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.

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 Corporation
I. Definition: Early adopters of web-based ePRO technology are able to reach
Web-based ePRO is an online browser-based method for PRO data expanding patient populations on all continents. It is estimated
capture 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.1
Similar to the surging interest expressed by regulatory agencies
for sponsors to collect data directly from patients, clinical In addition to the expanding pools of potential patients with
professionals are anxious to leverage the Internet to collect these Internet access, clinical and postmarketing study teams can realize
ePRO data for clinical studies and post-market surveys. Many significant cost savings in design, validation and hosting when
sponsors believe the Web can offer additional ease of use and cost collecting ePRO on the Internet. The Web is a familiar medium
benefit vs. other types of ePRO methods. When configured within to many patients, and using a website to enter information may
an ePRO System, Web-based ePRO can be an economical method not require instruction. Fundamental criteria such as instant edit
for collecting patient endpoint data from large populations, and checks and conditional branching and navigation may be standard
can 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. 2
Collecting 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. Online
many trials across Phase 2 and 3, peri- and post-approval study access by biostatisticians to massive post-market data can
professionals may gain the greatest advantages from collecting expedite baseline risk assessments essential for analysis of
ePRO on the Internet. Browser-based data collection can reach background risk and stratification of that data. Such real-time data
broad audiences to reassure the payor that the former clinical access can serve to readily confirm that outcomes are consistent
trial outcomes apply in real-world settings, and demonstrate across larger populations.
II. 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.
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 a
with 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 for
for 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 collection
method 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 safety
to the target population nor if the Internet is unavailable during
endpoint, such as studies designed to develop an optical
needed response time such as with episodic indications that may
rotation test, or evaluate immune response to concomitant
require data collection at any random time period. Additionally,
vaccination(s) that are a part of routine U.S. immunization
if a reminder system is required for improved diary completion
practice.
compliance, a Web-based ePRO System would require integration
with SMS or IVR reminder systems. Furthermore, patient privacy • Pharmacoepidemiologic studies designed to examine the
must be assured if data is being collected in a community setting, natural history of a disease or to estimate background rates for
academic institution or clinic. adverse events.3
Web-based ePRO is well suited for many post-approval • Clinical trials in which the primary endpoint is related to
studies and clinical trials as described in the FDA Draft further defining efficacy, designed to evaluate efficacy using
Guidance2 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. 3
Collecting 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. 4
Collecting 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. 5
Collecting PROs via the Web: Are Data Suitable for Regulatory Submissions?
IV. Supporting a Claim via Web-based ePRO, continued
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
As FDA warning letters are issued to sites and sponsors, PHT comments on the issues cited
conclusive clinical research
in order to inform our clients how PHT systems avoid or address the problems that others
programs resulting in
encounter. Ask your Account Executive for these documents, and register to receive regular
significant R&D cost savings.
updates at www.phtcorp.com.
Summary
The Web can effectively be used to • Easy availability at both the site and projected to mirror the maturation and
collect patient-reported outcome data for patient’s location, standardization of browsers and Internet
regulatory submissions and label claims, connections.
• Ease of use and simplicity with the use
post-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 of
economically access a growing global investment in hardware of any type, and administration to provide sponsors with
patient base that has ready access to more options for ePRO, and to enable the
• Increased brand exposure to target democratization of PROs. PHT remains
this mode of administration. Web-based patients and clinicians with a branded
ePRO 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 Studies
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