Collecting PROs via the Web: Are Data Suitable for Regulatory Submissions?

March 29, 2011

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The definition of web-based ePRO

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 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 web-based mode of administration for electronic patient reported outcome (ePRO). It will explain which types of trials are best suited for this mode of administration, discuss psychometric validations required, and explain how and when ePRO data collected via the web can support a claim.

Web-based ePRO is an online, browser-based method for PRO data capture that sends data to a central server and database that allows for web review by site and sponsor. 

Similar to the surging interest expressed by regulatory agencies for sponsors to collect data directly from patients, clinical professionals are anxious to leverage the Internet to collect these ePRO data for clinical studies and post-market surveys. Many sponsors believe the web can offer additional ease of use and cost benefit vs. other types of ePRO methods.  When configured within an ePRO System, web-based ePRO can be an economical method for collecting patient endpoint data from large populations, and can be used to submit PRO data to support a label claim.

Early adopters of Web-based data ePRO technology are able to reach expanding patient populations on all continents. It is estimated that 28.7% of the world’s population has Internet access, representing a 444% growth in the last ten years. Over 77% of the North American population has Internet access.1

In addition to the expanding pools of potential patients with Internet access, clinical and post-marketing study teams can realize significant cost savings in design, validation and hosting when collecting ePRO on the Internet. The web is a familiar medium to many patients, and using a website to enter information may not require instruction. Fundamental criteria such as instant edit checks and conditional branching and navigation may be standard since the web is highly structured for data collection.

While clinical trial managers can leverage web-based ePRO for many trials across Phase II and III, peri and post-approval study professionals may gain the greatest advantages from collecting ePRO on the Internet. Browser-based data collection can reach broad audiences to reassure the payer that the former clinical trial outcomes apply in real-world settings, and demonstrate improved outcomes and or comparative effectiveness. Online access by biostatisticians to massive post-market data can expedite baseline risk assessments essential for analysis of background risk and stratification of that data. Such real-time data access also serves to readily confirm that outcomes are consistent across larger populations.

Ideal trial conditions for collecting web-based ePRO

To 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 of data 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.

While data collection via web-based ePRO seems intuitively simpler and easy to deploy, it is not the preferred collection method for many trials and studies. Specifically, it is not suitable if an Internet connection is not reliable, constant, and available to the target population, nor if the Internet is unavailable during needed response time such as with episodic indications that may require data collection at any random time period. Additionally, if a reminder system is required for improved diary completion compliance, a web-based ePRO System would require integration with SMS or IVR reminder systems. Furthermore, patient privacy must be assured if data is being collected in a community setting, academic institution, or clinic.

Web-based ePRO is well suited for many postmarketing studies and clinical trials as described in the FDA Draft Guidance on same:2

  • 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, such as drug dose, timing of exposure, or patient characteristics.

  • Clinical trials with a primary safety endpoint, evaluated with pre-specified assessments.

  • Studies or clinical trials to evaluate the pharmacokinetics of the drug in the labeled population or in a subpopulation at potential risk for high drug exposures that could lead to toxicity.

  • 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.

  • Drug and biologic quality studies that do not have a safety endpoint, such as studies designed to develop an optical rotation test, or evaluate immune response to concomitant vaccination(s) that are a part of routine US immunization practice.

  • Pharmacoepidemiologic studies designed to examine the natural history of a disease or to estimate background rates for adverse events.3

  • Clinical trials in which the primary endpoint is related to further defining efficacy, designed to evaluate efficacy using a withdrawal design or evaluate long-term effectiveness or duration of response.

To summarize, the optimal trial or study conditions for collecting web-based ePRO involve available patient populations in North America and western Europe; regularly scheduled or infrequent data collection time periods; and, relatively simple diaries or questionnaires.

Psychometric validations required for web-based ePRO

Similar to all PRO instruments that are transitioned from paper to electronic capture, the web-based ePRO instruments must be documented to capture all of the most clinically important concepts and items. These items must be complete, relevant (appropriate), and understandable to the patient. 

Similar to all other ePRO modes of administration, the  FDA Final Guidance on PRO4 and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines recommend instruments migrated to a new modality be validated with cognitive debriefing, equivalence testing or full psychometric validation, depending on the type of modification made to the diaries or questionnaires.

The Final FDA Guidance advises that every small change in application or format does not necessitate “…extensive studies to document the final version’s measurement properties. Additional qualitative work may be adequate depending on the type of modification made. Examples of changes that can alter the way that patients respond to the same set of questions include:

  • Changing an instrument from paper to electronic format

  • Changing the timing of or procedures for PRO instrument administration within the clinic visit

  • Changing the application to a different setting, population, or condition

  • Changing the order of items, item wording, response options, or recall period or deleting portions of a questionnaire

  • Changing the instructions or the placement of instructions within the PRO instrument5

Upgrading subsequent trials or studies to collect data via web-based ePRO are an acceptable reason for PRO Instrument change according to the Final Guidance6

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.

Among the agencies with regulations and guidelines for data collection are the United States Food and Drug Administration (FDA), the European Medicines Agency (EMEA), the European Union (EU), the International Conference on Harmonization 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. Data security may be provided through the ePRO vendor’s software applications, data transmissions, physical data storage, database and documentation backups, and audit trails. 

In summary, the web can effectively be used to collect patient-reported outcome data for regulatory submissions and label claims, postmarketing studies, and clinical trials. Unlike other data collection methods, web-based ePRO makes it possible to economically access a growing global patient base that has ready access to this modality. web-based ePRO provides key benefits:

  • Relatively larger screens, potentially eliminating any text abbreviations

  • Visible progress bars to illustrate progression through the questionnaire

  • Easy availability at both the site and patient’s location

  • Ease of use and simplicity with the use of familiar technology.

  • Highly compliant ePRO data without an investment in hardware of any type

  • Increased brand exposure to target patients and clinicians with a branded ePRO portal for review

Early adopters of this modality may shorten trial timelines and access larger patient populations. The demand for collecting web-based ePRO is projected to mirror the maturation and standardization of browsers and Internet connections.

Sheila Rocchio is Vice President of Marketing at ePRO Systems provider PHT Corporation. Her mission is to deliver high value ePRO products that delight trial sponsors and provide an excellent end user experience to sites and subjects. She can be reached at srocchio@phtcorp.com

References

  1. http://www.internetworldstats.com/stats.htm
  2. FDA Draft Guidance for Industry. Postmarketing Studies and Clinical Trials—Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act US 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, US 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.
  6. Ibid, p. 9