PHT Insights

Contents

ePRO Collection Methods Suitable to Diabetes Trials, Studies and Registries

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Development and Conversion of the Diabetes Health Profile Questionnaire for Electronic Data Collection

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Commonly Asked Questions about Paper to ePRO Transitions for a Diabetes Indication

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Conclusions p.8

Diabetes has rapidly become a global epidemic affecting more than 238 million people. That number is expected to increase to 438 million people by the year 2030. The economic burden of the disease totalled 376 billion dollars in 2010. As such, biopharmaceutical companies and researchers around the world are working to identify new, effective and safe treatments to help this growing patient population.

Diabetes clinical research often includes patient reported outcomes (PROs) to measure symptoms and safety over the course of the trial, quality of life and the economic burden of the disease. Data are collected directly from patients on diaries and/or questionnaires, which are either printed on paper or available on electronic devices. The use of electronic patient reported outcomes (ePROs) in clinical research is increasing as regulatory authorities acknowledge the credibility of such data, particularly in comparison to paper and pencil self-reports completed in unsupervised settings. Many sponsors leverage technologies by collecting symptom, event,

and quality of life (QOL) data on the same electronic platform, simplifying and streamlining the entire data collection and management process.

Transitioning a diary or questionnaire from paper to electronic formats requires physically modifying the appearance of the diary or questionnaire to fit on the screen of a device. The primary goal when transitioning from the use of paper questionnaires to versions administered electronically is to preserve psychometric validation by minimizing the degree of change between the paper version and the electronic one. The likelihood of comparability or measurement equivalence of the ePRO version to the paper one depends on the degree to which there is modification of the content, format, and usability of the PRO items and scales.

This edition of Insights highlights the conversion from paper to ePRO for a PRO instrument designed to assess the impact of diabetes on the quality of life of patients with diabetes.

ePRO for Clinical Trials, Observational Studies and Registry Studies of Patients with Diabetes

Featuring ‘Creating and Validating the Diabetes Health Profile (eDHP-18) for Electronic Data Collection’ by Dr. Keith Meadows, Founder & Director DHP Research

& Consultancy Ltd

“Although paper–based PROs are an

established and accepted medium which

are easy to reproduce and distribute,

ePROs offer a number of distinct advantages

over paper.“

Dr. Keith MeadowsFounder & Director DHP Research & Consultancy Ltd www.dhpresearch.com

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For many sponsors and CROs, the decision to collect patient data on paper diaries or electronic ones is an economic issue. When the trials or studies are not collecting endpoint data, the disadvantages of paper methods may be manageable. If the data are intended to support an endpoint with the diabetes trial or study collecting data for submission or post-marketing verification, the following issues with paper become too expensive in terms of risk and resources :

1. Real time data are not available to support timely enrollment decisions, to manage compliance, to detect emerging problems in the trial or to support adaptive trial designs.

2. Incomplete diaries and reports are common.

3. Safety review teams and regulatory authorities must work from low quality records.

4. Logical inconsistencies in the records occur as subjects fail to follow conditional branching properly, usually necessitating the expense and difficulty of source data verification and clarification.

5. There are no real-time automated alerts if symptom thresholds or other criteria are exceeded.

6. Contingent messages and reminders to participants are more difficult to generate and are delayed.

7. Side effects and unexpected problems that deserve review by investigators are unstructured and unavailable in a timely fashion.

8. Recall bias is introduced when subjects do not complete PROs according to the protocol’s schedule. This bias can obscure real signals from the study medication.

Of the five different ways to collect ePRO, Sponsors and CROs prefer the tablet, smartphone (handheld) and Internet for diabetes research. The digital pen and integrated voice response (IVR) do not integrate with glucometers to capture blood glucose levelsautomatically. The PHT SitePad® [tablet], LogPad® [smartphone handheld] family and NetPRO™ [Internet] have been used to collect ePRO symptom and safety data, and integrate that data with glucose readings recorded directly from wireless connected glucometers.

PHT Insights - Q2 2011ePRO Collection Methods Suitable for Type I and II Diabetes Clinical Trials, Observational Studies and Registries

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PHT has provided capture and review systems for hundreds of global ePRO trials, including many investigating treatments for subjects with Type 1 or Type 2 diabetes. The shared objective of all such trials is obtaining “substantial evidence” for claims of efficacy or safety for pre-approval treatments. Capture of data of high quality and unimpeachable integrity is the keystone that helps scientists and reviewers at regulatory authorities trust findings of studies that support label claims. Diabetes programs are similar to other therapeutic areas, but often require these additional components:

• Patient data collection at various locations - the site, at home, at work, at school, etc.,

• Study designs with inclusion and exclusion criteria that involve daily measures during screening;

• Complex randomization schemes and various defined treatment regiments;

• Requirements for treatment and management of emergent events anticipated with these patients; and

• Safety alerts and reminders.

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Insulin Treatment Satisfaction Questionnaire (ITSQ)

Brief Pain Inventory Short Form (BPI-SF)

SF-36v2™ Health Survey (Standard)

EuroQol-5 Dimensions (EQ-5D)

McGill Pain Questionnaire (SF-MPQ)

Neuropathic Pain Scale (NPS)

SF-36v2™ Health Survey (Acute)

Profile of Mood States - Brief (POMS)

3PHT Insights - Q2 2011ePRO Collection Methods Suitable for Type I and II Diabetes Clinical Trials, Observational Studies and Registries

IntroductionDiabetes Mellitus is a prevalent chronic condition affecting approximately 55.5 million adults in Europe and 29.5 million adults in North America. The long term health impacts of diabetes may include heart disease, kidney failure and microvascular complications such as neuropathy and retinopathy. Alongside these health complications, diabetes can also have an adverse impact on the patient’s psychological and emotional functioning , and social activity and behaviour.

The importance of using patient reported outcome (PRO) measures in the care and treatment of people with diabetes has over the past two decades gained significant prominence. This has resulted in the development of a variety of diabetes-specific outcome measures to assess the impact of living with diabetes and its treatment including, quality of life, health-related

quality of life (HRQoL), health status, treatment satisfaction and symptoms.

One such instrument is the Diabetes Health Profile (DHP-18) which as a quality life questionnaire was initially developed as a patient self-completion instrument for use across a range of settings including clinical trials, research, clinical practice and population surveys.

The Diabetes Health Profile– An OverviewDerived from the original 32-item DHP-1 , the DHP-18 has been developed specifically to assess the impact of diabetes-related aspects of psychological and behavioural functioning on the quality of life of people with Type 1 and Type 2 diabetes aged 18 years and older and as such offers a significant benefit for example in assessing the efficacy of different treatment modalities such as changing from pre-insulin to insulin.

The tablet, smartphone (handheld) and Internet provide easy-to-read screens for electronic diaries and questionnaires, enabling clearquestion displays and unambiguous areas for touch-screen or stylus responses. PHT has managed many trials for Diabetic Neuropathy, Diabetes, Diabetic Peripheral and Neuropathy indications. PHT has implemented a number of standardized questionnaires…

By Dr. Keith Meadows, Founder & Director DHP Research & Consultancy LtdCreating and Validating the Diabetes Health Profile (eDHP-18) for Electronic Data Collection

Special Insights FeatureThe DHP-18 is a ubiquitous diabetes questionnaire that has been extensively used in its paper form to capture QOL data from diabetes patients. PHT is pleased to have Dr. Keith Meadows, the DHP-18 questionnaire developer and copyright owner, present his scientific views on how this questionnaire was adapted for electronic administration, and why electronic questionnaires are preferable to paper.

Reliability, Clinical Utility and User Acceptability of the DHP-18The DHP-18 has been evaluated and described as having good evidence for reliability and internal and external construct validity and is one of the few diabetes-specific outcome assessment instruments to have involved diabetes patients in its development.

The clinical utility of the DHP-18 has been demonstrated by its abil-ity to discriminate between patients groups treated with insulin, oral treatment and diet, presence of microvascular complications, weight gain, non-adherence to treatment and severe hypoglycae-mic episodes. To further enhance the clinical utility of the DHP-18, work is in progress by a team led by John Brazier, Professor of Health Economics at the University of Sheffield to derive a utility

scale from the DHP-18 for calculating Quality-Adjusted Life Years (QALYs).

To date the DHP-18 has been administered mainly as a patient self-completion pencil/paper format and has been shown to have high user acceptability with questionnaire postal response rates of approximately 70% and total item completion rates of 90%. Results from cognitive debriefings across a wide range of language groups have also shown there to be minimal difficulties in patients understanding of the meaning of the 18-items.

The paper version of the DHP-18 has been translated for use in 26 languages for use across Europe including, Bulgarian, Czech, French, German, Slovak, Slovenian, Spanish and Swedish as well

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Comprising 18-items which are scored using a 4-point Likert type scale, items are summed to provide three subscale scores using a 0-100 metric for: (i) Psychological distress, (ii) Perceived barriers to activity and (iii) Eating problems, which despite the importance of eating behaviour in the management of diabetes, is largely neglected in the majority of diabetes-specific PROs. The DHP-18 can be administered through a range of modalities including paper, read to the respondent face-to-face as well as administered over the telephone, with average completion times of 6-8 minutes.

Globally, the DHP-18 has been completed by nearly 5000 respondents participating in clinical trials, community surveys, academic research studies and educational intervention programmes both in the UK and across Europe. At present the DHP-18 is being applied in the assessment of quality of life in a variety of settings including, Phase III trials across Europe and research projects in Australia, Ireland, Martinique, North America and national funded research in the UK. The DHP-18 is also the diabetes-specific outcome measure selected by the UK Department of Health which is currently being used in their pilot study to evaluate the efficacy of patient reported outcome measures (PROMs) for long term conditions in primary care. Planned international diabetes clinical trials include the use of the DHP-18 in a number of countries including the USA, Canada, China, southern and northern Europe.

The DHP Database comprising information on nearly 5000 people with Type 1 and Type 2 diabetes who have completed the DHP-18 is currently being utilised to:

1. Estimate the minimally important difference (MID) of the DHP-18 for both Type 1 and Type 2 diabetes using anchor and distribution based approaches. 2. Develop norm referenced scores 3. Estimate the association between the DHP-18 responses and EQ-5D utility values by response mapping 4. Develop a shorter version of the DHP-18 using Rasch analysis

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as Spanish (USA). The DHP-18 has also been adapted for use in the USA (English) and Canada (English and French) and is currently being adapted for use in a further three languages including Mandarin.

Creating and Validating the DHP-18 for Electronic Data CollectionDespite evidence of patient acceptability, high item completion rates and the overall integrity of data collected using the paper version of the DHP-18, there is both a strong scientific and business case for the creation of a validated electronic version of the measure (eDHP-18), which is underpinned by the use of electronic patient reported outcomes as increasingly being seen as essential by clinical trial sponsors for ensuring data integrity and regulatory support.

Benefits of ePROAlthough paper based PROs are an established and accepted medium which are easy to reproduce and distribute, ePROs offer a number of distinct advantages over paper. Apart from enabling administration of the eDHP-18 in a consistent, standardised and objective manner, a key advantage is the ability to date and time stamp PRO data to avoid the recognised limitation of paper-based PROs ‘parking lot effect’ where study participants retrospectively and prospectively enter data. As a result sponsors are assured that data are collected at the point of experience and as a result reduces variance in the data which can enhance the study’s ability to show efficacy. An eDHP-18 also offers less administrative and participant burden, minimises missing data and reduces data entry errors. Further and significant benefits of the DHP-18 for electronic data capture include the ability to

• Integrate eDHP-18 data with other electronic data capture, for instance primary clinical endpoints such as patients HbA1c levels and

• Extend to web-browser data collection.

Migrating from paper to electronic data collection is a significant movement in the field of PRO measurement and there is a range of modalities available for data collection including: smartphone (handheld), tablet, IVR and Internet. To retain the integrity of the different administration modalities of the DHP-18, an eDHP-18 can be administered using the PHT LogPad for self-administration, the PHT SitePad for reading face-to face to the respondent and PHT NetPRO for administration over the Internet. However, there is the requirement that sponsors provide evidence to support the comparability or measurement equivalence of the eDHP-18 to the paper-based version from which it has been adapted.

Validating the eDHP-18The level of evidence to support the comparability or measurement equivalence of the ePRO to the paper-based PRO from which it has been adapted will vary in accordance with the magnitude of the modification and its effect on the content, format and interpretation of the PRO items and scales. There is substantial evidence however to suggest that the psychometric properties of the original measure will still hold for the ePRO version if only minor modifications have been carried out and that cognitive debriefing and usability testing will likely suffice as the level of evaluation. In cases where substantial modifications have been made, establishing the measurement equivalence of the ePRO is likely to include full psychometric evaluation.

Keith is Founder and Director of DHP Research & Consultancy which he established in 2010 to provide selection,

design, validation and implementation services of patient reported outcomes and experience measures to

the pharmaceutical and biotech industries. He has over 25 years experience in health services research, with

expertise in the psychosocial impact of living with diabetes, health-related quality of life, user involvement

and patient reported experience. Keith has authored nearly 90 research papers, book chapters, abstracts and

presentations; lectures at the post graduate level at the Universities of London and Brighton; and is the author

and copyright owner of the Diabetes Health Profile (DHP), a globally used quality of life questionnaire designed

to identify the impact of living with diabetes on the patient.

Dr. Keith Meadows

Founder & Director DHP Research & Consultancy Ltd www.dhpresearch.com kmeadows dhpresearch.com

6PHT Insights - Q2 2011ePRO Collection Methods Suitable for Type I and II Diabetes Clinical Trials, Observational Studies and Registries

DHP-18 and the eDHP-18 InstrumentsHere is a comparison of one question from the DHP-18 in paper format, and the electronic version on a PHT LogPad VL [handheld] and PHT SitePad [tablet]:

As shown here, questions on both paper and electronic devices are the same but the response mechanics are different. Also,

the electronic version requires that answers be complete before progressing to the subsequent question, improving data quality and compliance.

When there is only a little change between paper and the electronic instrument as shown below, a cognitive debrief is required to demonstrate the similarities and differences between the visuals.

Your Diabetes and You

The following questions ask about your feelings and the effect that diabetes may have on your life.

Please answer each question by ticking the box that best describes you and your diabetes.

Please make sure that you tick only one box for each question.

Thank you.

1. Does food control your life?Always Usually Sometimes Never

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Paper Version

DHP-18 DHP-18

The following questions ask about your feelings and the effects that diabetes may have on your life. Please answer each question by SELECTING THE BOX next to the answer that BEST describes YOU and YOUR DIABETES.

Thank you.

Does food control your life?

Always

Usually

Sometimes

Never LogPad Electronic Version

Does food control your life?

Back Next

Always

Usually

Sometimes

Never

SitePad Electronic Version

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1. What are the leading ePRO migration challenges?

While the reuse of validated questionnaires seems intuitive and practical, there remain some obstacles to transitioning questionnaires to electronic versions. Developers do not license screen shots of validated instruments and this makes it difficult for ePRO providers to provide fully reusable versions of questionnaires based on a published specification. Sponsors often regard validated instruments as private assets and a competitive advantage and are reluctant to publish any studies done to establish the validity of such assets. Additionally, the compensation of the authors and copyright holders of the questionnaires necessitates licensing of copyright and other logistical matters.

The virtue of providing validated instruments to the industry at large is certainly recognized, and academic societies, industry groups and distribution channels are evolving to support this need. One such group which has recently formed is the ePRO Consortium which is working with the Critical Path Institute on this goal.

2. How do you determine the level of validation required when mitgrating a PRO instrument from paper to electronic mode of administration?

The level of validation depends on the degree to which the appearance, operation and content may be changed. An ISPOR publication distinguishes small, medium and large changes. • Small changes are exemplified by simple alterations in instruction wording, such as asking the responder to select

a response option by “tapping” a screen rather than by “drawing a circle” on the paper. Another example is changing the presentation from several questions on a page to one per screen.

• Medium changes include changing modes of presentation from one sensory channel to another such as reading questions and responses to listening to someone else read them, or introducing an operation such as scrolling a screen in order to view what would appear on a single page on paper • Large changes are those that affect the meaning of the questions or the content of the measure (additions, deletions).

Simply putting a paper questionnaire on an electronic device with no other changes may need only some usability and cognitive testing to support suitability for use. The level of change dictates the type of validation work required, ranging from cognitive debriefing with target patient populations to equivalence studies between the paper and electronic versions of the instruments.

3. Who owns the electronic version?

The questionnaire author owns the content copyright. Usually the technology provider owns the code and programming that present that content on particular platforms. Sponsors who pay for validation work have typically not authorized the publica-tion of the results, which is resulting in duplication of validation work to support conversion of a PRO instrument from paper to an electronic version.

Commonly Asked Questions about Paper to ePRO Transitions for a Diabetes Indication

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FDA and | SPOR Guidelines

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 © 2011 PHT Corporation

Rev 2.2011

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

PHT Corporation500 Rutherford AvenueBoston, MA 02129 USA

Toll-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-Hubert

1213 Petit-Lancy, Geneva, SwitzerlandPhone: 41.22.879.91.00

www.phtcorp.comCopyright © 2011 PHT Corporation

Rev 6.2011

ePRO for Clinical Trials, Observational Studies and Registry Studies of Patients with Diabetes

PHT, LogPad, NetPRO and SitePad are registered trademarks of PHT Corporation.

iCenters for Disease Control and Prevention (CDC). National diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2007. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2007. iihttp://www.idf.org/diabetes-burden-shifting-developing-countriesiiihttp://www.phtcorp.com/resources/insights/5ProvenWaystoCollectePRO.pdf ivIDF, 2010vKohen et al., 1998; Polonsky, 2002; Wexler et al., 2006vihttp://www.diabeteshealthprofile.com/General/dhp-1.htmlviiGarratt et al, 2002viiiRecommendations on Evidence Needed to Support Measurement Equivalence

PHT has captured ePRO data directly from patients in many

diabetes trials including those for Diabetic Neuropathy,

Diabetes and Diabetic Peripheral Neuropathy indications.

4. Can translations previously done and validated for paper instruments be used in the electronic implementations with out supplemental validation work?

Yes, but only if the questionnaire is identical to the one previously validated, and only with agreement of the questionnaire owner.

5. What are the biggest advantages ePRO provides vs. paper for diabetes research?

The electronic methods provide: • Automated transfer of blood glucose readings from radio-enabled glucometers.

• Validated time stamps for completion of contextual information pertaining to each glucose reading.

• Clear instructions for sites and subjects to help them comply with their protocol (e.g.reminder at end of timed assessment), including automation of contingent branching to prevent logically inconsistent data.

• Episodic diaries that can be completed in real time, which prevent errors in recall.

• Review screens to prevent duplicate reports into an episodic diary.

• Remote monitoring for significant changes in health status.

• Ready access to data on remote participants, enhancing trial management and the safety of subjects.

Electronic data collection is a powerful means to ensure data integrity of patient reported outcomes within diabetes indications. Electronic diaries and questionnaires for diabetes trials, studies and registries have enabled faster projects with more compelling data.

The eDHP-18 remains a universal diabetes questionnaire and provides additional value now that it has been converted for presentation as an electronic instrument.

For more information on the eDHP-18, ePRO or validating diaries and questionnaires contact PHT at 877.360.2901 or www.phtcorp.com/diabetes_experience.

Conclusion

Commonly Asked Questions about Paper to ePRO Transitions for a Diabetes Indication (continued)

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