The importance of learning how patients feel and function when taking a new clinical therapy has been acknowledged by the FDA, EMA and other global regulatory authorities. Sponsors currently engaged in drug development programs appreciate and leverage the added value of patient-reported outcome (PRO) data. They no longer ask if PROs should be collected, but what phase to begin PRO collection. This issue of Insights is intended to identify the costs (delays and expenses) of collecting patient-reported outcomes on paper; and compare these against electronic PRO capture. The intention of this issue to provide clinical teams with industry data that can refute the presumption that paper methods are cheaper than ePRO.

1. PHT Insights — When and How to Justify Electronic
Patient-Reported Outcomes (ePROs)
Trial conditions dictate whether and when ePRO should
supersede paper diaries.
The importance of learning how patients feel and function But many mid-sized pharmaceutical companies and CROs are
when taking a new clinical therapy has been acknowledged just beginning to explore ePRO. For them, comparing the costs
by the FDA, EMA and other global of paper diaries to ePRO requires assigning
regulatory authorities. Sponsors costs to the associated support functions
currently engaged in drug development ‘…patient reported outcome for paper methods. Such costs (in time and
programs appreciate and leverage evidence is increasingly money) are distributed across departments
the added value of patient-reported viewed as an essential (clinical operations, data management,
outcome (PRO) data. They no longer complement to traditional submissions, etc.) and it can be nearly
ask if PROs should be collected, but objective clinical evidence impossible to fully account for the many
what phase to begin PRO collection. for establishing a product’s distributed costs of paper.
While it is well known that collecting competitive advantage in This issue of Insights is intended to identify
subjective data on electronic devices the marketplace.’ 1
the costs (delays and expenses) of collecting
(instead of on paper diaries) reduces patient-reported outcomes on paper; and
trial costs and duration, quantifying compare these against electronic PRO
the return on investment ePRO provides by trial phase can capture. The intention of this issue to provide clinical teams
be elusive. Most major pharmaceutical companies have with industry data that can refute the presumption that paper
declared ePRO as the de facto standard for PRO endpoints. methods are cheaper than ePRO.
Contents
Trial conditions dictate whether and when ePRO should p.1 How to Determine if ePRO
supersede paper diaries.
Suits Your Trial Conditions
eClinical Trial Solutions Market, Global, Cost Saving p.2 This issue of Insights assumes
Scenario of ePRO Solutions, 2008 that the reader understands
that ePRO is a good fit for a
Step 1- Identify and select your company’s trial technol- p.2
trial, and needs to justify the
ogy adoption stage
costs of automation.
Step 2- Identify the hidden cost centers for collecting p.3
A previous issue of Insights
PRO on paper diaries
entitled ‘Collecting Electronic
Step 3 - Compare your trial conditions to average or p.3 Patient-Reported Outcomes (ePROs): Comparing the 5 Proven
median costs for global trials within Phases 2 & 3 Ways to acquire Attributed Patient-Reported Data’ details
Table II: How to Quantify Specific ePRO Benefits p.4 how to determine if ePRO is appropriate for a particular trial.
This is available for download at http://www.phtcorp.com
Conclusion p.6 /resources/insights_newsletters/

2. 2
When and How to Justify Electronic Patient-Reported Outcomes (ePROs)
M any clinical trial managers within Sponsors and CROs are
familiar with the data quality and integrity benefits of ePRO,
Step 1:
and recommend ePRO for phase 3 trials where PRO measures serve as
endpoint data. Documented advantages of ePRO include
This document is intended to assist in calculating the
• Simplification of site tasks (storing, correcting, shipping paper diaries),
financial advantages of ePRO over Paper in 3 steps
• Reductions in data variance,
Step 1: Identify and select your company’s trial technology adoption stage;
• Shorter study duration,
Step 2: Identify the hidden cost centers for collecting PRO on paper diaries; and
• Improved protocol compliance through real-time monitoring
(via time-stamped data entry reports), and Step 3: Compare your trial conditions to average or median costs for trials
within Phases 2 & 3.
• Reduced time to database lock.
Identify and select your company’s trial
Cost Saving Scenario of ePRO Solutions technology adoption stage:
To frame the context of your decision, clinical trial managers should
Paper Diaries ePRO
acknowledge the current level of ePRO adoption at their organization. PHT
has found the stage of ePRO adoption, as defined below, helps frame the
Subject decision and ROI for using ePRO in a particular trial. The adoption stage
helps specify which ePRO attributes will be most important to a given trial
Site Review and ROI evaluation. The stages:
Colection
Site Monitor X Saved Cost Stage1
Sent to DM
Sponsors are starting to use a basic ePRO system for simple uses, such
as integrated voice response (IVR) for patient qualification, enrollment
Data Entry
and/or randomization. Paper is the most frequently utilized method of
data collection.
Sponsor DB
Stage2
Medical Monitor and
Statistician IT groups within Sponsors are adopting EDC technologies to gain trial data
efficiencies. Having recognized value from simple IVR ePRO use, these
Source: GBI Research
sponsors are testing other ePRO modalities such as mobile data capture
devices for the subject and/or for the site. Since ePRO systems drive cross-
The paper diary method is a lengthier process than ePRO, resulting functional benefits, data management and health outcome professionals
in increases in cost and time. If Pharmaceutical Companies are collaborate on ePRO evaluations.
adopting ePRO solutions, they save considerable cost and time.2
Stage3
These Sponsors have shifted from paper to EDC. For those trials where
Sponsors and CROs recognize that the ‘…efficiencies linked to new
primary and secondary endpoints will be drawn from data collected directly
technologies generally increase over time as end users gain familiarity with
from patients, the clinical teams expect to use ePRO. Clinical and data teams
them through repeated use.’3 As a result of the quantifiable efficiencies and
prefer ePRO over paper although in some instances management may require
downstream savings of ePRO, more clinical trial managers are also electing
them to use paper for certain trials. For sponsors at this stage, outsourcing
ePRO for their phase 2 trials. Given the critical proceed or stop decisions
professionals are often responsible for selecting CROs and ePRO systems that
that are often made based on Phase 2 results, this makes sense even when
are proven to be successful for large international projects and who have an
there are relatively fewer subjects and a shorter timeline. Such decisions
unblemished record with regulatory authorities.
benefit from a full understanding of the experience of each of the subjects,
and ePRO consistently delivers more pertinent information per subject.
Stage4
Unlike their counterparts within the top ten pharmaceutical giants who All Sponsor clinical management systems are fully integrated with one or more
have come to regard paper diary collection as the exception, clinical trial EDC systems. All note taking, signatures, lab results, imaging and ePROs are
managers within mid-sized pharmas and biotechs must demonstrate electronic. ePRO Systems are used for trials in phases 2 and 3, and in phase
the financial advantages of collecting PRO electronically, since their 4 (post marketing surveillance) trials. Sponsors seek long-term partnerships
organizations are still accustomed to paper diaries. with vendors, especially those willing to share trial risks.

3. 3
When and How to Justify Electronic Patient-Reported Outcomes (ePROs)
Step 2: Step 3:
Identify the hidden cost centers for Compare your trial conditions to
collecting PRO on paper diaries: average or median costs for global
After identifying your adoption stage, the next step is to identify trials within Phases 2 & 3:
which ePRO benefit(s) are most relevant to the evaluation of paper
Refer to Table II–How to Quantify Specific ePRO Benefits on
vs. ePRO data collection.
page 4 to identify which ePRO benefit to quantify, based on your
For example, clinical trial managers whose organization or organization’s technology phase:
therapeutic division is in Stage1 for technology adoption are advised
Example1: Sponsor in Stage1 technology adoption
to focus on reduced site burden, increased compliance, confirmed
time-stamped data entry, increased data availability, reduced data Phase 2 trial with 160 subjects and 19 sites.
loss and decreased enrollment tracking time: Average cost $4,160,000.
ePRO will conservatively save 10% ($416,000.)
of trial costs for these reasons:
Technology Stage • Reduced site burden $300,000.
ePRO Benefits • Increased compliance 67,000.
Stage1 Stage2 Stage3 Stage4
• Confirmed time-stamped data entry 141,000.
A. Reduced site burden X X X X
• Increased data availability 162,000.
B. Timeliness of diary presentation X X X X
• Reduced data loss 52,000.
C. Confirmed time stamped data entry
X X X X
• Decreased enrollment tracking time 15,000.
D. Increased data availability X X X X
Using calculations from Table II, the
E. Reduced data loss X X X X
projected savings would be $737,000. (18%)
F. Decreased enrollment tracking time X X X X
G. Decreased Data Variance
X X X X
Example2: Sponsor in Stage2 technology adoption
H. Decreased Database Lock time
X X X
Phase 3 trial with 800 subjects and 50 sites.
I. Fewer queries and faster resolution time X X X
J. Reduced trial duration X X X
Average cost $15,440,000.
K. Decreased monitoring visits X X
ePRO will conservatively save 10% ($1,544,000.)
of trial costs for these reasons:
L. Increased reuse of systems & components
X X
• Reduced site burden $600,000.
• Increased compliance 247,000.
• Confirmed time-stamped data entry 525,000.
• Increased data availability 602,000.
“Using an e-diary is always recommendable, • Reduced data loss 193,000.
when assessing principal criteria, whatever the • Decreased enrollment tracking time 56,000.
phase (II or III). In this case, the improvement • Decrease in data variance 154,000.
in data quality with ePRO far exceeds the • Decreased database lock 1,315,000.
• Fewer queries and faster
investment in technology.”
resolution time 309,000.
Mrs. Silvia Munoz Chimeno Using calculations from Table II, the
Clinical Project Manager projected savings would be $3,901,000. (25%)
Servier Spain

4. 4
When and How to Justify Electronic Patient-Reported Outcomes (ePROs)
Table II: How to Quantify Specific ePRO Benefits
Benefit of ePRO How to Calculate7 ePRO Savings
A. Reduced site burden When enrollment criteria for studies is calculated by ePRO, a significant
burden from staff is removed. ePRO also ensures that only patients who
belong in the study are actually enrolled.4
Cost benefit of Reduced Site Burden:
• It costs $20,000 to activate a site and $2,000/mo to maintain one
• Average number of sites in Phase 2 & 3 global trials is 35
• Average duration of Phase 2 & 3 global trials is 33 months
• Average site activation and maintenance is $3,000,000
with paper PRO
ePRO reduces site burden of paper administration by 20% $600,000
B. Increased compliance The worthlessness (inaccuracy, untimeliness) of [paper diary] data is
now well accepted, beginning with anecdotal evidence experienced
by researchers decades ago and proven in controlled examination like
that published in the British Medical Journal in 2002.5
Cost benefit of Increased Compliance:
• Data Cleaning consumes 8% of trial time and cost
• Average cost of Phase 2 & Phase 3 global trials is $9,800,000
• Data Cleaning costs $784,000 with paper PRO
ePRO improves compliance by 20%, saving that in Data Cleaning $157,000
C. Confirmed time-stamped data entry When evaluating PRO-based claims, we intend to review the
clinical trial protocol to determine what steps were taken to ensure
that patients understood the instrument recall period.6
Cost benefit of Timely Diary Presentation:
• Patient treatment after enrollment costs 17% of the trial
• Average cost of Phase 2 & Phase 3 global trials is $9,800,000
• Patient treatment after enrollment costs $1,700,000
with paper PRO
ePRO reduces patient treatment costs by 20%, eliminating the cost
of diary data that cannot be submitted due to illegible, untimely
or irrelevant paper entries $340,000
D. Increased Data Availability Cost benefit of Increased Data Availability:
• Site Monitoring consumes 7% of trial time and cost
• Average cost of Phase 2 & Phase 3 global trials is $9,800,000
• Site Monitoring costs $685,000 with paper PRO
• Increased data availability with ePRO reduces site visits by 20% $137,000
• Subject Monitoring consumes 10% of trial time and cost
• Average cost of Phase 2 & Phase 3 global trials is $9,800,000
• Subject Monitoring costs $980,000 with paper PRO
• ePRO reduces study coordinator time required to collect, review
and assign new paper Daily Diaries at each visit, by 25% $245,000
Total ePRO savings of increased data availability $382,000

5. 5
When and How to Justify Electronic Patient-Reported Outcomes (ePROs)
Table II: How to Quantify Specific ePRO Benefits continued
Benefit of ePRO How to Calculate ePRO Savings
E. Decreased Data Loss Cost benefit of Decreased Data Loss:
• Statistical Analysis consumes 5% of trial time and cost
• Average cost of Phase 2 & Phase 3 global trials is $9,800,000
• Statistical Analysis costs $490,000 with paper PRO
ePRO reduces statistical analysis by reducing paper
data loss by 25% $122,500
F. Decreased Enrollment Tracking Time Cost benefit of Decreased Enrollment Tracking Time:
• Site Selection/Enrollment/Contract consumes 12% of trial
time and cost
• Average cost of Phase 2 & Phase 3 global trials is $9,800,000
• Site Selection/Enrollment/Contract consumes $1,176,000
with paper PRO
• Enrollment tracking consumes 6% or $588,000 with paper PRO
ePRO decreases study coordinator enrollment tracking
time by 50% $294,000
G. Decrease in Data Variance Cost benefit of Decreased Data Variance:
• Statistical Analysis consumes 5% of trial time and cost
• Average cost of Phase 2 & Phase 3 global trials is $9,800,000
• Statistical analysis costs $490,000 with paper PRO
ePRO reduces data variance by 20% $98,000
H. Decreased Database Lock Time Cost benefit of Decreased Datase Lock Time [valid for Phase 3 trials]:
• Data Cleaning consumes 8% of trial time and cost
• Average cost of Phase 3 global trials is $15,440,000
• Data Cleaning consumes 8% , or $1,235,000 with paper PRO
• ePRO reduces data cleaning by 20% $247,000
• Average cost of Phase 3 global trials is $15,440,000
• Database lock consumes 37% of the trial time and cost, or $5,712,800
• ePRO reduces database lock time by 18.7% $1,068,000
Total ePRO savings of decreased database lock time. $1,315,000
I. Fewer Queries & Faster Resolution Time Cost benefit of Reduced Queries:
• Subject Monitoring & Administration consumes 10% of trial
time and cost
• Average cost of Phase 2 & Phase 3 global trials is $9,800,000
• Subject Monitoring & Administration costs $980,000
with paper PRO
• Queries and data cleaning consumes 25% of Subject Monitoring
& Administration, or $245,000
ePRO reduces queries by 80%, saving 2% of trial time and cost $196,000

6. 6
Call PHT for these FREE ePRO decision tools:
Conclusion
There are many tangible economic reasons to utilize PRO Selection Tool:
ePRO instead of paper diaries in a clinical trial. Data
• Which collection method for PRO data will best
supports the solid business case to elect ePRO for trials
support your trial—Paper or ePRO?
across phases whenever the patient perspective is
critically important to prove the safety and efficacy of a
therapy. Even if the patients’ perspective is NOT critical,
Sponsors may elect ePRO to remain competitive and
elicit maximum data regarding patient experiences, side 1. Will PRO data be
used to support
2. Is the PRO data
intended for an
3. Are you collecting
sensitive, personal
4. Is subject recruitment
difficult?
PAPER
a claim? FDA/EMEA/other data? • Paper is practical for supervised
effects, outcomes and the overall benefits a given drug
PRO data collection where the
agency Fast Track, subject population is abundant,
Accelerated Approval PRO data are not personal, or
when there are no plans for PRO
NO or Priority Review? NO NO NO data submission.
YES YES YES YES
offers vs. the competition. ePRO
• Regulatory agencies recommend that the PRO
data collection method be capable of ensuring
that reports are done on schedule, as defined by
ePRO
• ePRO on-demand data enables rapid access for
independent evaluation or analysis, and is appropriate
for any regulatory body that will want to meet with
ePRO
• Subjects welcome the opportunity to record without
embarrassment, and appreciate that caregivers and
family lack access to their personally revealing
ePRO
• ePRO data has been shown to cluster to the mean
value (lower standard deviation) compared to paper
data, enabling smaller sample sizes in Phase 2
ePRO
• Provides regulatory agencies
the protocol time requirement. “If a patient diary the sponsor regularly to review the data (possibly for information. trials and more rapid, conclusive Phase 3 trials. with proof that the protocol
or some other form of unsupervised data entry is an expedited process). time requirements were met
used, we plan to review the clinical trial protocol • Subjects are more willing to provide more
to determine what steps are taken to ensure that • Rapid access to data enables adaptive design and complete data. • Provides on-demand data for
other trial efficiencies. evaluation or analysis
patients make entries according to the clinical
trial design and not, for example, just before a • Improves subject compliance
More robust online ROI and ePRO Decision Tools are
clinic visit when their reports will be collected.” when private or sensitive data
is collected
• Enables smaller sample sizes
Insist on ePRO data for rapid analysis.
available from your PHT Account Executive. These Tools
are designed to guide clinical trial managers through www.phtcorp.com
©2010 PHT Corporation
v12010
Trust Your Patient Data
US 1.877.360.2901
EUR 41.22.879.91.00
a short series of questions about their trial, in order to
summarize which ePRO modality is best suited for the
trial, and how to quantify and justify collecting trial data Online ePRO Decision Tool:
on ePRO vs. paper diaries.
• Which ePRO collection method will best support your protocol?
PHT SitePad Tablet
–The mobile
touch-screen tablet
for ePRO data
collected at sites
US 1.877.360.2901 • EUR 41.22.879.91.00
1
Doward et al, “Patient reported outcomes: looking beyond the label claim”, August 2010.
PHT LogPad– 2
GBI Research, “The Future of eClinical Trial Solutions - Market Forecasts to 2015, Competitive
Hand Held Benchmarking and Case Studies,” GBI Research, GBIHC021MR (December 2009): p.3.
for patients 3
Applied Clinical Trials, “The Upfront Cost Hurdle of EDC”, April 2010: p. 52
on-the-go 4
Pompa et al, GlaxoSmithKline, July 2008 Powerpoint presentation “ePRO Awareness Session”.
5
Stone, et al., Patient non-compliance with paper diaries, BMJ 324: 1193, 18 May 2002.
6
FDA, Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development
to Support Labeling Claims, p.14, December 2009”
7
Paraxel’s Bio/Pharmaceutical R&D Statistical Sourcebook 2009/2010, with extrapolations.
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