How to Justify ePRO


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Trials with patient reported endpoints are reporting increased efficiencies when using electronic patient reported outcomes (ePRO), compared to paper diary data collection methods. To date, approximately 20% of all trials with patient reported endpoints are using ePRO solutions to collect efficacy data. As the adoption of electronic patient reported outcomes continues to increase, sponsors are finding new ways to justify this technology’s ROI, and identify the types of trials that are best suited to ePRO (versus paper). This article will describe how several market-leading sponsors have quantified the benefits of better data quality, with case examples from recent trials implemented by PHT Corporation (PHT). These analyses are provided with the intention to inform the clinical research community, and provide the frameworks for further ROI determinations.

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How to Justify ePRO

  1. 1. PHT Insights — First Quarter 2009 Improving Trial Efficiencies: Making the Business Case for ePROHow to Quantify ePRO ROI: The Four Types of Paper PatientsWhat Does Paper Cost?Most organizations haven’t assigned a cost to paper 1. Perfect PatientsPROs, unless they’re outsourcing the entire function complete every field clearly, andof data collection and management to CROs. Here in the proper format. Even in thisare the numbers: rare best case scenario, the only way to know it was completed at• A typical study includes 250–300 patients who are 8:00 pm is because the subject in trial for 3 months, required to complete 1 diary said so. daily. This translates into 90 diaries per patient.• Processing each diary involves form creation, printing, translation, binding and shipping to sites; followed by data entry, transfer, 2. Forgetful Patients reconciliation, queries and changes; and finally are a data manager’s dream, but return shipment. The estimated cost is $20/page. a clinical researcher’s nightmare. The worst part is, you have no way Per Patient Cost Paper PRO $1800 of knowing that you’re losing data Per Patient Average Cost PHT ePRO $1300 until 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 PatientsDoes ePRO Data Quality Differ from Paper? force you to make assumptions -Improvements in data quality provided by electronic did the subject mean Decemberpatient-reported outcome systems are widely or February? Was the medicationreported and accepted throughout the clinical taken? Doing anything otherresearch community. Patient diary data collected than throwing this away could beelectronically is time-stamped, legible and logical dangerous.with real-time validation provided to patients whileentering diary information. ePRO supports multi-siteinternational trials with remote data monitoring viathe web with real-time status reporting overall and 4. Enthusiastic Patients haveper site, participant status tracking and on-demand tremendous energy and wantsubject randomization. to provide as much information as they can. But it is illogical,Contrary to paper diaries, ePRO data collection illegible and likely contains AEs.can ensure complete patient responses. With This is an ideal patient for antrustworthy data, trial sponsors no longer run the eDiary!risk of having a promising compound rejected dueto unreliable paper PRO data. Paper diary examples courtesy of Dr. Stuart Donovan
  2. 2. 2 Enhanced data integrity further enables What is the FDA position on ePRO? Which Trials are Best Suited for ePRO? 1. Attributable, legible, contemporaneous, The FDA has reviewed ePRO vs. PRO, and cites Trials with patient-reported endpoints– original and accurate (ALCOA) patient data that unsupervised data entry as a major drawback whether in home or in medical offices–report is complete and time-stamped through the use to paper reported outcomes. PRO instruments rapid gains in efficiencies and data integrity of alarms, branching logic and edit checks; [paper] that require patients to rely on memory, with ePRO. Trials within these therapeutic areas 2. Reduced data variance for improved quality especially if they must recall over a period of time, (TAs) have been early adopters of ePRO: of study results and reduced number of or to average their response over a period of • Neurology/CNS patients to show efficacy; time, may threaten the accuracy of the PRO data. • Respiratory 3. Real time access to diary data between According to the FDA, “If a patient diary or • Behavior Modification visits for enhanced safety and compliance some other form of unsupervised data entry is • Gastrointestinal monitoring; used, the FDA plans to review the protocol to • Genitourinary determine what measures are taken to ensure • Immunology 4. Adaptive trial designs with pre-programmed that patients make entries according to the adaptations and reduced standard deviation for PHT has also demonstrated ePRO efficiencies study design and not, for example, just before a more conclusive planned interim analyses; and within clinic visit when their reports will be collected.”1 5. Libraries of experience and metrics with • Oncology data including compliance and data variance/ The European Medicines Agency (EMEA) has • Endocrine and metabolic disorders standard deviations for specific indications. also commented on ePRO vs. PRO, providing • Dermatology this Guidance on endpoints in asthma: “If home How Does ePRO Enable Faster Trials? • Ears, nose, throat, eye and teeth recording equipment is used, reproducibility is Cycle times and therefore trial times can be • Musculo-skeletal particularly important and an electronic diary reduced with electronic patient-reported record should be considered to validate the Trials across TAs where patient-reported data outcomes. Electronic data capture eliminates timing of measurements.”2 ; and on efficacy for is sensitive in nature, where it’s critical to manual data entry times and other data point steroid contraceptive, “The separate calculation track adverse symptoms between visits such changes. Final data analysis sets can be of the Pearl Index for method failure requires as worsening symptoms, rescue medications, provided within days after a trial’s conclusion. reliable methods for recording of compliance specific events such as suicide ideation also By reducing data variance, fewer patients (e.g. electronic patient diaries) not to include received increased ROI when utilizing ePRO. are required especially in Phase II trials. non-compliers in the denominator.”3 Summary Scientific outcomes are more conclusive, Sponsors, trial managers and health outcome and greater power of study is achieved by directors continue to obtain greater degrees reduced standard deviation. of data quality, program efficiency and patient ePRO does not eliminate the need for accurate safety with ePRO. For more information, contact data review and monitoring, but it does enable PHT at 1.877.360.2901. trial sponsors to improve power of study with smaller samples, and to reach no-go decisions 1) Lines 334-337, ‘Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. DRAFT GUIDANCE.’ U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and much faster than they could otherwise. Research (CBER), Center for Devices and Radiological Health (CDRH). February 2006 2) Section 8.1, ‘Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Asthma’, The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human Use, November 2002. 3) Section 3.1, ‘Note for Guidance on Clinical Investigation of Steroid Contraceptives in Women, The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human Use, February 2000. Case Study: Novartis The FDA approved a Novartis drug for chronic Once the study was already underway, the FDA surprised constipation for use with women, but indicated more Study power was Novartis by deciding to approve the drug for men without data would be needed for men. Therefore, Novartis reached with less further data. Novartis stopped the trial, but allowed the 322 planned another study and estimated a sample size enrolled subjects to complete treatment. To the amazement than one-third of 1,026 male subjects would be required to prove of the clinical team, study power was reached with 69% efficacy based on traditional paper variance statistics. the planned- fewer subjects - representing less than one-third the planned Subsequently, the pharmaceutical company elected to sample size! sample size! use PHT’s LogPad® System instead of paper.
  3. 3. 3Case Study: Merck Research Laboratories Merck initiated the first randomized trial to evaluate the relative MORNING QUESTIONA IRE (Continued capacities of paper diaries and electronic patient diaries 8. How would ) you describ e the quality of your sleep 1= Excellent ❑ 2= Good ❑ 3= Fair ❑ last night? (ch 4= Poor ❑ eck only one box.) (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 results from the arms in many categories. Figure 1: A study question on the LogPad and paper diary Figure 2: Paper Distribution Figure 3: LogPad Distribution Figure 4: Distribution OverlayData Analysis ResultsData captured from both arms revealed statistically equivalent Analysis performed by Merck showed a 35% lower standard deviationmeans (118 minutes from paper, 109 minutes from the LogPad), but for LogPad data as compared to paper. Merck calculated that thisthe ranges were different. As shown in Figure 2, the distribution of reduced variance would have enabled them to reach study power withresponses on paper varied widely from -20 to 380. This means one 56% fewer patients–saving an estimated $340,000 (assuming $6,000subject claimed to have average 20 minutes less sleep per night, while per patient).another reported an additional 6 hours. Further, the distribution tends In addition, Merck had to process three times more data changesto cluster around 30-, 60- and 90-minute intervals. This suggests and notification forms to clarify paper data, and incurred 58 hoursevidence of recall bias, as responses are more general and less precise of data entry compared to zero for the LogPad arm. Compliance waswhen made after-the-fact. high in both arms (96% for paper, 92% for LogPad), but as discussedConversely, the LogPad distribution in Figure 3 is much tighter around earlier only ePRO compliance can be verified as opposed to purportedthe mean and more Gaussian, with fewer and less extreme outliers. by subjects.Meanwhile, continuous responses indicate more accurate data These findings were presented by Jay Pearson, Senior Director at Merck.reporting. A visual inspection of Figure 4 shows the comparisonof variance.
  4. 4. Electronic Patient-Reported Outcome (ePRO) SolutionsRead About:Banning Paper DiariesWhy Paper Diaries Should Be Banned inClinical TrialsPharmaceutical Executive Europe, March, 2009PHT author Valdo Arnera, MD, outlines specificreasons why pharmaceutical and biotechnologycompanies should replace paper diarieswith ePRO.Read it online at: PHT Electronic Patient-Reported Outcome (ePRO) System ComponentsFor more information: LogPadUS Account Executives: 1.877.360.2910 SitePad® PHT LogPad – The mobileEuropean Account Executives: 41.22.879.91.00 StudyWorks® Hand Held for home eDiaries eSense™ Sensors ePRO DesignerAbout PHT Corporation Study ArchivePHT is the global innovator in ePRO (electronic patient-reported PROVision™ Scientific Servicesoutcome) systems that simplify clinical data management andstreamline eClinical trials. Since 1994, patient experiences Trial Success Program™ (TSP)captured by PHT’s ePRO System have been used successfully PHT Support Centerin over 440 global trials by more than 100 biopharmaceutical Scientific Review and Validationcompanies, resulting in at least 14 regulatory submissions Site Telecom Assessmentsand 11 approvals. By capturing high-quality and time-stamped Technology Transferassessments, trial sponsors are able to run smaller, safer andmore conclusive clinical research programs resulting in significantR&D cost savings. For more information, review the educationalcontent and interactive PHT ePRO System demonstrations at “I believe the SitePad Tablet is something that canPHT’s award-winning site help our entire industry, and patients, as well,” says Joachim Löwin, Clinical Information Science Leader, AstraZeneca.PHT Corporation PHT Corporation Sàrl Insights Q1 2009500 Rutherford Avenue 2, chemin Louis-Hubert www.phtcorp.comBoston, MA 02129 USA 1213 Petit-Lancy, Geneva, Switzerland Copyright © 2010 PHT CorporationToll-Free: 877.360.2901 Phone: 41.22.879.91.00 v8.2010