The ePRO evolution

Kurt Mussina is Vice President of CRF Inc. He has over 17 years of experience spanning Research, Marketing and International Business Development in the Pharmaceutical and Contract/Clinical Research Organization (CRO) industries. His areas of expertise include strategic sales and marketing, clinical research services, brand-building initiatives, product development, market research, corporate financing, and competitive intelligence.

Mr. Mussina holds a MBA from Duke University’s Fuqua School of Business and a BS in Chemistry from Montclair State University.

According to the U.S. Food and Drug Administration (FDA), there has been a marked slowdown in the number of new drug and biologic submissions to regulatory agencies worldwide in the past five years. This is due primarily to the costs, inefficiencies and challenges related to the drug development process. On average, it costs $802 million and takes 15 years for a pharmaceutical company to develop a new prescription medicine and obtain FDA approval.

Traditional paper collection methods for biopharmaceutical clinical trials are time consuming, expensive and can result in incomplete, invalid or illegible data. The adoption of electronic clinical trial (ECT) technology has grown rapidly over the past four years as clinical trial leaders seek new ways to streamline the drug development process, while improving data quality and maintaining the highest levels of patient safety. In 2004, 16 percent of clinical trials utilized ECT technology, up from only 3 percent in 2001.

One of the fastest growing segments of the ECT market is electronic patient reported outcomes (ePRO) technology, including electronic patient diaries (eDiaries). Industry experts attribute the growth of eDiaries to the declining price of personal digital assistant (PDA) and other data collection devices; the ease of use in which eDiaries can be integrated into existing clinical trial processes; and the general public’s familiarity and increased comfort level with PDA-type devices, which minimize the time, effort and expenses needed train study subjects.

Studies have shown that eDiaries reduce overall clinical development costs, increase patient compliance rates, improve the quality of patient reported data, and minimize the time and effort required for study set-up and database lock. For clinical trial leaders, an eDiary is more than just a questionnaire in a box. It is a comprehensive study and patient management tool that can be used to conduct complex clinical trials that could never be effectively accomplished with paper. eDiaries provide clinical trial leaders with real-time access to valuable patient data, allowing trial leaders to make educated decisions throughout the trial process and intervene immediately if a problem occurs.

CRF Inc. – Driving the Change to Paper-Free Clinical Trials

One company in particular has driven the change to safer and more efficient paper-free clinical trials. Through innovative technology and a thorough understanding of drug development and mobile computing, CRF Inc. pioneered the development of eDiaries and has set the standard for industry experience and results. The company conducted the first wireless clinical trial, was the first company to adopt Clinical Data Interchange Standards Consortium (CDISC) worldwide technology standards, and has managed the largest ever eDiary study in the industry.

CRF Inc.’s mobile technology has connected more patients than any other ePRO vendor – more than 100,000 patients across 58 countries and in 54 languages – making the company’s product, TrialMax™, the most widely used eDiary technology in the world. In addition, the company has consistently achieved the industry’s highest patient compliance rates - over 95 percent across patient populations.

CRF Inc.’s clinical team has experience in 32 indications with particular acuity in pain, oncology, gastrointestinal and genitourinary conditions, metabolic disorders, dermatology, and respiratory disease. The team has designed studies for pediatric to geriatric patients and every age group in between.

Cost Savings with eDiaries

The average cost of a clinical trial has tripled in the past 12 years. Since eDiaries streamline the clinical trial process and minimize data entry and management, trials conducted electronically can be significantly more cost effective than those conducted with paper. Recent studies have demonstrated this benefit.

Researchers from the University of Medicine in Berlin, Germany collected data from more than 10,547 inpatients and outpatients between 1989 and 2003 at the Department of Psychosomatic Medicine Charite, Humbolt University, Berlin. Of these patients, 2,892 used paper diaries while 7,655 used eDiaries (PDA-based). The patients reported data based on six psychometric scales: anger, elevated mood, anxious depression, involvement, apathy, and tiredness.

The researchers found that eDiaries reduced costs by 40 percent compared with paper diaries. While the hardware costs associated with eDiaries (PDAs) were higher than those for paper diaries, the costs associated with staff and materials (copies, etc.) were much lower.

CRF Inc.’s eDiary technology has proven ability to significantly reduce costs associated with staff time and resources. A global pharmaceutical company used CRF Inc.’s TrialMax to manage a clinical trial for a Rotavirus vaccination. The trial involved remote monitoring and analysis of more than 15,000 pediatric patients across three countries whose parents/caregivers used TrialMax-enabled cell phones to report safety and symptom data. The sponsor reported that CRF Inc.’s technology radically reduced follow up costs associated with the trial, resulting in a cost savings of approximately $2.7 million compared with traditional paper diaries.

CRF Inc.’s clients have also reported a dramatic increase in their return on investment (ROI) with TrialMax compared with paper diaries. In one case, a leading pharmaceutical company used TrialMax-equipped PDAs to collect data on statin interaction rates from 20,000 patients at 100 sites across Europe. As a result, the company’s market share increase with ROI was 400 percent.

eDiary Benefits Beyond the Financial

Patient Compliance and Data Accuracy

Recent studies have shown that eDiaries can significantly improve patient compliance and data accuracy compared with traditional paper diaries. Many clinical trials suffer from the “parking lot syndrome,” patients sitting in the parking lot filling out multiple diary entries prior to a site visit. This practice results in inaccurate data since patients tend to over or underestimate symptoms and other relevant information when they are forced to recall their experiences from memory. Patients have also been known to fill out diary entries ahead of time, fabricating experiences and symptoms.

Since eDiaries incorporate a number of features to ensure that patients report experiences in real-time, they prevent this “diary hoarding” practice and improve overall compliance and accuracy. These features include alarms that remind patients when they need to input information, time-stamped entries that confirm when the responses were provided, edit checks that question illogical or incomplete data, and help windows that assist the user throughout the data entry process.

A study published in the May 2002 British Medical Journal (BMJ) clearly illustrates how electronic patient diaries can improve patient compliance and data accuracy. The patients who used paper diaries reported 90 percent compliance, while the actual rate of compliance was only 11 percent. Actual compliance for the eDiaries, on the other hand, was 94 percent. The study revealed that paper diary hoarding was a significant problem. 75 percent of patients using paper diaries had at least one day of hoarding and 32 percent of the study days contained no diary openings at all.

eDiaries have also been shown to improve compliance rates and data accuracy in clinical trials involving children. A study published in the February 2004 issue of Pain compared eDiary and paper diary usage by sixty children suffering from headaches or juvenile idiopathic arthritis. The children were randomly assigned to an eDiary or paper diary and were asked to record information on pain and distress, somatic symptoms, and activity limitations over a period of seven consecutive days.

The children using eDiaries completed an average of 6.6 days and 83 percent completed all seven days, while the children using paper diaries completed an average of 3.8 days and only 47 percent completed all seven. In addition to higher compliance rates, the data from the eDiaries was significantly more accurate than the data from the paper diaries. 100 percent of the data reported with eDiaries was accurate, versus only 51 percent of the data reported with paper diaries.

CRF Inc.’s clients have consistently reported patient compliance rates of over 95 percent across all studies, yielding high quality data and minimizing costs and risks of error-prone paper studies, which have compliance rates of 10 to 60 percent. CRF Inc.’s compliance rates are the highest that have ever been consistently reported in real-life studies.

Between November 2002 and February 2004, one of the world’s leading pharmaceutical companies used TrialMax to manage a Phase III trial for Irritable Bowel Syndrome (IBS). With TrialMax, the researchers were able to collect an estimated 2,000,000 pages of real-time, primary efficacy data from 5,000 patients in 23 countries in the Americas, Europe, Africa, and Australia. The compliance level for this study was an astonishing 97 percent – only 3 percent of the data expected was missing.

Ease of Use

Since the majority of individuals use some sort of portable electronic device on a daily basis, such as PDAs, laptops and cell phones, eDiaries go well with our mobile lifestyles. Studies have shown that eDiaries are accepted by a wide range of patient populations – from children to the elderly – due to their easy to use, intuitive design. Helpful features include alarms that remind patients when to input data or take medication, and help windows that guide patients through the data entry process.

A subset of research from the larger University of Medicine, Berlin study referenced above demonstrates the acceptance and ease of use of PDA-based eDiaries, specifically with elder populations. Researchers surveyed 454 patients who had been using eDiaries between November 2004 and April 2005 on the usability and acceptance of PDA-based assessment. The mean age of these patients was 41, with 25 percent over the age of 50.

94 percent of all patients reported that the PDA-based eDiary was easy or very easy to use and 78 percent felt the size of the font on the screen was just right. When the researchers questioned patients over the age of 50, 97 percent reported that the PDA-based eDiary was easy or very easy to use and 74 percent felt the size of the font on the screen was just right.

On the opposite end of the spectrum, the study referenced above from the February 2004 issue of Pain found that children between the ages of eight and 16 find eDiaries both acceptable and easy to use. 83 percent of children reported that eDiaries made it easy or very easy to remember to input data, compared with only 53 percent of children using paper diaries. 61 percent of children said they liked eDiaries, while only 33 percent liked paper.

In clinical studies supported by CRF Inc., up to 100 percent of patients have stated that TrialMax is easy to use and is an acceptable alternative to paper diaries. TrialMax’s intuitive design and ease of use make it an ideal solution for a broad range of patient populations and therapeutic indications.

At the conclusion of the pediatric Rotavirus vaccination study referenced above, 90 percent of parents said that they would be happy to participate in a similar trial. The feedback from nurses and doctors was equally positive:

• 100 percent would like to use the system in the future
• 100 percent preferred this technology to traditional methods
• 100 felt that their involvement with the system was positive

Time Savings

eDiaries can significantly reduce the time required to set-up and manage a clinical trial. While clinical trial teams spend endless hours deciphering and manually entering information written in paper diaries, eDiaries streamline the process by transmitting patient reported outcomes data directly to a central database. Since site teams have immediate access to patient data, they can monitor a trial’s progression in real-time and intervene if needed.

The University of Medicine, Berlin study found eDiaries saved one whole working day per 100 questionnaires compared with paper diaries. eDiaries reduced preparation time by 67 percent, eliminated the need for data entry, and reduced data bank organization and patient report time by 78 percent.

CRF Inc.’s TrialMax has been proven to save time for clinical trial teams. On average, TrialMax can cut set-up time in half compared with other ePRO technology.

TrialMax also reduces time to database lock. In April 2004, CRF Inc. closed a database for the largest-ever conducted eDiary study in the industry. The phase III study included 5,000 patients who recorded diary entries across 23 countries in 19 languages. The trial sponsors achieved database lock on patient diary data in only five days from the last patient visit – a process that takes an average of 30 days with paper diaries.

The Future of eDiaries

The global pharmaceutical and biotechnology industries are adopting eDiaries with increasing frequency. Today, fourteen of the world’s top 20 pharmaceutical firms use CRF Inc.’s eDiary technology.

As eDiary use continues to grow, three trends have emerged: eDiary use in more complex clinical trials, the integration of eDiaries with medical devices and the use of eDiaries in patient disease management programs. CRF Inc. is leading the charge on each of these trends.

More Complex Clinical Trials

Since CRF Inc.’s founding in 2000, the company has seen eDiary technology evolve from an interesting concept to a proven solution. As CRF Inc.’s eDiaries become a standard in clinical research, pharmaceutical companies are relying on the technology to manage even their most complex clinical trials – involving thousands of patients in multiple countries inputting data in a variety of languages.

Today, the average clinical study that CRF Inc. supports requires the deployment of both landline and wireless data transmission technology. Typically studies also involve more than 1,000 patients in three countries reporting efficacy, quality of life and safety data in five different languages.

Medical Devices

One of CRF Inc.’s latest initiatives involves eDiary solutions that capture patient data directly from a medical device and transmit it wirelessly to a mobile device equipped with CRF Inc.’s TrialMax software. This year, CRF Inc. launched two new eDiary solutions: a Bluetooth™ enabled solution for respiratory clinical trials and a wireless infrared solution for diabetes trials.

The respiratory solution captures patient data directly from a peak flow meter and transmits it via a Bluetooth wireless communication system to a PDA equipped with TrialMax software. The diabetes solution captures patient data from a blood glucose meter and automatically transmits it to a CRF Inc. eDiary via a built-in, wireless, infrared communication system. These new solutions have the potential to dramatically improve clinical trials since they enhance the collection, accuracy and reliability of patient data.

Disease Management

Due to an increasing need for more convenient, cost-effective medical care outside of traditional healthcare settings, CRF Inc. is also developing new eDiary applications that will enable patients to manage chronic conditions in their homes, at work or on the road. In the near future, patients will be able to record symptoms, medication use, data from medical devices, and other condition-specific information using a TrialMax-equipped PDA or mobile phone. They will then be able to wirelessly transmit this information to their healthcare providers who can, in turn, manage each patient’s condition in real-time and provide valuable feedback to improve the quality of care.

Conclusion

Electronic patient diaries have revolutionized the way study teams manage the clinical trial process – reducing costs, time and effort, and increasing patient compliance and data quality. Traditional paper diaries are rapidly becoming obsolete as the pharmaceutical industry embarks on the ePRO revolution.

With innovative technology, in-depth clinical knowledge and unmatched industry expertise, CRF Inc., is leading the charge toward paper-free clinical trials. The result will be a new generation of safer, more effective medical treatments that are developed, approved and delivered to patients sooner.