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ePRO ROI
1. PHT Insights — First Quarter 2009
Improving Trial Efficiencies: Making the Business Case for ePRO
How to Quantify ePRO ROI:
What Does Paper Cost? Spotlight On:
Most organizations haven’t assigned a cost The Four Types of Paper Patients
to paper PROs, unless they’re outsourcing
the entire function of data collection and
management to CROs. Here are the numbers:
• A typical study includes 250-300 1. Perfect Patients
complete every field clearly, and in
patients who are in trial for 3
the proper format. Even in this rare
months, required to complete 1 best case scenario, the only way to
diary daily. This translates into know it was completed at 8:00 pm is
90 diaries per patient. because the subject said so.
• Processing each diary involves
form creation, printing,
translation, binding and shipping
to sites; followed by data entry,
transfer, reconciliation, queries
and changes; and finally return
shipment. The estimated cost is 2. Forgetful Patients
are a data manager’s dream, but a
$20/page.
clinical researcher’s nightmare. The
worst part is, you have no way of
Per Patient Cost Paper PRO $1800 knowing that you’re losing data until
Per Patient Average Cost PHT ePRO $1300 it’s too late.
Electronic capture savings per patient $500
• Average savings on a typical study
using ePRO vs. paper is $125,000
– $150,000. 3. Selective Patients
force you to make assumptions -
Does ePRO Data Quality Differ from did the subject mean December or
February? Was the medication taken?
Paper? Doing anything other than throwing
Improvements in data quality provided this away could be dangerous.
by electronic patient reported outcome
systems are widely reported and accepted
throughout the clinical research community.
Patient diary data collected electronically
is time-stamped, legible and logical with
real-time validation provided to patients
while entering diary information. ePRO
4. Enthusiastic Patients have
supports multi-site international trials tremendous energy and want to
with remote data monitoring via the web provide as much information as they
with real-time status reporting overall can. But it is illogical, illegible and
and per site, participant status tracking likely contains AEs. This is an ideal
and on-demand subject randomization. patient for an eDiary!
Contrary to paper diaries, ePRO data
collection can ensure complete patient
Paper diary examples courtesy of Dr. Stuart Donovan
responses. With trustworthy data,
2. PHT Insights - First Quarter 2009
Improving Trial Efficiencies: Making the Business Case for ePRO
trial sponsors no longer run the risk of
having a promising compound rejected Case Study: Novartis
due to unreliable paper PRO data.
Enhanced data integrity further enables The FDA approved a Novartis drug for chronic constipation for use
1. Attributable, legible, with women, but indicated more data would be needed for men.
contemporaneous, original and Therefore, Novartis planned another study and estimated a sample
accurate (ALCOA) patient data
that is complete and time-stamped size of 1,026 male subjects would be required to prove efficacy
through the use of alarms, based on traditional paper variance statistics. Subsequently, the
branching logic and edit checks; pharmaceutical company elected to use PHT’s LogPad System
2. Reduced data variance for
instead of paper.
improved quality of study results
and reduced number of patients to Once the study was already underway, the
show efficacy;
FDA surprised Novartis by deciding to ap- Study power
3. Real time access to diary data prove the drug for men without further was reached
between visits for enhanced safety data. Novartis stopped the trial, but al-
and compliance monitoring; with less than
lowed the 322 enrolled subjects to complete
one-third the
4. Adaptive trial designs with pre- treatment. To the amazement of the clinical
programmed adaptations and team, study power was reached with 69% planned sam-
reduced standard deviation for
fewer subjects - representing less than ple size!
more conclusive planned interim
analyses; and one-third the planned sample size!
5. Libraries of experience and metrics
with data including compliance and
data variance/standard deviations to rely on memory, especially if they reliable methods for recording
for specific indications. must recall over a period of time, of compliance (e.g. electronic
or to average their response over patient diaries) not to include non-
How Does ePRO Enable Faster Trials? a period of time, may threaten the compliers in the denominator.”3
accuracy of the PRO data.
Cycle times and therefore trial times
can be reduced with electronic patient According to the FDA, “If a patient 1) Lines 334-337, ‘Guidance for Industry. Patient-
reported outcomes. Electronic data diary or some other form of Reported Outcome Measures: Use in Medical Prod-
capture eliminates manual data entry unsupervised data entry is used, the uct Development to Support Labeling Claims. DRAFT
times and other data point changes. FDA plans to review the protocol to GUIDANCE.’ U.S. Department of Health and Human
Services, Food and Drug Administration, Center for
Final data analysis sets can be provided determine what measures are taken
Drug Evaluation and Research (CDER), Center for
within days after a trial’s conclusion. to ensure that patients make entries
Biologics Evaluation and Research (CBER), Center
according to the study design and
for Devices and Radiological Health (CDRH). Febru-
By reducing data variance, fewer not, for example, just before a ary 2006
patients are required especially in Phase clinic visit when their reports will be 2) Section 8.1, ‘Note for Guidance on the Clinical
II trials. Scientific outcomes are more collected.”1 Investigation of Medicinal Products in the Treatment
of Asthma’, The European Agency for the Evaluation
conclusive, and greater power of study is
achieved by reduced standard deviation. The European Medicines Agency of Medicinal Products, Evaluation of Medicines for
(EMEA) has also commented Human Use, November 2002.
ePRO does not eliminate the need for on ePRO vs. PRO, providing 3) Section 3.1, ‘Note for Guidance on Clinical In-
vestigation of Steroid Contraceptives in Women, The
accurate data review and monitoring, this Guidance on endpoints in
European Agency for the Evaluation of Medicinal
but it does enable trial sponsors to asthma: “If home recording
Products, Evaluation of Medicines for Human Use,
improve power of study with smaller equipment is used, reproducibility
February 2000.
samples, and to reach no-go decisions is particularly important and an
much faster than they could otherwise. electronic diary record should be
considered to validate the timing of
measurements.”2 ; and on efficacy
What is the FDA position on ePRO?
for steroid contraceptive, “The
The FDA has reviewed ePRO vs. PRO, and separate calculation of the Pearl
cites unsupervised data entry as a major Index for method failure requires
drawback to paper reported outcomes. PRO
instruments [paper] that require patients Continued on Page 4
3. For more information about the benefits PHT can provide
for your global clinical research programs, please visit
www.phtcorp.com
Case Study: Merck Research Laboratories
Merck initiated the first randomized trial to evaluate the relative
capacities of paper diaries and electronic patient diaries (Figure
1) to prove efficacy. 101 patients were randomized to two arms
based on data capture method (paper or LogPad®) and treated
with an approved drug for insomnia. The study examined primary
endpoint data of change in minutes of sleep time and compared Figure 1: A study question on the LogPad and paper diary
results from the arms in many categories.
Data Analysis
Data captured from both arms revealed statistically equivalent means (118 minutes from paper, 109 minutes from
the LogPad), but the ranges were different. As shown in Figure 2, the distribution of responses on paper varied widely
from -20 to 380. This means one subject claimed to have average 20 minutes less sleep per night, while another
reported an additional 6 hours. Further, the distribution tends to cluster around 30-, 60- and 90-minute intervals.
This suggests evidence of recall bias, as responses are more general and less precise when made after-the-fact.
Conversely, the LogPad distribution in Figure 3 is much tighter around the mean and more Gaussian, with
fewer and less extreme outliers. Meanwhile, continuous responses indicate more accurate data reporting. A
visual inspection of Figure 4 shows the comparison of variance.
Figure 2: Paper Distribution Figure 3: LogPad Distribution Figure 4: Distribution Overlay
Results
Analysis performed by Merck showed a 35% lower standard deviation for LogPad data as compared to paper.
Merck calculated that this reduced variance would have enabled them to reach study power with 56% fewer
patients - saving an estimated $340,000 (assuming $6,000 per patient).
In addition, Merck had to process three times more data changes and notification forms to clarify paper data,
and incurred 58 hours of data entry compared to zero for the LogPad arm. Compliance was high in both arms
(96% for paper, 92% for LogPad), but as discussed earlier only ePRO compliance can be verified as opposed
to purported by subjects.
These findings were presented by Jay Pearson, Senior Director at Merck.
![PHT Insights - First Quarter 2009
Improving Trial Efficiencies: Making the Business Case for ePRO
trial sponsors no longer run the risk of
having a promising compound rejected Case Study: Novartis
due to unreliable paper PRO data.
Enhanced data integrity further enables The FDA approved a Novartis drug for chronic constipation for use
1. Attributable, legible, with women, but indicated more data would be needed for men.
contemporaneous, original and Therefore, Novartis planned another study and estimated a sample
accurate (ALCOA) patient data
that is complete and time-stamped size of 1,026 male subjects would be required to prove efficacy
through the use of alarms, based on traditional paper variance statistics. Subsequently, the
branching logic and edit checks; pharmaceutical company elected to use PHT’s LogPad System
2. Reduced data variance for
instead of paper.
improved quality of study results
and reduced number of patients to Once the study was already underway, the
show efficacy;
FDA surprised Novartis by deciding to ap- Study power
3. Real time access to diary data prove the drug for men without further was reached
between visits for enhanced safety data. Novartis stopped the trial, but al-
and compliance monitoring; with less than
lowed the 322 enrolled subjects to complete
one-third the
4. Adaptive trial designs with pre- treatment. To the amazement of the clinical
programmed adaptations and team, study power was reached with 69% planned sam-
reduced standard deviation for
fewer subjects - representing less than ple size!
more conclusive planned interim
analyses; and one-third the planned sample size!
5. Libraries of experience and metrics
with data including compliance and
data variance/standard deviations to rely on memory, especially if they reliable methods for recording
for specific indications. must recall over a period of time, of compliance (e.g. electronic
or to average their response over patient diaries) not to include non-
How Does ePRO Enable Faster Trials? a period of time, may threaten the compliers in the denominator.”3
accuracy of the PRO data.
Cycle times and therefore trial times
can be reduced with electronic patient According to the FDA, “If a patient 1) Lines 334-337, ‘Guidance for Industry. Patient-
reported outcomes. Electronic data diary or some other form of Reported Outcome Measures: Use in Medical Prod-
capture eliminates manual data entry unsupervised data entry is used, the uct Development to Support Labeling Claims. DRAFT
times and other data point changes. FDA plans to review the protocol to GUIDANCE.’ U.S. Department of Health and Human
Services, Food and Drug Administration, Center for
Final data analysis sets can be provided determine what measures are taken
Drug Evaluation and Research (CDER), Center for
within days after a trial’s conclusion. to ensure that patients make entries
Biologics Evaluation and Research (CBER), Center
according to the study design and
for Devices and Radiological Health (CDRH). Febru-
By reducing data variance, fewer not, for example, just before a ary 2006
patients are required especially in Phase clinic visit when their reports will be 2) Section 8.1, ‘Note for Guidance on the Clinical
II trials. Scientific outcomes are more collected.”1 Investigation of Medicinal Products in the Treatment
of Asthma’, The European Agency for the Evaluation
conclusive, and greater power of study is
achieved by reduced standard deviation. The European Medicines Agency of Medicinal Products, Evaluation of Medicines for
(EMEA) has also commented Human Use, November 2002.
ePRO does not eliminate the need for on ePRO vs. PRO, providing 3) Section 3.1, ‘Note for Guidance on Clinical In-
vestigation of Steroid Contraceptives in Women, The
accurate data review and monitoring, this Guidance on endpoints in
European Agency for the Evaluation of Medicinal
but it does enable trial sponsors to asthma: “If home recording
Products, Evaluation of Medicines for Human Use,
improve power of study with smaller equipment is used, reproducibility
February 2000.
samples, and to reach no-go decisions is particularly important and an
much faster than they could otherwise. electronic diary record should be
considered to validate the timing of
measurements.”2 ; and on efficacy
What is the FDA position on ePRO?
for steroid contraceptive, “The
The FDA has reviewed ePRO vs. PRO, and separate calculation of the Pearl
cites unsupervised data entry as a major Index for method failure requires
drawback to paper reported outcomes. PRO
instruments [paper] that require patients Continued on Page 4](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)