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

The proliferation and global adoption of the Web are 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.

— Chris Hall, PHT Corporation

PHT Insights – Fourth Quarter 2010

Contents

I. Web-based ePRO Definition and Overview

p.1

II. Ideal Trial Conditions for Web-based ePRO

p.2

III. Psychometric Validations Required for Web-based ePRO

p.3

IV. Supporting a Claim using Web-based ePRO

p.5

Summary p.5

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 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 postmarketing 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.

Internet Users in the World-Distribution by World Regions 2010

I. Definition:

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.

2

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

While clinical trial managers can leverage Web-based ePRO for many trials across Phase 2 and 3, 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 payor 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 can serve to readily confirm that outcomes are consistent across larger populations.

Hand Held IVR Internet Pen Tablet

1. Hand Held Device: Electronic data capture on a mobile device

with a central system that allows for Web review;

2. IVR (Interactive Voice Response): Keypad or voice data capture

with a central system that allows for Web review by site and sponsor;

3. Internet Web data capture with a central system that allows for Web

review by site and sponsor;

4. Pen: Digital pen that captures data and uploads to a central system

that allows for Web review; and

5. Tablet: Electronic data capture on a tablet mobile device with a

central system that allows for Web review.

W hile 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 post-approval studies and clinical trials as described in the FDA Draft Guidance2 on same:

• 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 prespecified 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 U.S. 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.

II. Ideal Trial Conditions for Collecting Web-based ePRO

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.

3

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 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.

[Not] “…every small change in application or format necessitates 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 instrument”5

Table 1. Common Reasons for Changing Items during PRO Instrument Development

Item Property Reason for Change or Deletion Clarity or relevance Reported as not relevant by a large segment of the target population

Generates an unacceptably large amount of missing data points Generates many questions or requests for clarification from patients as they complete the PRO instrument Patients interpret items and responses in a way that is inconsistent with the PRO instrument’s conceptual framework

Response range A high percent of patients respond at the floor (response scale’s worst end) or ceiling (response scale’s optimal end) Patients note that none of the response choices applies to them Distribution of item responses is highly skewed

Variability All patients give the same answer (i.e., no variance) Most patients choose only one response choice 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 one assessment to the next

Inter-item correlation Item highly correlated (redundant) with other items in the same concept of interest

Ability to detect change Item is not sensitive (i.e., does not change when there is a known change in the concepts of interest)

Item discrimination Item is highly correlated with measures of concepts other than the one it is intended to measure Item does not show variability in relation to some known population characteristics (i.e., severity level, classification of condition, or other known characteristic)

Redundancy Item duplicates information collected with other items that have equal or better measurement properties

Recall period The population, disease state, or application of the instrument can affect the appropriateness of the recall period

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:

NO

NO

NO

Data from PRO will be used to support labeling claim or

promotional materials

Subjects with indication involved in item generation

Paper version is reliable, valid,

sensitive to change

YES

YES

Conversion to ePRO

Validation work at

sponsor’s discretion

Full Validation

Quantitative Testing

SMALL:CognitiveDebriefing

MEDIUM:Equivalence

Testing

LARGE:Full

Validation

YES

KEY

FDA

ISPOR

Validation Decisions: FDA and ISPOR Guidelines

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

4

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’s proprietary and validated rapid

design tool to facilitate the development of

reliable ePRO studies.

StudyWorks

Secure online system provides

real-time reports of subject compliance,

enrollment, and safety

Study Archive

Complete study documentation and

raw data for trial reconstruction and regulatory review

Integration with PEF Meters, Glucometers & other measurement devices

Mobile devices capture timely and reliable diary data from subjects

Mobile, touch-screen tablet captures multiple questionnaire data from subject and clinicians at sites

eSense Integration

LogPad Hand-Held

SitePad Tablet

PHT ePRO Data Collection Modalities

Browser-based ePRO & ClinRO collection from home or clinician sites

NetPRO DesktopInternet Collection

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.

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

5

Unlike other ePRO providers, there has never been a warning letter or other regulatory findings associated with the use of the PHT ePRO System by sites or sponsors. Since 1994, patient experiences captured by PHT’s ePRO System have been used successfully in over 450 global trials by more than 100 biopharmaceutical companies, resulting in at least 14 regulatory submissions and 11 approvals. By capturing high-quality and time-stamped assessments, trial sponsors are able to run smaller, safer and more conclusive clinical research programs resulting in significant R&D cost savings.

The Web can effectively be used to collect patient-reported outcome data for regulatory submissions and label claims, post-approval 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 mode of administration. Web-based ePRO provides some key benefits:

• Relatively larger screens, potentially eliminating any text abbreviations,

• Visible progress bar 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, and

• 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.

As the market leader and ePRO pioneer, PHT offers this additional mode of administration to provide sponsors with more options for ePRO, and to enable the democratization of PROs. PHT remains committed to helping sponsors collect faster, more efficient data, and to help the clinical research industry develop new therapies, treat disease and improve quality of life.

Summary

As FDA warning letters are issued to sites and sponsors, PHT comments on the issues cited in order to inform our clients how PHT systems avoid or address the problems that others encounter. Ask your Account Executive for these documents, and register to receive regular updates at www.phtcorp.com.

IV. Supporting a Claim via Web-based ePRO, continued

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

U S H E A D Q U A R T E R S :

PHT Corporation500 Rutherford AvenueBoston, MA 02129 USAToll-Free: 1.877-360-2901

E U R O P E A N H E A D Q U A R T E R S :

PHT Corporation Sàrl2, chemin Louis-Hubert1213 Petit-Lancy, Geneva, SwitzerlandPhone: 41.22.879.91.00

www.phtcorp.comCopyright © 2010 PHT Corporation

Rev 12.2010

6

1http://www.internetworldstats.

com/stats.htm 2FDA Draft Guidance for Industry.

Postmarketing Studies and Clinical

Trials — Implementation of Section

505(o) of the Federal Food, Drug,

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. 3Postmarketing 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. 4Guidance 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. 5Ibid, pp. 20-21. 6Ibid, p. 9

PHT NetPROTM

Web-based ePRO Collection

Access Global Populations Online

PHT NetPRO Collects ePRO Data via the Internet,

Reducing the Cost of Post-approval Studies