Collecting ePRO Online

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The proliferation and global adoption of the Web is prompting biopharmaceutical decision makers to ask how the Internet can be leveraged to expedite clinical trials. It is reasonable to presume that …

The proliferation and global adoption of the Web is prompting biopharmaceutical decision makers to ask how the Internet can be leveraged to expedite clinical trials. It is reasonable to presume that large populations of patients are Web-savvy and that they have Internet access. As such, it is possible to leverage the Web as a mode of administration for entering electronic patient reported outcome data for clinical research. A key question many sponsors are asking is can the Web be used to collect patient reported outcomes that support label claims?

This article will describe the browser-based electronic patient reported outcome (ePRO) collection method. It will explain which types of trials are best suited for this type of data collection; discuss psychometric validations required with this collection modality; and explain how and when ePRO data collected via the web can support a claim.

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  • 1. PHT Insights – Fourth Quarter 2010 Collecting PROs via the Web: Are Data Suitable for Regulatory Submissions? Contents The proliferation and global adoption of the Web are prompting biopharmaceutical I. Web-based ePRO Definition p.1 decision makers to ask how the Internet can be leveraged to expedite clinical trials. It and Overview is reasonable to presume that large populations of patients are Web-savvy and that II. Ideal Trial Conditions for p.2 they have Internet access. As such, it is possible to leverage the Web as a mode of Web-based ePRO administration for clinical research. A key question many sponsors are asking is can III. Psychometric Validations p.3 the Web be used to collect patient reported outcomes that support label claims? Required for Web-based ePRO This article will describe the Web-based mode of administration for electronic patient IV. Supporting a Claim using p.5 reported outcome (ePRO). It will explain which types of trials are best suited for this Web-based ePRO mode of administration, discuss psychometric validations required, and explain how Summary p.5 and when ePRO data collected via the Web can support a claim. — Chris Hall, PHT CorporationI. Definition: Early adopters of web-based ePRO technology are able to reachWeb-based ePRO is an online browser-based method for PRO data expanding patient populations on all continents. It is estimatedcapture that sends data to a central server and database that that 28.7% of the world’s population has Internet access,allows for Web review by site and sponsor. representing a 444% growth in the last ten years. Over 77% of the North American population has Internet access.1Similar to the surging interest expressed by regulatory agenciesfor sponsors to collect data directly from patients, clinical In addition to the expanding pools of potential patients withprofessionals are anxious to leverage the Internet to collect these Internet access, clinical and postmarketing study teams can realizeePRO data for clinical studies and post-market surveys. Many significant cost savings in design, validation and hosting whensponsors believe the Web can offer additional ease of use and cost collecting ePRO on the Internet. The Web is a familiar mediumbenefit vs. other types of ePRO methods. When configured within to many patients, and using a website to enter information mayan ePRO System, Web-based ePRO can be an economical method not require instruction. Fundamental criteria such as instant editfor collecting patient endpoint data from large populations, and checks and conditional branching and navigation may be standardcan be used to submit PRO data to support a label claim. since the Web is highly structured for data collection. Internet Users in the World-Distribution by World Regions 2010
  • 2. 2Collecting PROs via the Web: Are Data Suitable for Regulatory Submissions?While clinical trial managers can leverage Web-based ePRO for improved outcomes and or comparative effectiveness. Onlinemany trials across Phase 2 and 3, peri- and post-approval study access by biostatisticians to massive post-market data canprofessionals may gain the greatest advantages from collecting expedite baseline risk assessments essential for analysis ofePRO on the Internet. Browser-based data collection can reach background risk and stratification of that data. Such real-time databroad audiences to reassure the payor that the former clinical access can serve to readily confirm that outcomes are consistenttrial outcomes apply in real-world settings, and demonstrate across larger populations.II. Ideal Trial Conditions for Collecting Web-based ePROTo date there are five proven methods for collecting ePRO data: via a device, Interactive Voice Response (IVR), Digital pen, Tablet and via the Internet.The optimal method or combination of methods depends on specific trial or study conditions such as where the data will be collected, frequency ofdata collection, and ediary complexity. Each ePRO collection method and device must be thoroughly vetted in order to comply with various FDA,EMA and country regulations and requirements for trustworthy data. 1. Hand 2. IVR 3. Internet Web 4. Pen: Digital 5. Tablet: Held Device: (Interactive data capture pen that Electronic data Electronic data Voice Response): with a central captures data capture on a capture on a Keypad or voice system that and uploads to tablet mobile Hand Held mobile device IVR data capture Internet allows for Web Pen a central system Tablet device with awith a central system that allows with a central system that allows review by site and sponsor; that allows for Web review; and central system that allows forfor Web review; for Web review by site and sponsor; Web review.W hile data collection via Web-based ePRO seems intuitively simpler and easy to deploy, it is not the preferred collectionmethod for many trials and studies. Specifically, it is not suitable • Studies or clinical trials designed to evaluate drug interactions or bioavailability when there are scientific data that indicate the potential for a serious safety risk.if an Internet connection is not reliable, constant and available • Drug and biologic quality studies that do not have a safetyto the target population nor if the Internet is unavailable during endpoint, such as studies designed to develop an opticalneeded response time such as with episodic indications that may rotation test, or evaluate immune response to concomitantrequire data collection at any random time period. Additionally, vaccination(s) that are a part of routine U.S. immunizationif a reminder system is required for improved diary completion practice.compliance, a Web-based ePRO System would require integrationwith SMS or IVR reminder systems. Furthermore, patient privacy • Pharmacoepidemiologic studies designed to examine themust be assured if data is being collected in a community setting, natural history of a disease or to estimate background rates foracademic institution or clinic. adverse events.3Web-based ePRO is well suited for many post-approval • Clinical trials in which the primary endpoint is related tostudies and clinical trials as described in the FDA Draft further defining efficacy, designed to evaluate efficacy usingGuidance2 on same: a withdrawal design or evaluate long-term effectiveness or duration of response.• Observational pharmacoepidemiologic studies designed to assess a serious risk attributed to a drug exposure or to quantify risk or evaluate factors that affect the risk of serious toxicity, To summarize, the optimal trial or study conditions for collecting such as drug dose, timing of exposure, or patient characteristics. Web-based ePRO involve• Clinical trials with a primary safety endpoint, evaluated with • Available patient populations in North America and western prespecified assessments. Europe,• Studies or clinical trials to evaluate the pharmacokinetics of the • Regularly scheduled or infrequent data collection time periods, drug in the labeled population or in a subpopulation at potential and risk for high drug exposures that could lead to toxicity. • Relatively simple diaries or questionnaires.
  • 3. 3Collecting PROs via the Web: Are Data Suitable for Regulatory Submissions? III. Psychometric validations required for Web-based ePRO S imilar to all PRO instruments that are transitioned from paper to electronic capture, the Web-based Validation Decisions: FDA and ISPOR Guidelines ePRO instruments must be documented KEY to capture all of the most clinically Validation Data from PRO will be used to support FDA important concepts and items. These work at sponsor’s NO labeling claim or items must be complete, relevant discretion promotional materials ISPOR (appropriate), and understandable to SMALL: the patient. YES Cognitive Debriefing Similar to all other ePRO modes of Full Subjects with NO indication involved administration, the FDA Final Guidance Validation in item generation MEDIUM: on PRO4 and International Society for Equivalence Testing Pharmacoeconomics and Outcomes YES Research (ISPOR) guidelines recommend instruments migrated to a new modality Quantitative NO Paper version is reliable, valid, YES Conversion to ePRO LARGE: Full Testing be validated with cognitive debriefing, sensitive to change Validation equivalence testing or full psychometric validation, depending on the type of modification made to the diaries or questionnaires. Upgrading subsequent trials or studies to collect data via Web-based ePRO are an [Not] “…every small change in application acceptable reason for PRO Instrument change according to the Final Guidance6: or format necessitates extensive studies to document the final version’s Table 1. Common Reasons for Changing Items during PRO Instrument Development measurement properties. Additional Item Property Reason for Change or Deletion qualitative work may be adequate Clarity or relevance Reported as not relevant by a large segment of the target population depending on the type of modification Generates an unacceptably large amount of missing data points made. Examples of changes that can alter Generates many questions or requests for clarification from patients as they the way that patients respond to the same complete the PRO instrument Patients interpret items and responses in a way that is inconsistent with the set of questions include: PRO instrument’s conceptual framework Response range A high percent of patients respond at the floor (response scale’s worst end) • Changing an instrument from paper to or ceiling (response scale’s optimal end) electronic format Patients note that none of the response choices applies to them Distribution of item responses is highly skewed • Changing the timing of or procedures Variability All patients give the same answer (i.e., no variance) for PRO instrument administration Most patients choose only one response choice within the clinic visit Differences among patients are not detected when important differences are known Reproducibility Unstable scores over time when there is no logical reason for variation from • Changing the application to a different one assessment to the next setting, population, or condition Inter-item correlation Item highly correlated (redundant) with other items in the same concept of interest Ability to detect change • Changing the order of items, item Item is not sensitive (i.e., does not change when there is a known change in the concepts of interest) wording, response options, or recall Item discrimination Item is highly correlated with measures of concepts other than the one it is period or deleting portions of a intended to measure Item does not show variability in relation to some known population questionnaire characteristics (i.e., severity level, classification of condition, or other known characteristic) • Changing the instructions or the Redundancy Item duplicates information collected with other items that have equal or better measurement properties placement of instructions within the Recall period The population, disease state, or application of the instrument can affect the PRO instrument”5 appropriateness of the recall period
  • 4. 4Collecting PROs via the Web: Are Data Suitable for Regulatory Submissions? IV. Supporting a Claim via Web-based ePRO Data collection from patients is a fundamental component within an ePRO System, but data collection as a standalone function is insufficient for data submission to support a claim. The ePRO System must include controls for open systems (a superset of those for closed systems), as defined by 21 CRF Part 11, Section B – Electronic Records. PHT ePRO System ePRO Designer PHT ePRO Data Collection Modalities StudyWorks Study Archive Integration with eSense PEF Meters, Integration Glucometers & other measurement devices Mobile devices PHT’s proprietary LogPad capture timely Secure online Complete study and validated rapid Hand-Held and reliable system provides documentation and design tool to facilitate diary data real-time reports of raw data for trial the development of from subjects subject compliance, reconstruction and reliable ePRO studies. enrollment, and safety regulatory review Mobile, touch-screen SitePad tablet captures multiple Tablet questionnaire data from subject and clinicians at sites NetPRO Browser-based Desktop ePRO & ClinRO collection Internet from home or Collection clinician sites The PHT ePRO System meets the requirements of the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), the European Union (EU), the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), and the Pharmaceuticals and Medical Devices Agency in Japan (PMDA) and others. These regulations and guidelines are intended to ensure that the electronic systems used in clinical research are valid and reliable and protected from tampering; that the electronic records such as ePRO diaries are accurate, reliable, and auditable; and that personal information of trial subjects is protected. PHT provides data security through its software applications, data transmissions, physical data storage, database and documentation backups and audit trails.
  • 5. 5Collecting PROs via the Web: Are Data Suitable for Regulatory Submissions?IV. Supporting a Claim via Web-based ePRO, continuedUnlike other ePROproviders, there has neverbeen a warning letter orother regulatory findingsassociated with the use ofthe PHT ePRO System bysites or sponsors. Since1994, patient experiencescaptured by PHT’s ePROSystem have been usedsuccessfully in over 450global trials by more than100 biopharmaceuticalcompanies, resulting inat least 14 regulatorysubmissions and 11approvals. By capturinghigh-quality and time-stamped assessments, trialsponsors are able to runsmaller, safer and more As FDA warning letters are issued to sites and sponsors, PHT comments on the issues citedconclusive clinical research in order to inform our clients how PHT systems avoid or address the problems that othersprograms resulting in encounter. Ask your Account Executive for these documents, and register to receive regularsignificant R&D cost savings. updates at www.phtcorp.com. SummaryThe Web can effectively be used to • Easy availability at both the site and projected to mirror the maturation andcollect patient-reported outcome data for patient’s location, standardization of browsers and Internetregulatory submissions and label claims, connections. • Ease of use and simplicity with the usepost-approval studies and clinical trials. of familiar technology, As the market leader and ePRO pioneer,Unlike other data collection methods,Web-based ePRO makes it possible to • Highly compliant ePRO data without an PHT offers this additional mode ofeconomically access a growing global investment in hardware of any type, and administration to provide sponsors withpatient base that has ready access to more options for ePRO, and to enable the • Increased brand exposure to target democratization of PROs. PHT remainsthis mode of administration. Web-based patients and clinicians with a brandedePRO provides some key benefits: committed to helping sponsors collect ePRO portal for review. faster, more efficient data, and to help• Relatively larger screens, potentially Early adopters of this modality may the clinical research industry develop eliminating any text abbreviations, shorten trial timelines and access new therapies, treat disease and improve larger patient populations. The demand quality of life.• Visible progress bar to illustrate progression through the questionnaire, for collecting Web-based ePRO is
  • 6. 6 1 http://www.internetworldstats. PHT NetPRO com/stats.htm TM 2 FDA Draft Guidance for Industry. Postmarketing Studies and Clinical Trials — Implementation of Section 505(o) of the Federal Food, Drug, Web-based ePRO Collection and Cosmetic Act. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), July 2009. 3 Postmarketing commitments can include surveillance and observational studies conducted with vaccines when data do not suggest a serious risk or signals of serious risk related to the use of the vaccine and when available data to not indicate the potential for serious risk. 4 Guidance for Industry. Patient- Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), December 2009. 5 Ibid, pp. 20-21. Access Global Populations Online Ibid, p. 9 6 PHT NetPRO Collects ePRO Data via the Internet, Reducing the Cost of Post-approval StudiesUS HEADQUARTERS: EUROPEAN HEADQUARTERS:PHT Corporation PHT Corporation Sàrl www.phtcorp.com500 Rutherford Avenue 2, chemin Louis-Hubert Copyright © 2010 PHT CorporationBoston, MA 02129 USA 1213 Petit-Lancy, Geneva, Switzerland Rev 12.2010Toll-Free: 1.877-360-2901 Phone: 41.22.879.91.00