they feel more comfortable responding to questions regarding sensitive topics to a non-judgemental ePRO tool in contrast to face-to-face interviews, where patients may acquiesce to the interviewer’s judgement or attempt impression management.” In a sexual dysfunction study, for example, patients need to be able to describe their experiences under treatment in a way that is both sensitive to their privacy and yet provides the required detail, frequency and data accuracy.

“ePRO studies can be used not only to evaluate the safety and efficacy of a new drug, but also to compare competitive products in post-marketing research,” says Paul Howard of the Heron Group. “Precise PRO data can be a powerful tool with a clear role in product differentiation and market positioning.”

Regulation and design

It is important, however, that we don’t get carried away on the technology alone – in many ways it is the least important part of an ePRO solution, unlike regulatory/validation issues.

Lys: “In lieu of a formal guidance document for ePRO, the FDA has recommended that drug developers submit their plans for incorporating ePRO tools. The agency is particularly interested in addressing the selection and validation of endpoints using ePRO tools. According to a presentation given by J. Scott of the FDA at the 2004 Drug Information Association meeting, if the ePRO instrument is adapted from paper or converted from an interview-based instrument, the original version (paper- or interview-based) of the instrument is required, as well as any evidence of their comparison in performance. In addition, cognitive debriefing studies can be included to confirm content validity, comprehensiveness of response choices and reactions to assessment. Finally, submission of the actual ePRO prototype or access and associated description of program specifications (details regarding the workflow of the instrument through the tool) is recommended.”

It is only when technology, behavioural science and seamless study execution are combined that the real benefits of an ePRO approach becomes apparent.

“A well designed eDiary needs to be user-friendly with a simple interface; patients need to be able to just tap the screen and go,” says invivodata’s Doug Engfer. “The device should also provide real-time feedback for patients and flag any difficulties for investigators. Ideally, the eDiary will be integrated into the study design from the start and be used to optimize the protocol. eDiaries can also be tailored to meet the needs of specific patient populations. For example, the degree of manual dexterity required to operate the device can be reduced for Parkinson's patients, and the font size and audible tone can be adjusted to improve clarity for elderly patients.”

eDiaries: gaining in popularity

PHT Corporation achieved a record year in 2004 by deploying approximately 20,000 handheld electronic patient diaries for use in clinical trials. To date, PHT has shipped more than 40,000 LogPad Systems, using palmOne devices, to thousands of subjects and clinical research sites in 46 languages and 48 countries around the globe since 2000.

“We believe the escalating demand for our integrated ePRO solutions is supported by a significant increase in market adoption. A rapidly growing number of biopharmaceutical companies are beginning to realize the benefits ePRO provides, including improved data quality, reduced variance and real-time access to data,” says Phil Lee, PHT president and chief executive officer.

eDiaries: now Bluetooth-enabled

CRF Inc. has collaborated with Ferraris Respiratory to develop the first-ever, Bluetooth-enabled eDiary solution for respiratory clinical trials. This new solution, integrates Ferraris Respiratory’s PiKo-1 Peak Flow Meter and CRF’s eDiaries.

“The seamless and wireless integration of devices like peak flow meters with e-Diaries is a great advancement for this industry. Our new solution is designed to be easy for trial sponsors and clinical sites to implement and very simple for patients to use. Furthermore, this technology has the potential to dramatically improve clinical trials - enhancing the collection, accuracy and reliability of patient data,” says Pamela McNamara, chief executive officer of CRF Inc.