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Improving Trial Efficiencies:
Making the Business Case for ePRO

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  1. 1. PHT Insights — First Quarter 2009 Improving Trial Efficiencies: Making the Business Case for ePRO How to Quantify ePRO ROI: What Does Paper Cost? Spotlight On: Most organizations haven’t assigned a cost The Four Types of Paper Patients to paper PROs, unless they’re outsourcing the entire function of data collection and management to CROs. Here are the numbers: • A typical study includes 250-300 1. Perfect Patients complete every field clearly, and in patients who are in trial for 3 the proper format. Even in this rare months, required to complete 1 best case scenario, the only way to diary daily. This translates into know it was completed at 8:00 pm is 90 diaries per patient. because the subject said so. • Processing each diary involves form creation, printing, translation, binding and shipping to sites; followed by data entry, transfer, reconciliation, queries and changes; and finally return shipment. The estimated cost is 2. Forgetful Patients are a data manager’s dream, but a $20/page. clinical researcher’s nightmare. The worst part is, you have no way of Per Patient Cost Paper PRO $1800 knowing that you’re losing data until Per Patient Average Cost PHT ePRO $1300 it’s too late. Electronic capture savings per patient $500 • Average savings on a typical study using ePRO vs. paper is $125,000 – $150,000. 3. Selective Patients force you to make assumptions - Does ePRO Data Quality Differ from did the subject mean December or February? Was the medication taken? Paper? Doing anything other than throwing Improvements in data quality provided this away could be dangerous. by electronic patient reported outcome systems are widely reported and accepted throughout the clinical research community. Patient diary data collected electronically is time-stamped, legible and logical with real-time validation provided to patients while entering diary information. ePRO 4. Enthusiastic Patients have supports multi-site international trials tremendous energy and want to with remote data monitoring via the web provide as much information as they with real-time status reporting overall can. But it is illogical, illegible and and per site, participant status tracking likely contains AEs. This is an ideal and on-demand subject randomization. patient for an eDiary! Contrary to paper diaries, ePRO data collection can ensure complete patient Paper diary examples courtesy of Dr. Stuart Donovan responses. With trustworthy data,
  2. 2. PHT Insights - First Quarter 2009 Improving Trial Efficiencies: Making the Business Case for ePRO trial sponsors no longer run the risk of having a promising compound rejected Case Study: Novartis due to unreliable paper PRO data. Enhanced data integrity further enables The FDA approved a Novartis drug for chronic constipation for use 1. Attributable, legible, with women, but indicated more data would be needed for men. contemporaneous, original and Therefore, Novartis planned another study and estimated a sample accurate (ALCOA) patient data that is complete and time-stamped size of 1,026 male subjects would be required to prove efficacy through the use of alarms, based on traditional paper variance statistics. Subsequently, the branching logic and edit checks; pharmaceutical company elected to use PHT’s LogPad System 2. Reduced data variance for instead of paper. improved quality of study results and reduced number of patients to Once the study was already underway, the show efficacy; FDA surprised Novartis by deciding to ap- Study power 3. Real time access to diary data prove the drug for men without further was reached between visits for enhanced safety data. Novartis stopped the trial, but al- and compliance monitoring; with less than lowed the 322 enrolled subjects to complete one-third the 4. Adaptive trial designs with pre- treatment. To the amazement of the clinical programmed adaptations and team, study power was reached with 69% planned sam- reduced standard deviation for fewer subjects - representing less than ple size! more conclusive planned interim analyses; and one-third the planned sample size! 5. Libraries of experience and metrics with data including compliance and data variance/standard deviations to rely on memory, especially if they reliable methods for recording for specific indications. must recall over a period of time, of compliance (e.g. electronic or to average their response over patient diaries) not to include non- How Does ePRO Enable Faster Trials? a period of time, may threaten the compliers in the denominator.”3 accuracy of the PRO data. Cycle times and therefore trial times can be reduced with electronic patient According to the FDA, “If a patient 1) Lines 334-337, ‘Guidance for Industry. Patient- reported outcomes. Electronic data diary or some other form of Reported Outcome Measures: Use in Medical Prod- capture eliminates manual data entry unsupervised data entry is used, the uct Development to Support Labeling Claims. DRAFT times and other data point changes. FDA plans to review the protocol to GUIDANCE.’ U.S. Department of Health and Human Services, Food and Drug Administration, Center for Final data analysis sets can be provided determine what measures are taken Drug Evaluation and Research (CDER), Center for within days after a trial’s conclusion. to ensure that patients make entries Biologics Evaluation and Research (CBER), Center according to the study design and for Devices and Radiological Health (CDRH). Febru- By reducing data variance, fewer not, for example, just before a ary 2006 patients are required especially in Phase clinic visit when their reports will be 2) Section 8.1, ‘Note for Guidance on the Clinical II trials. Scientific outcomes are more collected.”1 Investigation of Medicinal Products in the Treatment of Asthma’, The European Agency for the Evaluation conclusive, and greater power of study is achieved by reduced standard deviation. The European Medicines Agency of Medicinal Products, Evaluation of Medicines for (EMEA) has also commented Human Use, November 2002. ePRO does not eliminate the need for on ePRO vs. PRO, providing 3) Section 3.1, ‘Note for Guidance on Clinical In- vestigation of Steroid Contraceptives in Women, The accurate data review and monitoring, this Guidance on endpoints in European Agency for the Evaluation of Medicinal but it does enable trial sponsors to asthma: “If home recording Products, Evaluation of Medicines for Human Use, improve power of study with smaller equipment is used, reproducibility February 2000. samples, and to reach no-go decisions is particularly important and an much faster than they could otherwise. electronic diary record should be considered to validate the timing of measurements.”2 ; and on efficacy What is the FDA position on ePRO? for steroid contraceptive, “The The FDA has reviewed ePRO vs. PRO, and separate calculation of the Pearl cites unsupervised data entry as a major Index for method failure requires drawback to paper reported outcomes. PRO instruments [paper] that require patients Continued on Page 4
  3. 3. For more information about the benefits PHT can provide for your global clinical research programs, please visit Case Study: Merck Research Laboratories Merck initiated the first randomized trial to evaluate the relative capacities of paper diaries and electronic patient diaries (Figure 1) to prove efficacy. 101 patients were randomized to two arms based on data capture method (paper or LogPad®) and treated with an approved drug for insomnia. The study examined primary endpoint data of change in minutes of sleep time and compared Figure 1: A study question on the LogPad and paper diary results from the arms in many categories. Data Analysis Data captured from both arms revealed statistically equivalent means (118 minutes from paper, 109 minutes from the LogPad), but the ranges were different. As shown in Figure 2, the distribution of responses on paper varied widely from -20 to 380. This means one subject claimed to have average 20 minutes less sleep per night, while another reported an additional 6 hours. Further, the distribution tends to cluster around 30-, 60- and 90-minute intervals. This suggests evidence of recall bias, as responses are more general and less precise when made after-the-fact. Conversely, the LogPad distribution in Figure 3 is much tighter around the mean and more Gaussian, with fewer and less extreme outliers. Meanwhile, continuous responses indicate more accurate data reporting. A visual inspection of Figure 4 shows the comparison of variance. Figure 2: Paper Distribution Figure 3: LogPad Distribution Figure 4: Distribution Overlay Results Analysis performed by Merck showed a 35% lower standard deviation for LogPad data as compared to paper. Merck calculated that this reduced variance would have enabled them to reach study power with 56% fewer patients - saving an estimated $340,000 (assuming $6,000 per patient). In addition, Merck had to process three times more data changes and notification forms to clarify paper data, and incurred 58 hours of data entry compared to zero for the LogPad arm. Compliance was high in both arms (96% for paper, 92% for LogPad), but as discussed earlier only ePRO compliance can be verified as opposed to purported by subjects. These findings were presented by Jay Pearson, Senior Director at Merck.
  4. 4. PHT Insights - First Quarter 2009 Improving Trial Efficiencies: Making the Business Case for ePRO PHT has also demonstrated ePRO About PHT Corporation Read About: Banning Paper Diaries efficiencies within PHT is the market-leading provider of electronic patient reported outcome Why Paper Diaries Should Be Banned in Clinical • Oncology Trials (ePRO) solutions used in more than 390 • Endocrine and meta- Pharmaceutical Executive Europe, March, 2009 clinical trials by 110 biopharmaceutical bolic disorders clients. The proven LogPad® System PHT author Valdo Arnera, MD, outlines specific • Dermatology and revolutionary SitePad™ Tablet reasons why pharmaceutical and biotechnology • Ears, nose, throat, eye deliver the voice of the patient, in companies should replace paper diaries with ePRO. and teeth 80 languages, from homes and sites • Musculo-skeletal in 60 countries around the world. Read it online at: By capturing high-quality and time- Visit About Us and Making ePRO News Trials across TA where patient stamped assessments with minimal reported data is sensitive in nature, respondent burden, trial sponsors are where it’s critical to track adverse able to run smaller and more conclusive Which Trials are Best Suited for symptoms between visits such clinical research programs resulting ePRO? as worsening symptoms, rescue in significant R&D cost savings. Real- time study management through PHT medications, specific events such StudyWorks™ features eClinical data Trials with patient reported as suicide ideation also received integration, standard and custom endpoints – whether in home or increased ROI when utilizing ePRO. data summaries for compliance and in medical offices – report rapid enrollment, SafetyPRO™ email alerts, gains in efficiencies and data Summary and the industry’s premier study archive. integrity with ePRO. Trials within Patient experiences captured firsthand these therapeutic areas (TAs) by PHT’s ePRO Product Suite have Sponsors, trial managers and have been early adopters of ePRO: been used successfully in at least 11 health outcome directors continue to obtain greater degrees of NDA submissions and seven approvals • Neurology/CNS to date. For more information, review data quality, program efficiency • Respiratory interactive product demonstrations at and patient’s safety with • Behavior Modification the award-winning ePRO. For more information, • Gastrointestinal contact PHT at 1.877.360.2901. PHT, LogPad, eSense, StudyWorks, • Genitourinary SafetyPRO and SitePad are among • Immunology the registered trademarks and trademarks of PHT Corporation. Discover: The SitePad Tablet Read about PHT’s revolutionary site-based device in Insights Q1 2008 issue in detail. The large-screen device allows for finger-tip data entry and supports complex questionnaires and a response options such as the 10cm VAS. To learn more, visit the SitePad Tablet virtual launch center at and schedule an in-person demo today. “I believe the SitePad Tablet is something that can help our entire industry, and patients, as well,” says Joachim Löwin, Clinical Information Science Leader, AstraZeneca. PHT Corporation 500 Rutherford Avenue Boston, MA 02129, USA Copyright © 2009 PHT Corporation Toll-Free: 877-360-2901