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Improving Trial Efficiencies: Making the Business Case for ePRO

PHT Insights — First Quarter 2009

Spotlight On:The Four Types of Paper Patients

1. Perfect Patientscomplete every field clearly, and in the proper format. Even in this rare best case scenario, the only way to know it was completed at 8:00 pm is because the subject said so.

2. Forgetful Patientsare a data manager’s dream, but a clinical researcher’s nightmare. The worst part is, you have no way of knowing that you’re losing data until it’s too late.

3. Selective Patientsforce you to make assumptions - did the subject mean December or February? Was the medication taken? Doing anything other than throwing this away could be dangerous.

4. Enthusiastic Patients have tremendous energy and want to provide as much information as they can. But it is illogical, illegible and likely contains AEs. This is an ideal patient for an eDiary!

Paper diary examples courtesy of Dr. Stuart Donovan

What Does Paper Cost?

Most organizations haven’t assigned a cost 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 • patients who are in trial for 3 months, required to complete 1 diary daily. This translates into 90 diaries per patient.

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 $20/page.

Average savings on a typical study • using ePRO vs. paper is $125,000 – $150,000.

Does ePRO Data Quality Differ from Paper?

Improvements in data quality provided 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 supports multi-site international trials with remote data monitoring via the web with real-time status reporting overall and per site, participant status tracking and on-demand subject randomization.

Contrary to paper diaries, ePRO data collection can ensure complete patient responses. With trustworthy data,

How to Quantify ePRO ROI:

Per Patient Cost Paper PRO $1800Per Patient Average Cost PHT ePRO $1300

Electronic capture savings per patient $500

PHT Insights - First Quarter 2009


trial sponsors no longer run the risk of having a promising compound rejected due to unreliable paper PRO data. Enhanced data integrity further enables

Attributable, legible, 1. contemporaneous, original and accurate (ALCOA) patient data that is complete and time-stamped through the use of alarms, branching logic and edit checks;

Reduced data variance for 2. improved quality of study results and reduced number of patients to show efficacy;

Real time access to diary data 3. between visits for enhanced safety and compliance monitoring;

Adaptive trial designs with pre-4. programmed adaptations and reduced standard deviation for more conclusive planned interim analyses; and

Libraries of experience and metrics 5. with data including compliance and data variance/standard deviations for specific indications.

How Does ePRO Enable Faster Trials?

Cycle times and therefore trial times can be reduced with electronic patient reported outcomes. Electronic data capture eliminates manual data entry times and other data point changes. Final data analysis sets can be provided within days after a trial’s conclusion.

By reducing data variance, fewer patients are required especially in Phase II trials. Scientific outcomes are more conclusive, and greater power of study is achieved by reduced standard deviation.

ePRO does not eliminate the need for accurate data review and monitoring, but it does enable trial sponsors to improve power of study with smaller samples, and to reach no-go decisions much faster than they could otherwise.

What is the FDA position on ePRO?

The FDA has reviewed ePRO vs. PRO, and cites unsupervised data entry as a major drawback to paper reported outcomes. PRO instruments [paper] that require patients

Case Study: Novartis

The FDA approved a Novartis drug for chronic constipation for use with women, but indicated more data would be needed for men. Therefore, Novartis planned another study and estimated a sample size of 1,026 male subjects would be required to prove efficacy based on traditional paper variance statistics. Subsequently, the pharmaceutical company elected to use PHT’s LogPad System instead of paper.

Once the study was already underway, the FDA surprised Novartis by deciding to ap-prove the drug for men without further data. Novartis stopped the trial, but al-lowed the 322 enrolled subjects to complete treatment. To the amazement of the clinical team, study power was reached with 69% fewer subjects - representing less than one-third the planned sample size!

Study power was reached

with less than one-third the planned sam-

ple size!

to rely on memory, especially if they must recall over a period of time, or to average their response over a period of time, may threaten the accuracy of the PRO data.

According to the FDA, “If a patient diary or some other form of unsupervised data entry is used, the FDA plans to review the protocol to determine what measures are taken to ensure that patients make entries according to the study design and not, for example, just before a clinic visit when their reports will be collected.”1

The European Medicines Agency (EMEA) has also commented on ePRO vs. PRO, providing this Guidance on endpoints in asthma: “If home recording equipment is used, reproducibility is particularly important and an electronic diary record should be considered to validate the timing of measurements.”2 ; and on efficacy for steroid contraceptive, “The separate calculation of the Pearl Index for method failure requires

1) Lines 334-337, ‘Guidance for Industry. Patient-

Reported Outcome Measures: Use in Medical Prod-

uct Development to Support Labeling Claims. DRAFT

GUIDANCE.’ 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). Febru-

ary 2006

2) Section 8.1, ‘Note for Guidance on the Clinical

Investigation of Medicinal Products in the Treatment

of Asthma’, The European Agency for the Evaluation

of Medicinal Products, Evaluation of Medicines for

Human Use, November 2002.

3) Section 3.1, ‘Note for Guidance on Clinical In-

vestigation of Steroid Contraceptives in Women, The

European Agency for the Evaluation of Medicinal

Products, Evaluation of Medicines for Human Use,

February 2000.

Continued on Page 4

reliable methods for recording of compliance (e.g. electronic patient diaries) not to include non-compliers in the denominator.”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 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.

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.

Figure 1: A study question on the LogPad and paper diary

Figure 2: Paper Distribution Figure 3: LogPad Distribution Figure 4: Distribution Overlay

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Copyright © 2009 PHT Corporation

PHT Insights - First Quarter 2009


Discover: The SitePad Tablet

Read about PHT’s revolutionary site-based device in Insights Q1 2008 issue in detail.

The large-screen device allows for finger-tip data entry and supports complex questionnaires and a response options such as the 10cm VAS.

To learn more, visit the SitePad Tablet virtual launch center at www.phtcorp.com

and schedule an in-person demo today.

“ I believe the SitePad Tablet is something

that can help our entire industry,

and patients, as well,” says Joachim Löwin, Clinical Information Science Leader, AstraZeneca.

Read About: Banning Paper Diaries

Why Paper Diaries Should Be Banned in Clinical TrialsPharmaceutical Executive Europe, March, 2009

PHT author Valdo Arnera, MD, outlines specific reasons why pharmaceutical and biotechnology companies should replace paper diaries with ePRO.

Read it online at: www.phtcorp.com.

Visit About Us and Making ePRO News

About PHT Corporation PHT is the market-leading provider of electronic patient reported outcome (ePRO) solutions used in more than 390 clinical trials by 110 biopharmaceutical clients. The proven LogPad® System and revolutionary SitePad™ Tablet deliver the voice of the patient, in 80 languages, from homes and sites in 60 countries around the world. By capturing high-quality and time-stamped assessments with minimal respondent burden, trial sponsors are able to run smaller and more conclusive clinical research programs resulting in significant R&D cost savings. Real-time study management through PHT StudyWorks™ features eClinical data integration, standard and custom data summaries for compliance and enrollment, SafetyPRO™ email alerts, and the industry’s premier study archive. Patient experiences captured firsthand by PHT’s ePRO Product Suite have been used successfully in at least 11 NDA submissions and seven approvals to date. For more information, review interactive product demonstrations at the award-winning www.phtcorp.com

PHT, LogPad, eSense, StudyWorks, SafetyPRO and SitePad are among the registered trademarks and trademarks of PHT Corporation.

Which Trials are Best Suited for ePRO?

Trials with patient reported endpoints – whether in home or in medical offices – report rapid gains in efficiencies and data integrity with ePRO. Trials within these therapeutic areas (TAs) have been early adopters of ePRO:

Neurology/CNS• Respiratory• Behavior Modification• Gastrointestinal • Genitourinary• Immunology•

PHT has also demonstrated ePRO efficiencies within

Oncology• Endocrine and meta-• bolic disordersDermatology• Ears, nose, throat, eye • and teethMusculo-skeletal•

Trials across TA where patient reported data is sensitive in nature, where it’s critical to track adverse symptoms between visits such as worsening symptoms, rescue medications, specific events such as suicide ideation also received increased ROI when utilizing ePRO.

Summary

Sponsors, trial managers and health outcome directors continue to obtain greater degrees of data quality, program efficiency and patient’s safety with ePRO. For more information, contact PHT at 1.877.360.2901.