IMS AccessPoint - May 2012

Volume 2, Issue 4 • May 2012

AccessPoint

News, views and insights from leading experts in HEOR and RWE

Accounting for direct evidence gaps

New lifecycle demands for RWE Early planning is essential

Emerging markets in Asia Pacific move to formalize HTA Jon Resnick presents a lifecycle plan for real-world PageOUTCOMES 1 - Issue 1 evidence Page 10

Chris Blanchette Núria Lara Surinach, measures drug Xavier Badia and treatment exposure Núria Perulero 1 IMS HEALTH ECONOMICS AND OUTCOMES RESEARCH in asthma considerPage the growing Page 21 importance of PROs Page 16

THE MAGAZINE OF IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

Volume 2, Issue 4 • May 2012

AccessPoint

News, views and insights from leading experts in HEOR and RWE providers

Preparing for a lifecycle of real-world evidence Increasing demand brings a need for new capabilities, data considerations, and effective planning for RWE across the entire product lifecycle. page 10

Accounting for direct evidence gaps with indirect treatment comparisons Network meta-analysis offers growing potential. page 26

Who drives the lion’s share of costs?

Understanding healthcare spending in the commercially-insured US population under age 65. page 32

Pharmacogenomics comes of age Continued evolution of pharmacogenomics brings new considerations for RWE. page 44

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

“2012 is shaping a future that will be transformed by real-world evidence”

WELCOME

CONTENTS

Welcome to the fourth issue of AccessPoint, a twice-yearly highlight of news, views and insights from the international HEOR and Real-World Evidence Solutions team at IMS Health – casting an expert eye on the evolving dynamics that are changing the basis for healthcare decision making with potential for improved efficiency through real-world evidence (RWE) generation.

NEWS SECTION

RWE is not a new concept - HEOR researchers have been generating evidence for years - but growing demand is driving new opportunities to expand, enhance and do more. As we move through 2012, we see a year that is shaping a future where healthcare is transformed by RWE: the emerging markets of Asia Pacific (page 40) have joined a growing body of countries globally that depend on RWE to inform HTA; significant, too, is an important shift in the timeframe over which value is determined, extending the use of RWE far into the product lifecycle (page 10); at the same time, the science of personalized medicine (page 44) brings further potential for the expanded application of RWE; and underpinning these trends, the bar is being raised for real-world studies, setting new standards for their design and validation (page 16).

Today, regulators, HTA bodies, payers, practitioners, patients and manufacturers are united in the goal of improving treatment based on the best available evidence. IMS is committed to advancing the use of RWE to enable improved efficiency in healthcare and enrich the dialog across the healthcare setting. Our recent lead in a national debate on RWE studies in France (page 6) has already paved the way for a smoother process based on a new collaborative spirit, and in our joint initiative with AstraZeneca in Europe (Page 7) we look forward to leveraging a shared perspective on the transformative power of RWE in informing the delivery of effective and cost-efficient healthcare.

Fulfilling the potential of RWE requires new capabilities in managing, analyzing and leveraging real-world information. In responding to the demand for more compelling, credible evidence, companies will need to reconsider the way they collect and interact with real-world data.

IMS has a global team of more than 200 experts in outcomes research, economic modeling, RWE and market access. Our research calls for creative thinking to connect and integrate fragmented information and build the tools, interfaces and technical platforms that will enable faster, more robust RWE generation.

We continue to invest in research programs to ensure the strongest foundation for identifying, interpreting and communicating realworld outcomes. Our recent validations of the IMS CORE Diabetes Model (page 8) and integration of our global patient-level assets, including IMS LifeLink PharMetricsPLUS (page 2), confirm our ongoing efforts in this area.

I hope you find this issue of AccessPoint timely, informative and stimulating in a year that is defining a clearer path to stronger, evidence-based decision making.

Jon Resnick VICE PRESIDENT, HEOR AND REAL-WORLD EVIDENCE SOLUTIONS, IMS HEALTH Jresnick@uk.imshealth.com

ACCESSPOINT • VOLUME 2 ISSUE 4

2

IMS announces LifeLink PharMetricsPLUS

4

Oncology leads IMS research agenda

6

IMS drives French debate on RWE

7

Landmark RWE partnership with AstraZeneca

8

IMS CORE Diabetes Model maintains leadership position

INSIGHTS 10 REAL-WORLD EVIDENCE Developing a lifecycle plan 16 PATIENT-REPORTED OUTCOMES Increasing relevance adds to expectations 21 DRUG EXPOSURE MEASUREMENT Standardization key to meaningful results 26 INDIRECT TREATMENT COMPARISONS Accounting for direct evidence gaps 32 US PRIVATE HEALTHCARE SPENDING Who drives the lion’s share of costs?

40 IMPLEMENTING HTA IN ASIA PACIFIC Critical success factors in emerging markets 44 PHARMACOGENOMICS New imperatives for RWE strategy PROJECT FOCUS 50 IMS CORE BUDGET IMPACT MODEL Payer-relevant pharmacy analyses 52 GLAUCOMA Demonstrating cost-effectiveness in Asia 54 METASTATIC COLORECTAL CANCER Informing optimal treatment strategies IMS HEOR AND RWE SOLUTIONS OVERVIEW 56 ENABLING YOUR REAL-WORLD SUCCESS Locations, expertise, IMS LifeLink™

AccessPoint is published twice yearly by the IMS HEOR and Real-World Evidence Solutions team.

VOLUME 2 ISSUE 4. PUBLISHED MAY 2012.

IMS HEALTH 210 Pentonville Road, London N1 9JY, UK Tel: +44 (0) 20 3075 4800 • www.imshealth.com/heor HEORinfo@imshealth.com • RWEinfo@imshealth.com

©2012 IMS Health Incorporated and its affiliates. All rights reserved.

Trademarks are registered in the United States and in various other countries.

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NEWS | IMS LIFELINK PHARMETRICSPLUS Major investment extends the leverage of IMS linked patient-level data bringing new possibilities for health economics and outcomes research.

IMS announces LifeLink PharMetricsPLUS - the most comprehensive integrated database available in the US market medications, in-office procedures, lab results, vitals, Marking a strong commitment to advance the use patient demographics, cancer staging, tumor morphology, of real-world evidence (RWE) for assessing the way and metastatic identifier. in which a drug or medical device performs in actual clinical practice, IMS continues to make • Ambulatory EMR: Collected from GP/IM practices and clinics. Out-patient, clinical, patient-level charts in an significant investments to enhance and better electronic format with representative coverage of most leverage its existing patient-level datasets. regions. Provides detailed clinical and patient attributes, IMS is already widely recognized as a leading provider of the IMS LifeLink Health Plan Claims database. Formerly known as PharMetrics, this is the largest independent claims data source in the US, covering more than 73 million unique patients. With the acquisition of SDI in Q4 2011 came a range of complementary LifeLink Information Assets, providing insights into the total patient experience in the US - as patients receive care from providers, pharmacies, hospitals, labs and other facilities – and the way in which this care is influenced by other factors, such as patient characteristics and behaviors, past treatments, managed care coverage, and further key attributes.

IMS LIFELINK PHARMETRICSPLUS The SDI legacy further included established and published expertise in data linkage and integration which has now been leveraged to develop a new, integrated dataset, known as IMS LifeLink PharMetricsPLUS. LifeLink PharMetricsPLUS brings IMS Health Plan Claims data integrated with: • Hospital Charge Data Master: Collected from general medical-surgical and specialty hospital's in-patient and out-patient records. Includes detailed diagnoses, procedures, drugs, devices, applied charges, sites of service, as well as patient demographics and admission/discharge characteristics.

• Oncology EMR data: Collected in the out-patient office setting from medium and large community-based oncology urology, dialysis, radiation, cancer registry, hospital, and general/ambulatory practices. Provides detailed clinical data, including diagnoses, treatments, oral and injectable

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including diagnoses, written prescriptions, procedures, test results, and clinical variables (eg, BMI, BP).

• Lab data: Collected from a leading national lab provider, laboratory data including demographics, diagnosis, test date, test description, result, reference results ranges, and ordering provider's geographic location.

• Consumer attributes: Collected from a respected global leader in compiling unique consumer data including financial, demographic, race/ethnicity, mortality, and psychographic profiles.

• Retail purchasing OTC/CPG: Collected from a respected source of loyalty card purchasing data. Contains retail purchasing information which allows classification of consumers based on buying behavior.

• Medical claims: Pre-adjudicated claims (switch source) collected from office-based physicians and specialists.

Expands the demographics of the database to include populations and claims that might be under-represented in health plan claims data, including Medicare and Medicaid. The data include patient demographics, physician demographics, diagnoses, procedures, and in-office administered drugs.

• Pharmacy prescription data: Collected from retail, mailorder, long-term care and specialty pharmacy records.

Includes claims submitted for payment and other prescriptions directly from key pharmacy locations.

In addition to commercial and government payers, cash transactions are recorded.

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

IMS LIFELINK PHARMETRICSPLUS | NEWS IMS DE-IDENTIFICATION ENGINE

Source Retail & LTC Rx

Customer data

Medical claims Hospital charge detail master IMS de-identification De-identified data engine

Data warehouse

Healthcare provider attributes Labs Electronic medical records Consumer demographics & psychographics

IMS leverages its patented (HIPAA compliant) technology to link across IMS and others’ data

NEW ANALYTICAL POTENTIAL

EARLY ACCESS

Directly linked via unique patient identifiers, using a unique and proprietary algorithm for de-identification of patients, ensuring HIPAA compliance, these data open up new analytical possibilities, overcoming the limitations in scope or clinical detail of current databases. Analyses types enabled include:

As this exciting development progresses, work on establishing linkage for the various datasets continues, reflecting the significant level of investment involved in incorporating information provided by multiple health plans and other data sources. In advance of full commercialization, IMS is providing clients with early access to the new integrated dataset, LifeLink PharMetricsPLUS which is now ready for research. As from June 2012, the information available in the database can be used for client projects leveraging the analytical expertise and data knowledge of the IMS HEOR team. While the initial linked dataset is based on selected health plans, IMS anticipates significant growth in the size of the database over the course of the coming months, allowing even more research questions to be answered •

• Monitoring post-discharge outcomes of detailed in-patient clinical pathways • Adding health status variables (eg, biomarkers and vitals) to comparative effectiveness and cost-of-care analyses • Enhancing drug exposure measures impacted by administrative data loss • Expanding the availability of clinical endpoints such as mortality and progression in database analyses

If you would like to learn more about IMS LifeLink PharMetricsPLUS, the most comprehensive integrated database available in the US market, please email Michael Nelson at Mnelson@us.imshealth.com

ACCESSPOINT • VOLUME 2 ISSUE 4

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NEWS | IMS ONCOLOGY EXPERTISE The IMS HEOR Bibliography captures more than 2200 research publications with a history of 25 years across all key therapy areas. Oncology is one of our leading fields of research.

Oncology is a key research area for IMS HEOR The oncology market is experiencing spectacular growth and unprecedented innovation.

IMS HEOR ONCOLOGY PROJECTS SPAN ALL ASPECTS OF HEOR

It is predicted to become the largest single therapy sector in value terms by 2015 – worth US$75 billion.

New molecular targeted therapies, diagnostics, genomics and proteomics are changing the face of cancer treatment, spurring exciting opportunities - and also new challenges - for this healthcare sector worldwide.

14%

The IMS HEOR global team has completed projects on 20+ different tumor types, spanning all aspects of health economics and outcomes research, with particular emphasis on health economic modeling and retrospective outcomes research.

30%

The top ten cancers we have covered are: 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

Breast Lung [NSCLC/SCLC] Colorectal Lymphoma Melanoma/BCC Prostate Multiple myeloma Leukemias [CLL/CML] Mesothelioma Cervical

13%

43%

HE modeling

Retrospective outcomes research

Prospective outcomes research

Value communications

ONCOLOGY IS A LEADING AREA OF IMS HEOR EXPERTISE

116

107

150 330 233 259

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Diabetes

Oncology

Cardiovascular

Mental health

Neurological disorders

Respiratory diseases

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

IMS ONCOLOGY EXPERTISE | NEWS IMS HEOR Bibliography Our research expertise and therapy area knowledge are captured in more than 200 publications each year, spanning virtually all therapy areas and 50+ countries worldwide. Contact IMS (details on back cover) for a copy of the latest IMS HEOR Bibliography of published papers (2008-2012) or visit www.imsheorbibliography.com to explore our database online.

The IMS HEOR bibliography in oncology spans all key areas of health economics and outcomes research, including retrospective and observational analyses, budget impact, cost-effectiveness and cost utility modeling, model adaptations, epidemiology and burden of disease studies, indirect comparisons, and meta-analyses, bringing important new findings across all key tumor types and countries around the world.

Health economics review of bowel cancer in Australia NSW Cancer Institute, 2008, Sydney, Australia (Review) Bishop J, Glass P, Tracey E, Hardy M, Warner K, Makino K, Gordois A, Wilson J, Guarnieri C, Feng J, Sartori L

Second-line therapy for non-small cell lung cancer (NSCLC): A retrospective cost analysis

Five-year routine cervical cancer screening rates and intervals in a United States health plan

Epidemiologic study to assess patient involvement in choice of adjuvant chemotherapy in breast cancer (PROSA study)

Tumordiagn u Ther, 2008; 29:211-217

Current Medical Research and Opinion, 2008; 24(9):24292435

Clinical and Translational Oncology, 2009; 11(4):221-7

Gatzemeier U, Pirk O, Gabriel A, Kotowa W, Heigener D

Schabert VF, Ye X, Insinga RP, Singhal PK, Riedel AA

Tusquets I, Espinosa Arranz E, Méndez M, Gil JM, Guallar JL, Perulero N

Development of a co-morbidity scale in patients with chronic lymphocytic leukemia

Cost-utility analysis of dasatinib as a second-line treatment in the chronic phase of chronic myeloid leukaemia in Russia

A retrospective analysis illustrating the substantial clinical and economic burden of prostate cancer

ISPOR 13th Annual European Congress, Prague, Czech Republic, 6-9 November, 2010

ISPOR 13th Annual European Congress, Prague, Czech Republic, 6-9 November, 2010

Prostate Cancer and Prostatic Diseases, 2010; 13(2):162-167

Carbonell F, De La Serna J, Giraldo P, Lopez A, Rios E, Perulero N, Castro-Gomez AJ

Kuznetzov SV, Mungapen L, Samyshkin Y, Jakouloff D, Sbarigia U, van Baardewijk M

Economic model of granulocyte -colony stimulating factor (G-CSF) in primary (PP) and secondary prophylaxis (SP) of febrile neutropenia (FN) in Non-Hodgkin's Lymphoma (NHL) patients undergoing chemotherapy in France

Cost-effectiveness of cetuximab, bevacizumab, and panitumumab in first-line treatment of metastatic colorectal cancer (mCRC) for patients with KRAS wild-type (wt) tumors in the UK

Economic evaluation in the treatment of advanced and/or metastatic gastric cancer from the perspective of the public health system in Mexico

ISPOR 14th Annual European Congress, Madrid, Spain, 5-8 November, 2011

Journal of Clinical Oncology, 2011;29(Suppl):A16571

Breast cancer diagnostic process: Management and cost evaluation in Italy ISPOR 12th Annual European Congress, Paris, France, 24-27 October, 2009 Pantaleoni M, Marchese E

Perrier L, Sebban C, Leon N, Maurel F, Cohen-Nizard S, De Liège F

Samyshkin Y, Hertel N, Griebsch I

ACCESSPOINT • VOLUME 2 ISSUE 4

ISPOR 17th Annual International Meeting, Washington, DC, USA, 2-6 June, 2012 Lechuga D, Alva M, Salinas GE, Leyva V

Crawford ED, Black L, Eaddy M, Kruep EJ

Risk of treatment failure after first-line sunitinib therapy in patients with metastatic renal cell carcinoma Journal of Clinical Oncology, 2012; 30 (Suppl 5): Abstract 438 Chen CC, Hess GP, Liu Z, Gesme DH, Agarwala SS, Hill JW, Guo MA

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NEWS | REAL-WORLD EVIDENCE IN FRANCE Senior French healthcare stakeholders respond to IMS lead for tackling process bottlenecks hindering real-world evidence development.

IMS HEOR drives national debate on RWE studies in France IMS HEOR has taken a leadership role in France to address problems that are hindering the development of real-world evidence (RWE) studies required for market access regulation. By creating a platform for stakeholder discussion at the highest level, the IMS HEOR team in France, led by Principal, Dana Morlet-Vigier, has paved the way for alignment and solutions.

In France, every drug must pass through a value assessment by the High Authority for Health (HAS) and negotiation with the pricing committee (CEPS) to achieve reimbursement. Both government agencies are placing greater emphasis on RWE to determine how a new technology performs in actual clinical practice. Manufacturers can face significant financial sanctions if studies are not provided in a reasonable timeframe. However, the process for initiating RWE studies in France is currently slow and complex, involving multiple stakeholders. CEPS president, Gilles Johanet, has himself acknowledged the imperative for a more dynamic evaluative approach.

The workshop proved transformational, achieving consensus on issues compromising the timeliness and quality of RWE studies. It was so successful in reaching this point that IMS was invited to set up and moderate a second, follow-on session early in 2012, where specific recommendations for the scope and management of RWE studies were identified.

SMOOTHER PROCESS By coordinating brainstorming and communication between major public decision makers and pharma, this initiative has paved the way for a smoother process and helped to shape the future development of RWE in France. It also reaffirms the potential of alignment and collaboration in fostering positive change and advancing efforts to improve healthcare efficiency, ensure safety and demonstrate value for money. • 75 top decision makers in France came together at the invitation of IMS for a day of structured presentations and debate on RWE.

PROPOSAL FOR ACTION With the entire economic life of a drug dependent on compulsory post-listing, post-reimbursement studies, IMS recognized the need to kick-start change and approached CEPS direct with a proposal: as a “neutral” expert in RWE studies, the IMS HEOR team would organize and facilitate a workshop with all relevant stakeholders, as well as a specialist in process industrialization, to identify and analyze critical bottlenecks in the system.

Above: Gilles Johanet (left) and Dana Morlet-Vigier Below: Workshop sessions during the event

DRIVING ALIGNMENT The offer was accepted and in late 2011, 75 top decision makers in France came together at the invitation of IMS for a day of structured presentations and debate. Participants included pharma Directors/VPs of market access and HEOR, doctors/clinical investigators, and senior representatives from HAS, CEPS and other public policy stakeholders. The discussions, framed by IMS, focused on the need for RWE, its impact on the pharmaceutical industry, the process and subprocesses of RWE studies in France, database studies and ad-hoc observational trials.

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

REAL-WORLD EVIDENCE COLLABORATION | NEWS Groundbreaking partnership heralds potential for improving healthcare efficiency by advancing the use of real-world evidence (RWE) in Europe

IMS enters collaboration with AstraZeneca to expand real-world evidence Early in 2012, AstraZeneca announced a three-year agreement with IMS to advance the use of real-world evidence (RWE) - and establish standards for RWE generation - based on observational and retrospective studies throughout Europe, to inform the delivery of effective and cost-efficient healthcare.

The partnership with IMS Health will give AstraZeneca access to pre-existing anonymized electronic health records, which include clinical outcome, economic and treatment pattern data. In addition, the companies will jointly develop a customized research and data analysis platform. The information will provide a deeper insight into how medicines that are already on the market are working in real-world settings across Europe, painting a picture of unmet needs in the current standard of care and treatment patterns across a number of therapeutic areas, with an emphasis on chronic illnesses. The data will also be used to inform AstraZeneca’s discovery and clinical development programs.

The collaboration reflects the interest among healthcare decision makers in examining the cost and effectiveness of new and existing medicines and health technologies to help allocate their increasingly limited resources more efficiently.

Unlike controlled clinical trials, RWE studies use observational data such as electronic medical records, claims information, patient registries and patient surveys. By evaluating the data associated with the delivery of care, ‘real-world’ analyses can demonstrate treatment impact on measurable outcomes such as hospital length of stay, readmissions, overall health status and total cost of care.

This is how senior leaders from AstraZenca and IMS see the partnership: “Our collaboration with IMS is a key milestone in our commitment to understand the impact of our medicines in the real world, beyond what we see in controlled clinical trials.

This insight will help us and healthcare decision makers to improve the treatment of disease and ensure effective use of medicines to minimize the burden on individuals and healthcare budgets.”

Martin Mackay, President of Research and Development, AstraZeneca

“This joint initiative reflects a shared perspective on the transformative power of real-world evidence on global health systems. Our unique information assets, coupled with our services and technology capabilities, make IMS a leading partner for healthcare organizations in the identification, integration and interpretation of real-world outcomes.

We are extremely pleased to be working with AstraZeneca on this collaboration.”

Jon Resnick, Vice President of Real-World Evidence Solutions, IMS Health The press release has since received wide media coverage and has featured in more than 30 articles, including reports in the Wall Street Journal, The Pink Sheet and Pharma Times online.

In an interview on February 22 with PharmaExec, Jon Resnick, when asked how others could benefit from this partnership, confirmed that there will be active efforts to involve payers and other providers in “an honest set of conversations" about how to work with the information, both during and beyond the collaboration.

“For this to work, you need the buy-in,” says Jon. “You can’t create real information in a vacuum; you can’t work with a set of databases that are closed to the universe and then hand the information to a payer and say you want to charge 20 percent more.” Whichever data will eventually be made publicly available depends on the type of study it relates to, but Jon emphasizes that the IMS/AZ research is not just between the two companies. “Opening it up to academics and broader audiences is healthy if we want to maintain credibility. A broader set of participants will be needed to ratify the information.” • The full text of the press release can be found here: www.astrazeneca.com/Media/Pressreleases/Article/ 20120111--astrazeneca-and-ims-health For further information about IMS capabilities, please email Jon Resnick at Jresnick@imshealth.com

ACCESSPOINT • VOLUME 2 ISSUE 4

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NEWS | IMS CORE DIABETES MODEL Strong research-focused investment maintains IMS CORE Diabetes Model at the forefront of decision support for diabetes.

New validations enhance credibility of IMS CORE Diabetes Model 0.89 and 0.86 were produced for intensive and Since 2011, IMS HEOR has undertaken extensive conventional treatment in both short- and long-term work on the validation and practical applications observations. The study supports the CDM as a credible of its market leading IMS CORE Diabetes Model policy support tool for extrapolating health outcomes in (CDM). Marking a continued commitment to DCCT and UKPDS like populations.1 ensuring robust, contemporary decision support in • Risk-to-benefit ratio of glucose-lowering therapies in diabetes, the work has focused on enhancing the high cardiovascular risk Type 2 diabetes: In this study, model's credibility and providing users with insight the CDM was populated with characteristics consistent with the ACCORD trial to compare predicted 5-year relative into the range of potential applications for the risks of cardiovascular morbidity and all cause mortality CDM. The results will ensure that evaluations of to random effects meta-analysis of ACCORD, ADVANCE and new technologies in diabetes are supported by a VADT. Results were extrapolated over a lifetime to derive model that is at the forefront of health economic overall expected benefit. The CDM 5-year relative risk research in this area. reductions associated with intensive glucose control in Research abstracts have been submitted to several prestigious international conferences, including the ADA Scientific Sessions in Philadelphia and 1st Middle East Congress in Dubai; the EASD Meeting in Berlin; ISPOR in Washington, Berlin and Taipei; and the 2012 Mount Hood challenge in Baltimore – a particularly relevant platform for demonstrating the robustness of the CDM across a range of challenging validation exercises versus diabetes models from other research groups.

Fully exploiting important new features of the CDM, such as modeling patient-level data, this latest IMS research also develops diabetes modeling methodology. Some of the key studies covering validation, applications, methodologies and cost are summarized below:

MODEL VALIDATION • Type 1 and Type 2 long-term diabetes outcomes trials: Driven by extensive use of the CDM to estimate long-term clinical outcomes in diabetes, the goal of this study was to validate the model to trial data over a 20-30 year horizon against long-term observations of the DCCT (EDIC) and UKPDS, and to compare those to short- or intermediate time validations over 5 (Type 1) and 10 (Type 2) years. In Type 1 diabetes, simulations produced R2 values of 0.9 and 0.67 against 5-year and 30-year followup studies respectively. In Type 2 diabetes, R2 values of

high-risk Type 2 diabetes patients were consistent with meta-analysis results and fell within the 95% confidence intervals. Long-term projections suggest intensive therapy contributes to both increased life and quality adjusted life expectancy.2

PRACTICAL APPLICATIONS OF CONTEMPORARY ISSUES • Relationship between effect of glycemic control and avoided symptomatic hypoglycemia on QoL in Type 2 diabetes: Achieving optimal glycemic control (GC) while avoiding hypoglycemia is the basis of diabetes management. Tight GC, while reducing macro and microvascular complications also promotes hypoglycemia thus representing a barrier to low HbA1c values and directly impacting costs and health utility. Using the CDM, this equilibrium analysis showed that an HbA1c reduction of 0.54% is needed to achieve the same QoL benefit as achieved by avoiding one event of non-severe symptomatic hypoglycemia (NSHE) per year. The analysis is noteworthy in demonstrating the significant contribution to QALE by avoiding NSHE; particularly in comparison with levels of HbA1c change typically associated with current anti-hyperglycemic agents. The avoidance of NSHE is at least as powerful a driver of QALE as lowering HbA1c. continued opposite

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

IMS CORE DIABETES MODEL | NEWS

• Significance of HbA1c durability in costeffectiveness analysis of second-line oral therapies in Type 2 diabetes: Patients with Type 2 diabetes generally require dose escalation and/or combination therapies to maintain acceptable glycemic control (GC).

Time to escalation is a function of initial treatment effect and durability of GC. Durability can be assumed to be a key driver of cost-effectiveness especially when rescue therapies are expensive. The influence of different durability assumptions was explored in the CDM which evaluated scenarios to compare sulphonylurea vs DPP-4s as second-line therapies added to metformin, followed by insulin rescue therapy. CDM projections demonstrated that the annual rate of increase in HbA1c exerts considerable influence over predicted cost-effectiveness and is therefore an important variable in assessing value for money of new interventions for Type 2 diabetes.

COST QUANTIFICATION • Direct medical costs of diabetes mellitus in China: This research used the CDM to estimate annual cost of illness for all patients and lifetime diabetes costs for diagnosed patients in China. The 2011 cost of diabetes was estimated as CNY 13,326 per diagnosed patient and CNY 4,727 per undiagnosed patient, with the difference attributable to diabetes treatment and management costs.

Based on a total population approaching 1.4 billion and previously reported disease prevalence rates, the national cost of diabetes in 2011 was estimated as CNY 1,214 billion. In diagnosed patients the lifetime cost of diabetes was estimated as CNY 301,716 per patient (or CNY 18,253 billion nationally); diabetes complications comprised 53% of the lifetime cost burden.5 • For further information on recent research with the IMS CORE Diabetes Model, please email David Grant, Senior Principal HEOR, IMS Health at Dgrant@uk.imshealth.com

METHODOLOGICAL ASPECTS OF DIABETES MODELING • Correlating cost-effectiveness output with patientlevel data input: The CDM was used to ascertain if particular patient-level data (PLD) input profiles were predictive of cost-effectiveness sub-groups in Type 2 diabetes subjects treated with second-line oral therapies. A series of patient characteristics were identified as being associated with greater potential for health gain. The study showed that the analysis of PLD, alongside simulation model output, provides an additional mechanism for informing healthcare decision making.3

The IMS CDM allows comparison and correlation of input profile vs. output from patient-level data for each included patient – thereby offering the possibility of sub-group analysis. The graph below shows, for example, that patients with higher A1c level at baseline had a higher chance of being cost-effective vs. patients with lower levels.

• Reducing Monte Carlo error in stochastic simulations: This study sought to quantify the minimum run-time requirements for reducing Monte Carlo error to acceptable levels in probabilistic sensitivity analysis (PSA). Conducted with the CDM, it showed how Monte Carlo error can be quantified and put into context versus expected parameter uncertainty and further demonstrated that the degree of input parameter variability has an influence on the run-time requirements to reduce Monte Carlo error.4

1

Validation of the CORE Diabetes Model to type 1 and type 2 long-term diabetes outcomes trials. Accepted as poster presentation at ADA, Philadelphia, June 2012 Validation and evaluation of the risk-to-benefit ratio of glucose lowering therapies in high cardiovascular risk type 2 diabetes patients; Modeled projections using the CORE diabetes model. Accepted as oral presentation at ADA, Philadelphia, June 2012 3 Correlating cost effectiveness output with patient level data input via the IMS Core Diabetes Model (CDM). Accepted at Mount Hood 2012 Challenge, Baltimore.

4 Minimum run-time requirements to reduce Monte Carlo error in stochastic simulations. Accepted at Mount Hood 2012 Challenge, Baltimore 5 Direct medical costs of diabetes mellitus in China: Annual cost of illness and long-term projections using a validated diabetes model. Accepted at ISPOR 5th Asia Pacific Conference, Taipei, Sept 2012 2

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INSIGHTS | REAL-WORLD EVIDENCE The increasing demand for real-world evidence by a growing body of decision makers is creating a need for new capabilities, data considerations, and effective planning for RWE generation across the entire product lifecycle.

The authors Jon Resnick, MBA is Vice President HEOR and Real-World Evidence Solutions, IMS Health Jresnick@uk.imshealth.com

Jacco Keja, PHD is Regional Principal HEOR, IMS Health Jkeja@nl.imshealth.com

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

REAL-WORLD EVIDENCE | INSIGHTS

Preparing for a lifecycle of real-world evidence A global plan for success The concept of real-world evidence (RWE) is not a new one: researchers have been generating RWE to support product use among physicians and payers for nearly 20 years.

However, recent growth in the demand for RWE to inform market access decisions has shifted the timeframe over which value is determined far into the post-launch lifecycle with significant implications for manufacturers.

Traditionally, much of the work already completed for market access at the time of launch was based on evidence from randomized clinical trials (RCTs). While these remain the gold standard for demonstrating product safety and efficacy, the inherent limitations of their data – small sample size, controlled environment and focus on short-term outcomes – meant negotiations were primarily focused on qualitative documentation of value. Quantification was mainly extrapolated using health economic modeling.

Increased payer interest in RWE reflects a shift toward more quantitative measurements of value and acceptance of data sources and endpoints that are not explicitly derived from RCTs. This comes with growing acknowledgment that while RWE may have limitations in data quality relative to RCTs, its findings are more relevant to the payer perspective. Regulators, too, recognize the value of RWE on safety, relative to that offered by RCTs. Other trends are also broadening the use of RWE. In recent years, payers have been experimenting with approaches that shift the risk to manufacturers, such as value-based contracting and conditional reimbursement or access, as well as to other stakeholders through pay-for-performance and consumer-directed plans. Disease management pilots with riskshifting consequences are also underway in several European countries. These developments converge with another important trend - the deferral of risk to healthcare practitioners, who need to understand in detail the right patient for a product and the way in which treatment algorithms can be optimized in the real world. If these models form the basis of future practice in healthcare delivery, RWE perspectives and endpoints will need to start resonating with the broader range of stakeholders, including providers and patients, who have been delegated more decision-making power.

The future for RWE is one of certain challenge for all key stakeholders as scientific advancements and external dynamics place increasing demands on decision making. However, it is also one of tremendous potential for the expanded role of RWE.

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INSIGHTS | REAL-WORLD EVIDENCE

EVOLVING PATTERNS OF USE Currently, there is no global or regional model for the practical application of RWE: requests vary in the intended use of findings, the timing during the product lifecycle when manufacturers are expected to product RWE, and the endpoints or analyses that are prioritized when making RWE-supported decisions. In key markets, these mainly concern the permitted use of a product, although in some cases, market access or pricing is becoming conditional on the results of RWE studies (Figure 1). There is also localized interest in using RWE for labeling modifications, further entrenching product positioning based on post-launch evaluations. Over time, both the number of countries requiring RWE and the scope of its application will continue to expand, further increasing the heterogeneity of the market access landscape.

FIGURE 1:

EXAMPLES OF NATIONAL VARIATION IN THE APPLICATION OF RWE

Country

Context

Label

Application Price Market access

Use

Germany AMNOG ruling specifies that prices are to be re-asssessed post-launch France

Drug utilization studies specified as a condition of market access, pharmacovigilance

Sweden

Observational data used in post-launch decision making

Spain

Phase IV studies potentially influencing regional payer decisions

UK

Value-based pricing will potentially re-assess price post-launch

US

Private payer attention to Patient-Centered Outcomes Research Institute, private comparative effectiveness research, Food and Drug Administration Modernization Act Section 114 No application

Limited application

Application

DEVELOPING A LIFECYCLE RWE PLAN The complexity of logistics involved in fulfilling each country's RWE requirements calls for a heterogeneous approach, and fundamentally, early planning, to ensure the quality of responses, rational RWE spend throughout the lifecycle, and pro-activity to differentiation and positioning. This will be dependent on: 1. Careful and routinely updated analysis of current and future comparators, drilling down to actual/perceived differentiation on specific claims, to enable tactical planning of individual studies to address those differentiation claims.

2. A long-term view of supporting a product's claims with analyses of specific data sources, based on early inventory/vetting of databases that could support RWE studies of individual claims, and specific plans to address gaps by creating data sources where they are unavailable.

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REAL-WORLD EVIDENCE | INSIGHTS

3. A tactical evidence-generation plan enabling prioritization of data acquisition and analyses, both to anticipate external demands and to maximize the execution of a differentiation strategy.

Ideally, the lifecycle plan should be initiated no later than Phase II; some subsequent data development activities may require a head start several years before launch. It may be appropriate to start these plans at therapy area or indication level when pipelines include multiple similar candidates, to mitigate the risks of early investment in RWE planning.

1. Comparators • Pre-launch: RWE should focus here on documenting the real-world performance of existing comparators and the standard of care, particularly relative to the claims/endpoints that are central to the Target Product Profile (TPP). Patient segmentation and market sizing should also be completed pre-launch.

• Post-launch: RWE emphasis after launch should shift towards not only replicating RCT efficacy and safety findings in real-world settings, but also seeking explicit head-to-head differentiation from comparators in the real world. In addition to safety and efficacy claims, this should consider product usage characteristics, such as dose adjustments, adherence, appropriate use, and cost-consequences of treatment, which can influence its costeffectiveness or value equation.

• Established products: A range of RWE studies can be valuable for established products facing new market entrants or the generic conversion of comparators. By this stage in its lifecycle, the large body of RWE evidence supporting a product’s safety, effectiveness and use can be viewed as a competitive advantage – while competitive intelligence on the expected profile of new entrants can inspire RWE studies that cement differentiation claims before they can launch. RWE can also enhance generic defense strategies, highlighting the magnitude of a product's differentiation to prevent discussions coming down to price reductions alone.

2. Supporting claims Manufacturers are familiar with developing new evidence during R&D to secure approval of particular endpoints, such as patient-reported outcomes (PROs), as part of their labeling/promotional claims. However, this investment rarely extends to planning for these endpoints in RWE and manufacturers may be caught out by the fact that they are not easily accessible in commercialized datasets.

A good example is patient adherence to medication which continues to present a major problem for treatment effectiveness. In the US, poor medication adherence is reported to be responsible for between 33 and 69 percent of all medication-related hospital admissions, resulting in a cost of approximately $100 billion a year.1 The difficulty in understanding poor adherence is that many of its predictors are patient-related factors, such as cognition, motivation, and relationships with doctors – all issues which claims data cannot enlighten.

Classic retrospective approaches also have many confounders and sources of bias to overcome, including frequent under-reporting of diagnoses as well errors in diagnosis. The rate of inconsistencies is particularly high in pain, psychiatric and behavioral disorders. Primary care providers have been found to detect major depressive disorder in only one-third to half of patients with this condition.2 continued on next page

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INSIGHTS | REAL-WORLD EVIDENCE Additionally, the scope of the data is often very limited. With the primary focus on health insurance claims, pharmacy records, hospital discharge data, GP electronic patient records, etc, many aspects are simply not documented. Consequently, while prescription data, hospital data, diagnostic codes, tests and procedures are often captured, the elements that provide deep insight into patient status and motivation, such as quality of life, severity of symptoms, and treatment satisfaction, are not.

Given the increasing evaluation of these endpoints by payers for post-launch price and market access reviews, it is critical to plan for data development to maximize timely access to RWE for TTP claims.

Broader perspectives By giving consideration to the stakeholders who may use RWE, manufacturers can expand their thinking about data sources and endpoints that will be available and relevant for RWEsupported claims. • Payers: As payers have embraced RWE, their mindset has been shaped by the availability of their own billing and reimbursement claims data. This has allowed them to consider effects over longer time horizons, and costs from more sites of care and more diverse populations, than have typically been available in RCTs. Today, a growing number of patient-level health data initiatives, particularly in the US, are being built around claims data assets for outcomes research. However, payer data sources typically exclude key information on patient health status that drives medical decision making meaning that an even broader range of perspectives is required. • Providers and patients: As the importance of providers and patients grows in considering RWE, value determinations will be based more on the perspectives of disease management than market access. The alternatives considered by physicians will be driven by the types of health status information they typically record in their charts, practice management systems, and electronic records. RWE findings must be responsive to this and stratify patient populations appropriately. Patient choice is dominated by very practical considerations of ease of use and perceptions of anticipated benefits: RWE will be more likely to persuade them if it clarifies the behavioral costs and consequences of particular treatments.

Approaches that go beyond claims data are thus important to consider. Potential ways forward include patient charts, dedicated registries and observational methodologies. A high degree of sophistication will be essential to ensure the right level of granularity, as will the ability to couple different data sources to accommodate the sheer size of data assets required to reach a better understanding of patients and patient segmentation. This is a skill set that requires significant development, implying investment in enabling technologies and in turn, partnerships, transparency and trust.

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REAL-WORLD EVIDENCE | INSIGHTS 3.Tactical planning The final step in the planning process is to outline the specific tactical studies and activities required to execute an effective RWE strategy. This involves integrating the list of internal desires and external demands for RWE insights, mapping out the geographies where requests are relevant, and sequencing them for efficient budget and staffing allocation.

Companies may judge that certain claims do not require support in specific countries, based on an assessment of the RWE environment. It is better to actively decide against RWE tactics in certain regions based on the perceived gains than be forced into inaction because it is too late to identify appropriate data sources or execute quality analyses.

Developing an inventory of RWE activities further enables companies to optimize spending when new data sources are required to support specific RWE claims, as well as facilitate communication between global headquarters and affiliates. It can further become a platform for headquarters to communicate product strategy early to affiliates, who can in turn validate assumptions regarding the fulfillment of local demands for RWE to the satisfaction of local HTA bodies.

VALUE OF COLLABORATION To effectively execute an RWE plan, companies will need to consider and collaborate with internal and external stakeholders who are not always part of the standard operating model for market access teams, including R&D. Much of the investment in R&D goes beyond just demonstrating an outcome; they are also required to understand the drivers of outcomes and the mechanisms that make treatments work. These perspectives will be invaluable as lifecycle plans incorporate endpoints on product use factors such as dosing and adherence. R&D perspectives are also more closely aligned with those of the providers who may ultimately consider RWE findings as they take on added risk for patient care.

BENEFITS OF RWE PLANNING The future for RWE is one of certain challenge for all key stakeholders as scientific advancements and external dynamics place increasing demands on decision making. However, it is also one of tremendous potential for the expanded role of RWE. For manufacturers, the adoption of a global, coordinated, lifecycle plan for RWE needs will bring four key benefits: 1. Enable efficiency gains to be realized by anticipating environmental and competitive developments and investing in timely analyses with minimal duplication of effort 2. Ensure that the existing patchwork of data sources is effectively utilized to provide information for addressing internal and external needs 3. Increase the chance that staff and budgets will be available to produce high quality responses 4. Allow companies to effectively transition from passive or reactive players in evidence-based access to successful competitors and industry leaders Overall, these gains will translate into greater returns in markets with RWE opportunities and more rational investment to achieve those gains. RWE will be useful for all parties: for physicians to optimize care by finding exactly the right patient; for regulators to continuously monitor benefit/risk; for decision makers to devise policy on usage (including HTA agencies that assess cost-effectiveness); and for business-to-business negotiations between industry and payers. •

1 2

Osterberg, L, Blaschke, T N. Adherence to medication. N Engl J Med, 2005; 353:487–497 Institute for Clinical Systems Improvement. Major Depression in Adults in Primary Care, May 2011. http://www.icsi.org

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INSIGHTS | PATIENT-REPORTED OUTCOMES Patient-reported outcomes (PROs) are an increasingly relevant decision-making tool for a growing audience of stakeholders, capturing first-hand the disease and treatment experience from a real-world, patient perspective.

But alongside their growing significance are increasing expectations of their design and validity – meriting careful review of the attributes that must be considered.

The authors Núria Lara Surinach, MD, MSC is Principal HEOR, IMS Health Nlara@es.imshealth.com

Xavier Badia, MD, PHD, MPH is Senior Principal HEOR, IMS Health Xbadia@es.imshealth.com

Núria Perulero, BSC is Director HEOR, IMS Health Nperulero@es.imshealth.com

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

PATIENT-REPORTED OUTCOMES | INSIGHTS

Getting the measure of PROs A review of key considerations The importance of understanding a patient’s perception of their disease and the impact of treatment has become increasingly recognized in recent years. Today, a patient perspective, captured in patient-reported outcomes (PROs), is a key consideration in everyday practice as well as in clinical development (Figure 1).

FIGURE 1:

PROs ARE A MAJOR FOCUS FOR ALL KEY HEALTHCARE STAKEHOLDERS

Sponsor

Prescribers

• Ensure product provides benefits from a patient as well as clinical perspective

• Support optimal treatment decisions based on patient perception

PROs Decision makers

Patients

• Provide important information for product approval, pricing and reimbursement

• Enable greater patient involvement in clinical and therapeutic management

PRO GUIDELINES The increasing use of PROs to support manufacturer claims for medical products has given rise to the publication of specific guidance by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on the development and application of these measures.

The FDA, in guidelines on the use of PROs in labeling claims issued in 2009, defines a PRO as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. (…) In clinical trials, a PRO instrument can be used to measure the effect of a medical intervention on one or more concepts (…)”.1 According to the EMA, in a reflection paper on regulatory guidance for the use of healthrelated quality of life (HRQoL) measures in evaluating medicinal products, “any outcome evaluated directly by the patient himself and based on patient’s perception of a disease and its treatment(s) is called patient-reported outcome (PRO)”.2 The overarching term of “PROs” embraces all elements of patient-reported data, including treatment preference, satisfaction, and adherence as well as burden of symptoms and HRQoL (Figure 2 overleaf).

Although recommendations for PRO development are not mandatory, the bar is now set very high, particularly for outcomes that are complex and multi-domain, such as HRQoL. Broad claims invariably give rise to concern at the FDA. Simple, single items and single-domain instruments require less documentation, assuming adequate validation. Careful examination and analysis of PRO instruments can provide useful insights for improving the chances of success. continued on next page

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INSIGHTS | PATIENT-REPORTED OUTCOMES FIGURE 2:

PROs COVER ALL PATIENT-REPORTED HEALTH DATA

Burden of symptoms

Preference to treatment

Treatment or health service satisfaction

HRQoL

Adherence to treatment

KEY CONSIDERATIONS According to the FDA guidance, the use of a PRO instrument to support claims in medical product labeling includes consideration of: • Population enrolled in the clinical trial • Clinical trial objectives and design

• PRO instrument’s conceptual framework • PRO instrument’s measurement properties

The attributes of PRO instruments reviewed by the FDA include: • • • • • • •

Concepts being measured Number of items Conceptual framework of the instrument Medical condition for intended use Population for intended use Data collection method of administration Response options

• • • • • •

Recall period Scoring Weighting of items or domains Format Respondent burden Translation or cultural adaptation availability

PSYCHOMETRIC PROPERTIES The principal measurement properties for PROs are validity, reliability and ability to detect change.

1. Validity: The relevance of a PRO is evaluated in terms of both its content and construct validity.

• Content validity: Requires evidence that the instrument in question measures the concept of interest. This includes evidence from qualitative studies that the items and domains of an instrument are appropriate and comprehensive relative to its intended measurement concept, population and use. Testing other measurement properties will not replace or rectify problems with content validity.

• Construct validity: Requires evidence that relationships among items, domains and concepts conform to an a priori hypothesis concerning logical relationships that should exist with measures of related concepts or scores produced in similar or diverse patient groups.

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PATIENT-REPORTED OUTCOMES | INSIGHTS 2. Reliability: The reliability of a PRO is assessed on several levels.

• Test/re-test or intra-interviewer reliability: Stability of scores over time when no change is expected in the concept of interest • Internal consistency as determined by: • Extent to which items comprising a scale measure the same concept • Inter-correlation of items that contribute to a score • Internal consistency • Inter-interviewer reliability (for interviewer-administered PROs only): Agreement among responses when the PRO is administered by two or more different interviewers 3. Ability to detect change: This requires evidence that a PRO instrument can identify differences in scores over time in individuals or groups (similar to those in the clinical trials) who have changed with respect to the measurement concept.

VALIDATION PROCESS The validation process follows the structure shown in Figure 3. This involves evaluating the ability of the PRO to detect change (Group A), ensuring sufficient time between visits to allow for a treatment effect; assessing test/re-test reliability (Group B), with time between visits appropriate to ensure patient stability; and thirdly, determining construct validity in the general population as a control (Group C).

FIGURE 3:

PRO VALIDATION PROCESS

Group A: To evaluate ability to detect change

Group B: To evaluate test/re-test reliability

Group C (control): To evaluate construct validity

Patients diagnosed who need clinical and/or therapeutic intervention

Patients diagnosed who are stable according to clinical criteria

General population

Visit 1

Visit 1

Visit 2 Time between visits must be sufficient to allow for treatment effect

Visit 1

Visit 2 Time between visits must be sufficient to ensure patient stability

Once the appropriate questionnaire has been chosen, the frequency of assessments needs to be defined. This should correspond with the length of recall asked by the instrument’s response options, the natural history of the disease condition, the nature of treatment, the measurement properties and the specific research questions being addressed. Some diseases, conditions, or clinical trial designs may necessitate more than one baseline assessment and several PRO assessments during treatment.

DEMONSTRATING QoL BENEFITS WITH A PRO QUESTIONNAIRE IMS HEOR has many years experience in developing and validating disease-specific questionnaires incorporating relevant patient-reported outcomes - an example is presented overleaf... continued on next page

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INSIGHTS | PATIENT-REPORTED OUTCOMES Case in practice: Demonstrating QoL benefits with a PRO questionnaire One recent case study involved a large international pharmaceutical company that wished to explore the impact of a particular disease on quality of life (QoL) and show that as well as being more effective, their new product also significantly improved QoL relative to its competitors. The involvement of key opinion leaders and a high number of physicians would be key to providing new arguments for increasing market access and demonstrating superior outcomes. These would be supported by a strong value communication plan to disseminate the results in national and international journals and congress communications and to underscore the company’s core scientific orientation.

PRO questionnaire: IMS proposed the development and validation of a specific QoL questionnaire for patients with the disease in question. The two-stage process involved first the design of the questionnaire, leveraging input from an expert focus group, in-depth patient interviews, a consensus group of experts and a patient pilot to assess the questionnaire’s measurement properties; and secondly, comprehensive validation using an observational, naturalistic and prospective study with a sample of more than 200 patients (Figure 4).

FIGURE 4:

TWO-STAGE PROCESS TO STUDY DESIGN

Phase 1: Questionnaire development

Focus group with experts Interviews with patients Consensus group of experts Pilot study with patients

Phase 2: Questionnaire validation (observational, naturalistic and prospective study with sample of more than 200 patients)

Objective: to assess QoL before and after therapeutic intervention

Baseline visit Visit 1: certain period of time after baseline visit Visit 2: certain period of time after baseline visit Relevant, reliable tool: The resulting questionnaire was short and its scoring system easy to administer in routine clinical practice. The questionnaire was shown to be a relevant tool under realworld conditions in terms of reliability, validity and sensitivity to change. In addition to QoL, other patient-based variables, such as treatment satisfaction and therapeutic compliance, were assessed with very positive results for the company’s product.

Robust scientific validation of benefits: With patient-reported evidence demonstrating the disease impact on QoL, the company was able to position the product accordingly and communicate its benefits on the basis of proven clinical effectiveness and improved QoL. The involvement of multiple disease specialists significantly strengthened messaging to the scientific community. • 1 Guidance

for industry. Patient-reported outcome measures: Use in medical product development to support labeling claims. Accessed May 11, 2012 at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282 2 Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products.

Accessed May 11, 2012 at: http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003637.pdf

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DRUG EXPOSURE MEASUREMENT | INSIGHTS

Standardizing the measurement of drug exposure The ability to determine drug exposure in real-world clinical practice enables important insights for the optimal use of medicines and healthcare resources. With significant potential for treatment complexities to confound the measurement process, finding valid approaches to standardization can be key to meaningful results.

Here we consider a recent case study in asthma.

The author Christopher Blanchette, PHD, MS, MA is Principal HEOR, IMS Health Cblanchette@us.imshealth.com

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INSIGHTS | DRUG EXPOSURE MEASUREMENT

Standardizing the measurement of drug exposure A case study in asthma The measurement of drug treatment exposure can be complex, based on the underlying assumptions that drive the product’s use. These are most easily encountered with the classic 30-day prescription fills of oral medications. However, in cases where medications are prescribed as needed, where various routes of administration apply, or where dosing is inconsistent across diverse generics manufacturers, the accurate measurement of drug exposure becomes significantly more involved.

All three of these issues were encountered in a series of studies assessing short-acting beta agonists (SABA) exposure as a predictor of subsequent asthma-related exacerbations, most notably dealing with as-needed prescribing of SABA in either a metered dose inhaler (MDI) or in a nebulized inhalant form.1,2,3,4,5

STUDY DESIGN This retrospective analysis included both prevalent and incident asthmatics, to assess patients with various levels of severity during the available observation period (Figure 1). For all analyses, evaluations were performed for three groups: all subjects (ages 6-56 years), pediatrics (ages 6-17 years) and adults (ages 18-56 years).

CAPTURING DATA Data were obtained on subjects enrolled in a health plan that participated in the PharMetrics Patient-Centric Database between July 1, 2003 and June 30, 2007. The database comprises information from enrollment files as well as facility, professional service and out-patient pharmacy claims, from a variety of private healthcare benefit plans. Its coverage extends to more than 40 million patients enrolled in over 70 health plans across the US, with health plans providing data on a continuous basis. The number of plans contributing to the PharMetrics FIGURE 1:

RETROSPECTIVE STUDY DESIGN

Q2 Q1 SABA use exacerbation risk Q3 Q2 SABA use exacerbation risk Q3 SABA use

Baseline and medical characteristics assessed 1 year pre-index period Index date

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Q1

Q2

Q3

Q4 exacerbation risk

Q4

1 year post-index period

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

DRUG EXPOSURE MEASUREMENT | INSIGHTS dataset has increased over time. Demographic information (excluding race and ethnicity) is available for all patients. Most plans also provide information on dates of eligibility for medical and out-patient pharmacy benefits.

Data available for each out-patient pharmacy claim (“prescription”) included the drug dispensed (in National Drug Code [NDC] format) and the dispensing date. Most plans also provided information on the quantity and number of therapy days dispensed. Data available for each facility or professional service claim (“medical claim”) include dates of service and International Classification of Diseases 9th Edition, Clinical Modification (ICD-9-CM) diagnosis codes and ICD-9-CM procedure codes (facility claims) or Current Procedural Terminology,Version 4 (CPT-4) procedure codes (professional service claims). All plans provided information on payments. Most plans also provided information on billed charges.

Payments were imputed for claims with missing payment information (due to capitation arrangements). All claims for any given person could be linked using a unique encrypted identifier.

The dataset is fully de-identified and HIPAA compliant.

The criteria applied for the study population were as follows: Inclusion • Patients aged 6–56 years on the index date • Continuous enrollment in a health plan in the database for 2 years • Claim with asthma diagnosis (ICD-9 code 493.XX) • Claim for either a SABA or any asthma controller medication in each of the pre-index and post-index periods Exclusion • Any diagnosis of COPD, emphysema, chronic bronchitis, or bronchiectasis • Subjects with diagnoses requiring frequent oral corticosteroid (OCS) use • Subjects with a diagnosis of respiratory tract cancer

DRUG EXPOSURE EVALUATION APPROACH Since pharmacy use can only be identified in the PharMetrics dataset using National Drug Codes (NDC), the first step was to compile an exhaustive list of NDCs for each drug of interest. The starting point for this was to link the list of identified brand and proprietary drug names to the in-house, composite drug dictionary.

SABA dosing exposure standardization was determined through prior studies. These included the 2002 evaluation by Glauber and Fuhlbrigge which provided a compelling argument for using a canister-equivalent measure, comprised by inhaled and nebulized SABA, instead of just simple counts of medication.6 They introduced a scheme for standardizing doses of inhaled and nebulized SABA equivalent to two inhalations of albuterol, dispensed from a metered dose inhaler (MDI) as the standard for comparison.

Using a high threshold level of >8 SABA canisters (counts method) or >8 canister-equivalents, the canister-equivalent method increased the population identified as having high SABA use by 39% (16.6% vs. 11.9%) relative to the simple-count method. continued on next page

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INSIGHTS | DRUG EXPOSURE MEASUREMENT Thus, in studies that do not recognize the use of nebulized SABA there is likely to be substantial misclassification of patient risk based on high SABA utilization.

The present study utilized the method described by Chan, et al,7 being inclusive of almost all MDI and nebulized SABA types identified in the dataset. Canister equivalents were determined for each claim represented. A standard SABA canister size was defined to be one containing 200 metered actuations, which encompassed more than 97% of MDI SABA claims.

More than 96% of total SABA MDI claims were for albuterol; 2.2% were for pirbuterol; and 1.6% were for levalbuterol. In the case of pirbuterol, whose standard dispensing contains 400 actuations, claims were set to two canisters. Levalbuterol was considered to be equivalent in potency to albuterol. In cases where insufficient information was available to make the determination, canister size was imputed using days supply of medication. Thirty days supply or less was determined to be equivalent to one canister, 31 to 60 days supply as two canisters, etc.

Nebulized SABA canister claims comprised 12% of all SABA claims. Based on the Chan study method, canister-equivalents were derived for each nebulized SABA claim.

The vast majority of these claims were for albuterol or levalbuterol (considered equivalent in potency to albuterol), in which case one 3ml ampule was equivalent to 0.02 canister-equivalents, making fifty ampules of 3ml of medication equivalent to one canister.

The quantity of medicine is typically given in ml in the dataset. Each ampule typically contains 3ml of medicine and is most often dispensed in boxes of 24, 25 or 30, each of which was equated to a half canister of SABA.

FIGURE 2: SABA CANISTER FILLS 2ND QUARTER (POST-INDEX YEAR) N=93,444

5%

32%

64% 0 Canisters

It was determined that the most accurate method to represent these medication quantities was to round to the nearest halfcanister because most boxes contained 24, 25 or 30 ampules and most claims were in multiples of these. Less than 1% of claims observed were clear outliers (eg, >180 ampules). For these, the maximum dose was capped at three canister equivalents per claim.

â „2-3 Canisters

1

> 3 Canisters

FIGURE 3: Q3 EXACERBATION INCIDENCE BY Q2 SABA USE STRATA

Hospitalization ED/UC Visit OCS claim Any of the above

0 0 Canisters (n=59,653) â „2-3 Canisters (n= 26,525)

1

> 3 Canisters (n= 4,266)

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5

10

15

20

Percentage of Patients

ED = Emergency department UC = Urgent care OCS = Oral corticosteroid

Due to the heterogeneity of asthma controller medications, it was elected to use annual days supply during the pre-index and post-index years, and days supply per quarter for the quarterly analysis regardless of the medication being inhaled (eg, ICS) or oral (eg, leukotriene modifiers). Controller medications prescribed concomitantly and measured as covariates were assessed as the sum of days supply provided on the claims, a proxy for days of exposure. A similar method was used to describe use of nasal steroid sprays and antibiotics.

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

DRUG EXPOSURE MEASUREMENT | INSIGHTS FIGURE 4: RISK OF EXACERBATIONS BY Q2 SABA STRATA (REFERENCE=0 CANISTERS)

Hospitalization 1/2 -3 >3 ED/UC Visit 1/2 -3 >3 OCS claim 1/2 -3 >3 Any of the above 1/2 -3 >3

1

2

3

4

5

6

Odds Ratio (95% CI) ED = Emergency department UC = Urgent care OCS = Oral corticosteroid

All oral corticosteroid (OCS) claims, regardless of days supplied, were counted as one claim.

Ninety percent of prescription dispensing for OCS was found to be for 21 days or less. In the analysis, OCS were evaluated as a binary variable for the presence of one or more claims, and as a count of claims during the specified time period. Injectable corticosteroids were not captured, since these are typically administered in a physician’s office and are rarely registered as NDC-based claims.

CONCLUSIONS The study found that a quarterly assessment of SABA utilization can be used to identify patients at risk for asthma-related exacerbations. The incidence of an asthma exacerbation was associated with greater SABA use in the previous quarter (Figures 2,3,4).Variability in SABA exposure measurement and standardization between nebulized and MDI routes may have provided biased estimates on associated cost and asthma-related exacerbations.

Notwithstanding this caveat, however, these findings provided critical insights for optimizing the treatment and management of asthma patients. •

1 Blanchette

CM, Silver H, Petersen H, Kamble S, Meddis D, Gutierrez B. Quarterly assessment of short-acting ß-agonist use as a predictor of subsequent healthcare services use for asthmatics in the US. ISPOR 14th Annual International Meeting, Orlando, FL; May 16-20, 2009.

2 Blanchette CM, Silver H, Petersen H, Kamble S, Meddis D, Gutierrez B. Identification of a threshold for high utilization of short-acting ß2-agonists in a commercially insured adult asthmatic population in the United States. American Academy for Asthma, Allergy, and Immunology 2009 Annual Meeting, Washington, DC; March 13-17, 2009.

3 Silver H, Blanchette CM, Petersen H, Kamble S, Meddis D, Gutierrez B. Short-acting beta agonist utilization and risk of asthma exacerbation among a commercially insured pediatric population in the United States. American Academy for Asthma, Allergy, and Immunology 2009 Annual Meeting; Washington, DC; March 13-17, 2009.

4 Silver HS, Blanchette CM, Kamble S, Petersen H, Letter M, Meddis D, Gutierrez B. Relationship between short-acting ß2-adrenergic agonist use and healthcare costs. American Journal of Managed Care. 2011 Jan; 17(1):19-27.

5 Silver HS, Blanchette CM, Kamble S, Petersen H, Letter M, Meddis D, Gutierrez B. Quarterly assessment of short-acting ß2-adrenergic agonist use as a predictor of subsequent health care use for asthmatic patients in the United States. Journal of Asthma. 2010 Aug; 47(6):660-6.

6 Glauber JH, Fuhlbrigge AL. Stratifying asthma populations by medication use: How you count counts. Ann Allergy Asthma Immunol. 2002; 88:451-456.

7 Chan J, Hui RL, Spence MM. Effects on resource utilization of adding salmeterol in combination or separately to inhaled corticosteroids. J Manag Care Pharm. Jan-Feb 2007; 13(1):21-27.

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INSIGHTS | INDIRECT TREATMENT COMPARISONS Direct evidence from randomized trials remains the ultimate gauge of relative value when comparing competing technologies.

In its absence, the need for indirect methods is becoming increasingly accepted. Here, we consider the growing role of network meta-analysis and its evolving capabilities as a key enabler of indirect treatment comparisons.

The authors Mark Lamotte, MD is Principal HEOR, IMS Health Mlamotte@be.imshealth.com

Karen Moeremans, MD is Director HEOR, IMS Health Kmoeremans@be.imshealth.com

Tiago Fonseca, MSC is Consultant HEOR, IMS Health Tfonseca@uk.imshealth.com

Stijn Vandekerckhove, MSC is Analyst HEOR, IMS Health Svandekerckhove@be.imshealth.com

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INDIRECT TREATMENT COMPARISONS | INSIGHTS

Accounting for direct evidence gaps with indirect treatment comparisons Growing potential of network meta-analysis Direct, head-to-head comparisons via robustly designed randomized controlled clinical trials (RCTs) are still considered the gold standard for assessing the relative efficacy and safety of competing treatments. Where there are multiple trials of two interventions, pair-wise meta-analyses may be performed to obtain a pooled estimate and respective confidence interval for the relative efficacy of the target treatments, taking account of all available direct evidence. However, direct evidence is often lacking.

Several factors can contribute to critical gaps in the necessary head-to-head RCT evidence base: • RCTs supporting drug licensing approval only, often compare the new intervention with placebo; industry perceptions of excessive risk negate the commercial incentive to compare with an active control.

• Even if an active comparator is included in the RCT, it may not be relevant in all settings • As new evidence continues to be generated, available treatments change/increase over time.

This is particularly true for hematologic diseases and oncology. A recent IMS research project identified 115 Phase III trials, including more than 80 alternative therapy regimens, for the management of advanced non-small cell lung cancer over the last decade alone.

Thus, for some indications, it is unfeasible to incorporate all the competing interventions in a single clinical trial. Furthermore, the most relevant comparator at the time of assessment may well differ from the standard at the time of trial design.

These shortfalls in direct evidence impose challenges for the assessment of treatment pathways, leaving clinicians, patients, and health policy makers with an incomplete picture in determining which treatments are the most effective (and cost-effective).

TAKING THE INDIRECT ROUTE In cases where direct evidence is insufficient or non-existent, indirect comparisons and mixed treatment comparisons, also known as network meta-analyses (NMAs), can provide the opportunity to compare what may not otherwise have been compared. NMAs represent extensions of the pair-wise meta-analysis1: rather than pooling information on trials comparing treatments A and B, as in pair-wise meta-analysis, NMA combines data from different randomized comparisons: A vs B; A vs C; A vs D; and so on (Figure 1 overleaf).

Additional advantages of NMAs include the increase in sample size derived from the combination of studies, and the systematic and quantitative nature of the synthesis, enabling a full assessment of uncertainty about the relative results. Furthermore, NMAs allow quantification of relative treatment effects (eg, odds ratio, relative risk, or difference in change from baseline) of different therapeutic classes (eg, Glucagon-like peptide-1 (GLP-1) receptor agonists and insulins), different drugs within the same class (eg, exenatide and liraglutide), and different doses of the same drug (eg, exenatide BID or QW vs liraglutide 1.2mg or 1.8mg). continued on next page

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INSIGHTS | INDIRECT TREATMENT COMPARISONS FIGURE 1:

META-ANALYSIS AND NETWORK META-ANALYSIS

B A

B

B

A

A C

C D

Direct comparison

Indirect comparison

Meta-analysis

Mixed treatment comparison

Network meta-analysis Direct evidence

Indirect evidence

TRIAL SELECTION KEY TO QUALITY To ensure that all relevant trials are considered for inclusion, ideally the potentially eligible studies should be identified via a systematic review.

In order to obtain an internally consistent set of estimates, while respecting the randomization in the evidence, the underlying assumption is that the trials included are sufficiently homogeneous to be quantitatively combined, via a common comparator. This assumption requires not only similarity of trial populations (in- and exclusion criteria, patient characteristics, etc) but also methodological similarity (eg, trial quality, definition of outcomes, randomization method, etc). An example of consistency is that the treatment effect estimated by the BC trials would be the same as the treatment effect estimated by the AC and AB trials if they had included B and C arms.

Trial quality should be sufficient for consideration. It is important to bear in mind that a set of badly conducted studies does not lead to a good analysis; hence, the importance of defining a coherent set of inclusion and exclusion criteria at an initial stage – usually when systematically reviewing the literature.

NMAs enable the evaluation of competing treatment options that may not otherwise have been directly compared. Although the level of evidence they generate may be perceived to be inferior to that of gold standard RCTs, they nevertheless have important strengths.

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

INDIRECT TREATMENT COMPARISONS | INSIGHTS FIGURE 2:

EMBASE SEARCH RESULTS REVEAL MARKED RISE IN NMA, INDIRECT OR MIXED TREATMENT COMPARISONS

700

Hits

600 500

Number of hits

400 300 200 100 0

1992-1997

1997-2002

2002-2007

2007-2012 (week 15)

INCREASINGLY ACCEPTED ALTERNATIVE Today, the use of NMA methods is becoming more widespread and, possibly as a consequence, more widely accepted in informing healthcare stakeholders. An ad hoc search in EMBASE, using "network meta-analysis”, “indirect comparison” and “mixed treatment comparison” as search terms, identified more than 640 publications between 2007 and 2012 with any of these words in the title, abstract or as key word fields. Between 1992 and 1997 this number was only 12 (Figure 2). Experience at IMS confirms this trend, with an increase in client requests for these types of studies, primarily in support of market access submissions as well as to demonstrate (and communicate) product value.

ACKNOWLEDGED NEED Globally, more payers and HTA bodies are acknowledging the need for and acceptability of indirect comparisons to accommodate the lack of direct comparative evidence from RCTs. Some have published statements relating to the admissibility of methodologies within the indirect and mixed treatment comparisons area (Table 1).

The European Medicines Agency (EMA) notes that comparisons to active control will usually need to be ‘direct’ (ie, within the same trial) in order to estimate relative efficacy and safety, but acknowledges that there are some circumstances where an indirect comparison might be considered sufficiently reliable.8 In the US, the FDA has not as yet published guidelines on indirect comparisons (based on keyword searches April, 2012).

An Australian Indirect Comparison Working Group (IWCG) has written an extensive report on this topic for the Australian Pharmaceutical Benefits Advisory Committee (PBAC). This illustrates that the value of indirect comparisons largely depends on the underlying assumptions of the individual RCTs being compared.

continued on next page

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INSIGHTS | INDIRECT TREATMENT COMPARISONS TABLE 1:

PAYER/HTA PERSPECTIVE ON INDIRECT COMPARISONS IN KEY MARKETS

COUNTRY

PAYER/HTA

PERSPECTIVE ON INDIRECT COMPARISONS

Belgium

KCE

Indirect comparisons are only allowed under specific conditions: the choice of an indirect instead of direct head-to-head comparison between study treatment and comparator should be explained, and limitations of the indirect comparison described.2

Canada

CADTH

No formal guidance but best practices outlined by ISPOR and NICE should be considered for submissions.

HAS

Methodological guide, Oct 2011, states:”If direct comparative data are not available or are insufficient, it may be necessary to perform indirect comparisons according to validated methodologies”. Offers two techniques: simple adjusted indirect comparison (straightforward and transparent); and network Bayesian methodology (provides best solution to determine hierarchy of treatment pathways).3

Germany

IQWiG

Recognizes methods supported by NICE. Stares that indirect comparisons can be considered useful, necessary and inevitable in some cases. However, also claims that results based on indirect comparisons are associated with more uncertainty than direct comparisons.4

Netherlands

CVZ

Allows use of indirect comparisons while recognizing that this type of evidence is less valuable than direct comparisons.5

Scotland

SMC

Guidance notes (2012) stipulate requirement for indirect comparisons if head-to-head evidence is not available.6

France

Sweden

TLV

UK

NICE

No published statement on indirect comparisons but in evaluations of reimbursement dossiers, TLV has been pragmatic, evaluating on a case-by-case basis. The use of MTC and indirect comparisons has been accepted when well supported and scientifically robust.

NICE guidance states: “Data from head-to-head RCTs should be presented in the referencecase analysis, if available. When head-to-head RCTs exist, evidence from mixed treatment comparison analyses may be presented if it is considered to add information that is not available from the head-tohead comparison.” “If data from head-to-head RCTs are not available, indirect treatment comparison methods should be used.” “There may be circumstances in which data from head-to-head RCTs are less than ideal (for example, the sample size may be small or there may be concerns about the external validity). In such cases additional evidence from mixed treatment comparisons can be considered.”7

KEY CADTH: Canadian Agency for Drugs and Technologies in Health CVZ: College Voor Zorgverzekeringen HAS: Haute Autorité de Santé IQWiG: Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen

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KCE: Federaal Kenniscentrum voor de Gezondheidszorg NICE: National Institute for Health and Clinical Excellence TLV: Tand-och Lakemedelsformansverket

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

INDIRECT TREATMENT COMPARISONS | INSIGHTS The authors conclude that indirect comparisons are not randomized and so the associated uncertainty should be recognized in the submission. Nevertheless, suggestions are provided on producing a more convincing indirect comparison.9 An ISPOR task force published two reports in 2011 to help guide decision bodies on generating and interpreting evidence that involves indirect comparisons. 10

METHODOLOGICAL POSSIBILITIES When the indirect results are inconsistent with the direct evidence, it is important to investigate possible causes of discrepancy such as chance or heterogeneity across trials. For example, the synthesized evidence may be influenced by differences in the baseline characteristics of the patients across the included trials. In this case, statistical methods exist to produce a valid and coherent analysis.

The recent development of computational power allows the use of the Bayesian framework in NMAs. The results produced within this framework can be interpreted in terms of probabilities – an advantage over the classical approach in allowing treatments to be rank ordered and the best ones to be determined. Furthermore, with RCTs still considered the gold standard for assessing relative efficacy and safety, the inclusion of other types of studies (eg, observational) would be seen as a weakness of the analysis. However, RCTs are experiments conducted in extremely controlled environments which may limit the applicability of their findings to the real world. The Bayesian approach allows the combination of real-world evidence with that observed in the controlled environments of RCTs, thus increasing the external validity of the analysis, ie, the extent to which the results can provide a correct basis for generalization to other circumstances.

EVOLVING POTENTIAL NMAs enable the evaluation of competing treatment options that may not otherwise have been directly compared. Although the level of evidence they generate may be perceived to be inferior to that of gold standard RCTs, they nevertheless have important strengths. This topic continues to evolve; Bayesian methods are a good example of this evolution, allowing the expression of relative hierarchy of treatment efficacy and potentially increasing the generalizability of results to broader settings by combining RCT data with other sources, such as observational data. These methods are increasingly being used and accepted by authorities as solutions to address the absence of randomized direct comparative data. •

1 Pair-wise

meta analytic methods are typically restricted to comparisons of two interventions, using direct, head-to-head evidence alone.

I,Van Wilder P,Vrijens F, Huybrechts M, Ramaekers D. Richtlijnen voor farmacoeconomische evaluaties in België. Health Technology Assessment (HTA). Brussel: Federaal Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE Reports 78A (D/2008/10.273/23).

3 Guide méthodologique, choix méthodologiques pour l’évaluation économique à la HAS,Haute Autorité de santé, Octobre 2011.

Available from www.has-sante.fr 4 Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG). Stellenwert von Ergebnissen aus indirekten Vergleichen. Köln: IQWiG 2012.

5 College voor zorgverzekeringen (CVZ). CFH-criteria voor beoordeling therapeutische waarde. Diemen: CVZ 2010. Available from www.cvz.nl 6 Scottish Medicines Consortium. Guidance to Manufacturers for Completion of New Product Assessment Form (NPAF). November, 2011.

7 National Institute for Health and Clinical Excellence (NICE). Guide to the Methods of Technology Appraisal. London: NICE, 2008.

8 Reflection paper on the need for active control in therapeutic areas where use of placebo is deemed ethical and one or more established medicines are available. EMA/759784/2010. EMA, November 2010. Available from www.ema.europa.eu. Accessed 12/05/2012.

9 Indirect Comparisons Working Group (ICWG) (30/01/2012). Report of the Indirect Comparisons Working Group to the Pharmaceutical Benefits Advisory Committee: Assessing indirect comparisons. Available from www.health.gov.au Accessed 10/04/2012.

10 Jansen JP, Fleurence R, Devine B, Itzler R, Barrett A, Hawkins N, Lee K, Boersma C, Annemans L, Cappelleri JC. Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: Part 1.Value Health. 2011 Jun;14(4):417-28.

2 Cleemput

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INSIGHTS | US PRIVATE HEALTHCARE SPENDING The US Affordable Care Act is expected to extend health insurance coverage to an additional 44 million Americans through 2020. New research from the IMS Institute suggests that a deeper understanding of spending patterns among private plan enrollees – especially for the smaller number who significantly impact overall costs – will be essential to ensuring effective strategies for the future.

The author Murray Aitken, MBA is Executive Director, IMS Institute for Healthcare Informatics Maitken@theimsinstitute.org This article is summarized from “Healthcare Spending Among Privately Insured Individuals Under Age 65” published by the IMS Institute for Healthcare Informatics in February, 2012.

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

US PRIVATE HEALTHCARE SPENDING | INSIGHTS

Who drives the lion’s share of costs?

Understanding healthcare spending in the commercially-insured US population under age 65 Healthcare spending and utilization patterns among the privately insured population in the US are not widely understood – or widely available – yet are critical to addressing trends in cost growth and ensuring appropriate planning for this evolving population.

With limited access to information on the private sector, health services researchers have traditionally relied on analyses of publicly available data (principally Medicare) to advance policy recommendations. This analysis uses comprehensive, proprietary data for more than 10 million privately insured members under age 65 to examine their patterns of outpatient, inpatient and pharmacy healthcare spending and consider the potential implications. The analysis also highlights distinctions between IMS aggregated healthcare use and spending patterns and those commonly cited among health services researchers, including the Agency for Healthcare Research and Quality (AHRQ) and Centers for Medicare and Medicaid Services (CMS).

THE SCOPE OF THE STUDY The findings are derived from an analytic subset of the LifeLink™ Health Plan Claims Database, which comprises 6.7 billion medical and pharmacy claims, 79 health plans, and 79.4 million members from 2001 to the present. The time period covered was from January 1, 2009 through December 31, 2010. Only privately insured health plan members under age 65 with continuous enrollment and medical and pharmacy benefit coverage were included.

Cost and usage patterns across 17 chronic conditions, 12 cancers, and 10 auto-immune and other specialty conditions were evaluated in the study population. Costs reported reflect the plan-allowed amount (ie, plan paid amount plus member contribution) for a given service.

Members were identified by condition based on Year 1 experience, and their cost and utilization is reported based on Year 2.

More than 50% of the total cost was accounted for by just 5% of all health plan members.

More than 25% of total spending was for just 1% of all members. Conversely, only 3% of total cost was incurred by the 50% of members with the least annual spending.

continued on next page

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INSIGHTS | US PRIVATE HEALTHCARE SPENDING TOTAL HEALTHCARE SPENDING All payers In 2010, 184 million Americans, representing 63% of the insured population, were enrolled in a private health insurance plan (Figure 1). Collectively, they were responsible for $822 billion in healthcare expenditures. Medicare and Medicaid expenditures were $525 billion and $400.7 billion respectively.

By 2020, enrollment in private health insurance is expected to be 198 million with expenditures reaching $1.4 trillion. Private health insurance enrollees are projected to remain the largest segment (57%) of the overall covered population and their expenditures the largest share of insurance spending (41%), even as the impact of implementing the Affordable Care Act transforms the healthcare landscape. Medicare and Medicaid will represent 27.7% and 26.7% of total healthcare spending on insurance respectively.

FIGURE 1:

US ENROLLMENT IN PRIVATE HEALTH INSURANCE REACHES 197.8 MN BY 2020

25.9

25.8

21.1

162.8

24.8 5.2

18.8 7.3

48.5

183.9Mn individuals, 63% of insured population

168.9

195Mn individuals, 58% of insured population

167.8

1.4

5.2 5.9

197.8Mn individuals, 57% of insured population

83.5

80.6

53.7

2010 Uninsured CHIP

62.3

55.4

46.8

2016 Exchanges Medicaid

2020 Other Private Medicare

Employer

Source: Centers for Medicare & Medicaid Services, Office of the Actuary, National Health Statistics Group1, Dec 2010

Understanding at a more granular level the profile, behavior and usage patterns of the privately insured under age 65 health plan members who will have the greatest overall impact on healthcare costs, is key to the design and implementation of more effective, efficient care management programs.

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

US PRIVATE HEALTHCARE SPENDING | INSIGHTS PRIVATELY INSURED Highly concentrated For the total sample of more than 10.6 million privately insured health plan members, average healthcare spending in 2010 was $3,840, or $320 per member per month. However, more than 50% of the total cost was accounted for by just 5% of all health plan members. More than 25% of total spending was for just 1% of all members. Conversely, only 3% of total cost was incurred by the 50% of members with the least annual spending (Figure 2). Understanding the profile, behavior and interventions that can be optimally applied to the relatively small number of members who have a substantial impact on overall healthcare costs is thus critical.

Age-related increase Health plan members between the ages of 45 and 64 expended, on average, nearly twice the amount on health services annually as their counterparts between the ages of 20 and 44, and four times that of members in the youngest group of 0 to 9 years of age. Analysis of Medicare enrollees also shows increased spending with age, with average annual spending per enrollee higher than for the IMS privately-insured study population.

FIGURE 2:

DISTRIBUTION OF SPENDING IN THE US PRIVATELY INSURED 96.9%

80.7%

85.4%

74.3% 65.2% 50.6%

25.6%

3.1% Top 1%

Top 5% Top 10% Top 15% Top 20% Top 25% Top 50%

(>=$44,957) (>=$14,947) (>=$8,582) (>=$5,773) (>=$4,169) (>=$3,130) (>=$874)

Bottom 50% (<$874)

PERCENT OF HEALTH PLAN MEMBERS, RANKED BY HEALTHCARE SPENDING ($)

Source: IMS LifeLink Health Plan Claims Database, Dec 2010

Outpatient driven The largest share of all spending of the privately insured under age 65 population was for outpatient services, which represented 59% of total spending. Expenditures for retail pharmacy and inpatient services accounted for the remaining 21% and 20% of spending respectively. continued on next page

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INSIGHTS | US PRIVATE HEALTHCARE SPENDING This distribution of costs differs significantly from that reported by the Medical Expenditure Panel Survey (MEPS) for all payers and for the Medicare 65 and over population2.

In particular, Medicare 65 and over population spending on inpatient services represented 43% of total spending, while outpatient and pharmacy services were 39% and 18%, respectively (Figure 3).

The differences in spending distribution between the privately insured under age 65 population and the Medicare 65 and over population are substantial and highlight the need for correspondingly differentiated analysis, understanding, and actions aimed at bending the overall US healthcare cost curve.

FIGURE 3:

SIGNIFICANT DIFFERENCES IN DISTRIBUTION OF SPENDING BY PAYER TYPE

21%

22%

18%

39% 47%

59%

43% 31% 20%

IMS Privately Insured Under Age 65 Inpatient

MEPS All Payers Outpatient

MEPS Medicare 65 and Over Pharmacy

Source: IMS LifeLink Health Plan Claims Database, Dec 2010; Medical Expenditure Panel Survey2, 2009

Disproportionate for certain conditions Among health plan members, there were noteworthy differences in treatment patterns across diseases, which were outpatient driven among those with chronic or oncology conditions, and pharmacy driven for members with auto-immune or other specialty conditions.

Members with chronic conditions like diabetes, congestive heart failure, chronic renal failure or back pain, were responsible for a disproportionate share of spending. When the prevalence of the 17 chronic conditions evaluated was compared to total spending for members affected by these conditions, their impact was immediately evident and dramatic: more than one third of members had at least one chronic condition and accounted for more than two-thirds of total spending for all members.

Members with cancers, auto-immune or other conditions treated with specialty medications also accounted for larger shares of spending. Those with cancers accounted for only 1.5% of all health plan members and almost 8% of total spending, while members with auto-immune or other specialty conditions represented 1.7% of all members, and were responsible for 7% of total spending.

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

US PRIVATE HEALTHCARE SPENDING | INSIGHTS OUTPATIENT SPENDING Outpatient services represented the largest share of total spending, averaging $2,251 per member per year, or $188 per member per month. Professional and facility visits accounted for 74% of overall outpatient spending, with emergency room visits a further 10%.

Outpatient medical drug therapy, including office, facility and home-based injections and infusions, represented 5% of all outpatient spending, or $9 per member per month on average.

However, outpatient drug therapy for oncology, auto-immune and other specialty condition populations studied were significantly higher, amounting to 19% and 18%, respectively.

INPATIENT SPENDING Facility-based costs represented 84% of the total inpatient spending, with the balance being professional service costs. Spending per inpatient admission was $14,248 on average, and represented 20% of overall spending per member.

Members with chronic conditions accounted for the largest share of all hospital admissions at 63%, equating to 29 admissions per 1,000 members. They also had the largest share of professional visits, at 219 per 1,000 members. Average spending per admit was $15,566, with an average 4.5 days of stay.

Members with oncology conditions had the highest average cost per admission at $20,074 but admissions only totaled 2.8 per 1,000 members. Oncology patients also had a longer average length of stay compared to the overall member population and members with chronic conditions, making cancer admissions the most expensive.

Inpatient services were only 16% of all spending among members with auto-immune or other specialty conditions.

PHARMACY SPENDING Average pharmacy spending – including outpatient drug claims for both specialty and nonspecialty medicines – amounted to 21% of total healthcare spending for the privately insured under age 65 population. For every 1,000 members, 11,950 prescriptions were filled in 2010, of which 78% were for members with chronic illnesses. Those with oncology and those with auto-immune or other specialty conditions filled only 4% and 5% of the total number of prescriptions, respectively.

Specialty drugs represented about 1% of total pharmacy prescriptions but 17% of total pharmacy spending. Relative to total healthcare spending – including inpatient costs, outpatient medical costs and non-specialty pharmacy costs – specialty drug therapy and outpatient medical drug therapy were particularly high for members with auto-immune or other specialty conditions, representing 33% of their total healthcare spending. This reflects the growing availability of treatment options for members with auto-immune or other specialty conditions, where medications can be administered outside of the hospital setting.

By comparison, these drugs accounted for 17% of spending for oncology patients, and just 6% for those members with chronic conditions.

TOP 1% SPENDING COHORT Consistent with patterns across the healthcare system, privately insured under age 65 health plan members who are among the top 1% in annual spending were found to be vastly disproportionate users of healthcare resources, averaging almost $100,000 in annual spending per member. continued on next page

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INSIGHTS | US PRIVATE HEALTHCARE SPENDING Within the top 1% cohort, our analysis shows that 77% of the members had at least one chronic condition, 16% had one or more cancers, and 13% suffered from auto-immune or other specialty conditions (some members had conditions in more than one of these groupings). Oncology patients had the highest average spending, of $118,000 per year.

The distribution of spending in the 1% cohort is similar to that of the Medicare 65 and over population, with 45% of spending being for inpatient, 45% for outpatient, and 10% for pharmacy services.

Average spending for the top 1% of members with specific chronic conditions was up to ten-fold the average spending for all members with the same conditions. For example, members with diabetes averaged $11,858 in annual spending while those in the top 1% cohort suffering from diabetes averaged $102,465 in annual spending. Similarly, those with chronic renal failure on average spent $33,801 per year, but those within the top 1% cohort spent over $150,000 annually.

POTENTIAL IMPLICATIONS What is clear from these findings is that health plan management strategies for privately insured, under age 65 members cannot simply be an extension of Medicare strategies, given their lower share of expenditure for inpatient service spending, and higher shares for outpatient and retail pharmacy spending. Out-patient service pricing, use and management are important to the ability of private payers to manage costs across their membership, particularly as health exchanges result in large numbers of new entrants to the privately insured population.

Effective benefits packages will need to fully consider services used by the three high-cost member segments – those with chronic conditions, cancer, and those with auto-immune or other specialty diseases.

1. Chronic conditions Members with chronic conditions are responsible for the majority of healthcare expenditure in the overall as well as the top 1% spending cohort populations studied. These members and their plans would benefit from: • Employer-led wellness efforts • Prospective outpatient service management and outreach to reduce co-morbidity and complication risks • Healthcare payment and delivery model innovations that reward primary care physicians for coordinating specialty care for chronic care patients and align incentives to facilitate care coordination across providers • Care management programs targeting reductions in re-admission rates among members with conditions such as MI, stroke, diabetes or chronic renal failure, which could lead to system cost savings and improved member quality of life Managing health status among health plan members with chronic conditions may result in cost savings for Medicare into the future, if investment in these individuals reduces or delays complications.

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

US PRIVATE HEALTHCARE SPENDING | INSIGHTS 2. Cancer Members with cancers remain a small proportion of all members but have high per patient spending and higher proportions of outpatient spending, including medical drug therapy.

• These patients could benefit from treatment pathway and setting management initiatives that align incentives among providers for care coordination • Where possible, providing coverage for self-administered therapies through retail pharmacy outlets may lead to greater efficiency and better quality of life for members with cancers • Emerging guidelines around cancer screening and treatment may improve treatment effectiveness, lower cost, and improve quality of life for patients with different cancers 3. Specialty In certain disease populations, the increased use of specialty retail drug therapy may lead to decreased overall member spend.

• Specialty medications dispensed through the traditional or specialty retail pharmacy setting are a key cost driver and need contracting and utilization management • At the same time, patients with autoimmune and other specialty conditions had lower spending and use rates for inpatient services than members with cancers or for chronic conditions without specialty drugs • Additionally, members with auto-immune and other specialty conditions in the top 1% cohort, including MS and RA, had lower overall per member spending, despite higher shares of retail pharmacy spending Medicare and private payers face similar challenges managing spending and utilization for drug therapy administered in an outpatient facility, office or home setting and paid under the medical benefit. These include: • Coordinating the management of outpatient medical and retail pharmacy drug use, spending, and appropriateness • Evaluating effects of offering specialty medications through the retail or home health setting, in addition to or instead of in the outpatient facility or office setting, when clinically possible

SUMMARY Efforts to address healthcare spending levels and ensure optimal care for patients require detailed understanding from timely and robust information. This analysis is intended to focus attention on the patient segments, care settings, and treatment options that can best bring improved health outcomes at lowest cost to those in need. Understanding at a more granular level the profile, behavior and usage patterns of the privately insured under age 65 health plan members who will have the greatest overall impact on healthcare costs, is key to the design and implementation of more effective, efficient care management programs. Addressing the health needs of this evolving population efficiently will bring significant benefits to the entire healthcare system. •

1

National Health Expenditure Projections 2010-2020. Centers for Medicare & Medicaid Services, Office of the Actuary, National Health Statistics Group. 2010. https://www.cms.gov/nationalhealthexpenddata/downloads/proj2010.pdf

2

Medical Expenditure Panel Survey:Tables of Expenditures by Health Care Services. Agency for Healthcare Research and Quality, 2009. http://www.meps.ahrq.gov/mepsweb/data_stats/quick_tables_results.jsp

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INSIGHTS | IMPLEMENTING HTA IN ASIA PACIFIC In their efforts to optimize healthcare resources while improving access to new innovations, more emerging markets in Asia Pacific are signaling the move to a formal process for assessing healthcare technologies.

While opportunities beckon for industry to help shape the landscape, challenges remain for successful implementation of HTA in the region.

The author Joe Caputo, BSC is Regional Principal HEOR, Asia Pacific, IMS Health Jcaputo@sg.imshealth.com

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

IMPLEMENTING HTA IN ASIA PACIFIC | INSIGHTS

Implementing HTA processes in the emerging markets of Asia Pacific Critical factors for success Across the emerging markets of Asia Pacific, government health ministers continue to emphasize their desire to develop and implement formal pharmacoeconomic guidelines in their respective countries.

The political desire of many of the region’s authorities to provide broader access to healthcare for its populations, along with the growing prevalence of non-communicable diseases (NCDs) such as cancer and diabetes, are placing a strain not only on government budgets but also on the healthcare infrastructure across Asia Pacific. As in the West, increasing life expectancy is giving rise to the greater burden associated with ageing populations, while governments struggle to balance growing costs with a need to expand healthcare provision to all.

APPROACHES TO COST CONTAINMENT At the heart of any cost-containment strategy is a set of tools, ranging from complex risk-sharing schemes and health technology assessment (HTA) through to more simplistic mechanisms, such as prescribing controls and mandatory price cuts. Analysis of cost-management trends across Asia Pacific, relative to Europe and North America, suggests a leaning towards less complex approaches (Figure 1 overleaf).

One postulated reason for this is that before being able to even contemplate more sophisticated initiatives, governments must first address basic infrastructure needs. These include having sufficient doctors and clinics to diagnose and treat patients or, even more fundamentally, ensuring the provision of clean water and sanitation – as is the case in Indonesia.

At the same time, there is growing appreciation that cost containment can only be effective when implemented in a systematic manner. Hence, the use of more complex tools is gaining in popularity across the region. South Korea and Taiwan already have formal guidelines in place and are now considered ‘mature’ markets in terms of HTA adoption. However, with Japan and China, amongst other Asian countries, announcing their intention to develop and implement pharmacoeconomic assessments, there is an opportunity for industry to engage with payers and governments to help shape the HTA environment and become a valued stakeholder in the healthcare process.

CHALLENGING PATH TO IMPLEMENTATION The caveat, here, is that declaring a wish to establish an HTA process and effectively implementing that process are two very different things. Success – or otherwise – will be contingent on a number of factors, including technical expertise, availability of local data, stakeholder education and last, but not least, transparency of decision making.

• Technical expertise: Lack of technical expertise among the regional and national health authorities is a key challenge for moving the agenda forward. Many of the region’s authorities are looking to countries with established approaches and organizations such as continued on next page

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INSIGHTS | IMPLEMENTING HTA IN ASIA PACIFIC FIGURE 1:

COST CONTAINMENT IN ASIA PACIFIC HAS FOCUSED ON LOW-COMPLEX MEASURES EU

DECREASING COMPLEXITY OF TOOL

Cost containment tools

FR DE

IT

APAC

ES UK AUS CH IN

ASEAN

JP KR TW ID MY PH SG TH VT

VBP/Risk-sharing agreements HTA/cost-effectiveness assessments Quality/innovation/ therapeutic value rating Generics promotion International price referencing Spending caps Patient contributions Prescribing controls Mandatory price cuts

Most cost-containment tools used are at the relatively low complexity end of the scale

Only recently implemented/limited application

FR: France, DE: Germany, IT: Italy, ES: Spain, UK: United Kingdom, AUS: Australia, CH: China, IN: India, JP: Japan, KR: South Korea, TW: Taiwan, ID: Indonesia, MY: Malaysia, PH: Philippines, SG: Singapore, TH: Thailand, VT: Vietnam

NICE (National Institute for Health and Clinical Excellence) in the UK, for guidance on the design and implementation of their HTA processes. Even with the relevant expertise in place, the issue of which therapy areas to prioritize remains a critical question. â&#x20AC;˘ Data availability and real-world evidence: The effective working of an HTA process relies heavily on local data, be they clinical data in the local population (particularly important in populations where genetic differences may result in different levels of efficacy), or healthcare resource use and cost data which will be used to evaluate the costeffectiveness of different treatment options relative to the current standard of care. Hence, the growing demand for real-world evidence (RWE) to support HTA submissions.

For the emerging Asian markets, the need for RWE in itself brings another set of challenges.

Local databases are scarce; even when they exist they tend not to be readily available. They are invariably limited in scope, restricted to a particular locality or condition, or provide only a sub set of relevant information (eg, diagnosis but no test results). Traditionally not collected for research purposes, data are neither gathered nor coded in a consistent manner, meaning that databases cannot necessarily be combined to give an accurate bigger picture.

This reality reflects the relatively early stage of HTA programs across the region; however, it will have to change in the future, with greater investment in databases and generation of RWE evidence fast becoming a priority.

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IMPLEMENTING HTA IN ASIA PACIFIC | INSIGHTS • Stakeholder education and understanding: Stakeholder awareness will also be critical to the success of any HTA process. Experience from Europe has taught us that the role of HTA differs from country to country. Factor in the complex and diverse nature of Asian markets and this is also likely to be the case across Asia Pacific.

Stakeholder understanding of the role of HTA for each country will be a key factor, although this also represents an opportunity for Asia Pacific to learn from Europe’s experience and fast forward through the learning process.

• Transparency: Finally, any HTA process that is implemented will need to be transparent in its decision making and influence. One of the criticisms leveled at authorities by industry currently is that even in cases where manufacturers are invited or permitted to submit pharmacoeconomic data there is a lack of transparency as to how this data is actually used.

When the sweeping price cuts announced on a regular basis by health ministers are added into the mix, the industry could be forgiven for weighing up the benefits and risks of complying with the process.

THE TIME IS NOW Despite the obvious challenges, some would argue that the time for HTA has arrived in Asia Pacific. Implemented correctly, it can play a role in the future of the region, not only as a key component of cost containment but also as a pivotal enabler for the efficient use of resources, as governments look to provide broader access to affordable healthcare for all.

In this regard, Asian markets can learn from the experience of countries in Europe, whilst industry can also take the opportunity to help shape their healthcare strategy and become a key stakeholder in that process. Should they choose to ignore the lessons from addressing growth in costs and demand for healthcare in Europe, Asia Pacific may well face a decade of potentially painful development. •

For the emerging Asian markets, the need for RWE in itself brings another set of challenges.

Data are neither gathered nor coded in a consistent manner, meaning that databases cannot necessarily be combined to give an accurate bigger picture. It will have to change in the future, with greater investment in databases and generation of RWE evidence fast becoming a priority.

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INSIGHTS | PHARMACOGENOMICS The full potential of pharmacogenomics may still be to come but as its role in healthcare continues to evolve, there are new priorities to consider and address â&#x20AC;&#x201C; including a deeper understanding of the impact and implications for real-world evidence generation.

The authors Jacco Keja, PHD is Regional Principal HEOR, IMS Health Jkeja@nl.imshealth.com

Maartje Smulders, MSC, MPH is Director HEOR, IMS Health Msmulders@nl.imshealth.com

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PHARMACOGENOMICS | INSIGHTS

Pharmacogenomics comes of age Imperatives for a real-world evidence strategy On completion of the Human Genome Project in the early 2000s, pharmacogenomics (PGx) was hailed as the research area that would transform the pharmaceutical landscape; knowledge about the effects of DNA variation in man would revolutionize research and development (R&D) and approaches to diagnosing, treating and even preventing diseases.

Now, ten years on, it seems those expectations may have been too high.

In other words, PGx has not so far delivered the revolutionary outcomes that were promised.

With hindsight, this is perhaps not surprising given the complexity of general health, drug response and toxicity and the way in which they vary by not only genotype presentation and manifestation, but also environmental factors.

INCREASING VISIBILITY Notwithstanding the slower than anticipated progress to date, there is no doubt that in the coming decade, PGx will be more visible in research and clinical applications. It has the potential to accelerate drug discovery and development by identifying better drug targets, and to establish preferred segmented patient populations, thereby improving safety, efficacy and effectiveness profiles in clinical practice. Accordingly, the number of useful biomarkers for predicting drug response is expected to increase rapidly both in quantity and quality.1,2 In fact, some currently available biomarkers are already integrated into drug label inserts by the US FDA and European Medicines Agency (eg, HercepTest, TPMT test) and are required for reimbursement. Overall, PGx is now a reality of doing business. Clear progress is being made, especially in the field of cancer.

A number of factors have been influential in the development of PGxs. These have been well elaborated by Garrison, et al, including public policy issues and the challenges in linking pharmacogenomics-based diagnostics and drugs for personalized medicine.3,4,5 This article focuses on two critical success factors for PGx: coping with the (perhaps negatively-perceived) impact of associated increased market segmentation; and the consequent increased need for more detailed and complex patient-centric data.

DOES PHARMACOGENOMICS LEAD TO DECREASED MARKET POTENTIAL? The prevailing view in the pharmaceutical industry has been that many executives, marketing and sales people held back on PGx – a resistance that was possibly driven by concerns about PGx reducing market size and cases where it had negatively affected commercial success.

Consider, for example, the many drug withdrawals that may have been a direct result of pharmacogenomic differences among small patient sub-populations (eg, Seldane®, Baycol®, Redux®, Rezulin®), and the potential of poor responders to negatively impact overall safety and efficacy in product development.

continued on next page

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INSIGHTS | PHARMACOGENOMICS However, perceptions have been evolving since then, amid growing recognition that PGx has the potential to impact product market size in a number of ways – both good and bad (Figure 1). As Bernard has observed in analyzing the myths of PGx, the introduction of PGx testing may yield loss of market share (A, B, C). On the other hand, it may drive an increase in share as a result, for example, of: earlier market approvals enabled by faster identification of drug targets and responsive patients during R&D (D); recruitment of patients from less effective competing products (E); identification of patients who refused treatment due to efficacy/safety concerns (F); and potential for higher pricing or reimbursement advantage for drugs that, with the test, can identify the patients who will respond favorably (J)6.

FIGURE 1:

MARKETING A GENERIC TEST WITH A PRODUCT CAN PRODUCE BOTH SHARE LOSS AND GAIN, POTENTIALLY RESULTING IN A MARKET SHARE INCREASE

Product X’s Market Share without Pharmacogenomics

Product X’s Market Share with Pharmacogenomics

Y

Increased use in diagnosed but untreated patients

Market Share = Y

Recruitment of patients from less effective drugs

Expansion of treatment to new subgroup/diseases

F E

Earlier market introduction with faster approvals

G

D

Y

Earlier/ preventive use

H

A vent risk Adverse e

C

ers nd

Share Loss

I

resp ond ers

J

Low

po res n No

B Enhanced patient compliance

Potential for higher pricing reimbursement for best-in-class drug

Share Gain

Market Share = Y - (A+B+C+) + (D+E+F+G+H+I+J) Source: Bernard S., The 5 myths of pharmacogenomics. Pharmaceutical Executive, 2003; October 1: 70-78

Thus, by monitoring PGx development and thoroughly analyzing the potential impact of PGx early, an appropriate assessment of commercial impact can be made. It is imperative that this type of evaluation is undertaken prior to Phase II development. One key question to address is the potential for higher pricing and improved reimbursement to be enabled by a PGx approach. It is here that health economics and outcomes research plays a quintessential role.

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PHARMACOGENOMICS | INSIGHTS DO WE NEED DATA? PGx has the potential to establish preferred segmented patient populations, thereby improving safety, efficacy and effectiveness profiles in clinical practice. Here, the need for real-world evidence (RWE) is implicit.

In the EU and US, changing safety regulations, risk management procedures and reimbursement requirements already require RWE and hence access to patient-centric longitudinal data. These data enable follow-up of patients over time to understand disease progression, (drug) treatment and associated outcomes, as well as safety. With advancements in PGx, the need for more detailed and complex patient-centric data will grow even further.

Manufacturers should look to establishing RWE plans early in drug development and anticipate on co-development of RWE programs to collect, or enable a certain level of access to, the complex patient-centric data that are needed.

The challenge is that access to real-life patient-centric data in general is limited for industry, due to privacy regulations, security systems, laws and public opinion. This is even more the case for genotypic information. Additionally, acceptance of and requirements for data use vary among countries, due to differing systems infrastructure, regulations and stakeholder trust.

Furthermore, the fragmentation of data sources necessitates linkage of multiple data assets – calling for bespoke and well-governed approaches. Consider the example of oncology.

PGx IN ONCOLOGY Data content considerations in oncology are challenging; for robust observational pharmacoepidemiology and pharmacovigilance research to support payer and regulatory requirements successfully, there are multiple data issues to address: • Longitudinal and patient-centric • Sufficiently large • Covering all population ages (not just >65) • Tumor staging, grading and patient wellbeing • Biomarkers • Exposure (drug treatment, including chemotherapy, radiotherapy, surgery) • Outcomes as mortality and hospitalizations continued on next page

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INSIGHTS | PHARMACOGENOMICS Taking the aforementioned considerations into account, much of the relevant data is actually already routinely collected in practice. However, the sources are fragmented. Consequently, often de novo data collection projects are being developed which provide the full and complete information that is needed. However, these are expensive and time consuming.

An alternative is the linkage of several routine databases (+/- ad hoc data collection). In this case, linking pathology and/or (pharmaco-) genomics databases, cancer registries and administrative healthcare or claims databases would provide an ultimately comprehensive RWE platform allowing for robust pharmacoepidemiology and pharmacovigilance research in oncology (Figure 2). In Europe, pathology and laboratory databases and cancer registries provide more details on diagnosis (eg, staging, histological classification, receptor status, etc); administrative healthcare databases (EMR) and to a certain extent claims data, generally provide insights into treatment and (co-) morbidities; pathology databases provide more information on, for example, biomarkers to the extent that they are used in real-world practice.

In terms of the patient population segmentation driven by PGx, sample size is an important consideration and often limiting factor in pharmacoepidemiology and pharmacovigilance. To increase sample size, multiple national databases would need to be harmonized and integrated.

The importance of managing the heterogeneity of underlying healthcare systems, coding and treatment pathways, and technical aspects (hardware limits) must be taken into account, particularly in relation to biobanks and PGx databases given their extensive size.

FIGURE 2:

LINKING FRAGMENTED DATA SOURCES COVERING CANCER CARE

Genotypic data Cancer register

Rx (community & in-patient)

PATIENT CORE

Pathology

Microbiology

Mortality

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GP

Hospitalizations

Clinical Lab

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

PHARMACOGENOMICS | INSIGHTS INITIATIVES AND TRENDS The good news is that many different initiatives are ongoing at national and international level. Specifically in PGx, biobanks and PGx databases are being developed and becoming more open to research by third parties, in some cases providing industry with a seat at the table. A good example of such collaborative effort is the Biotech Cluster Rhine-Neckar (http://www.biorn.org/biorn-start/).

There are multiple ongoing national and international biobank harmonization and linking initiatives in the EU and US. Several multi-country consortia exist, whose overall aim is (stimulating) pooling of data, including the development of harmonized measures and standardized computing infrastructures to enable the effective pooling of the data.

Examples include BioSHaRE (http://www.bioshare.eu/), BBMRI (http://www.bbmri.eu) and PharmGKB.7 Further, in response to recent calls for the development of common principles applying to data access and use, several networks are working on an international data-sharing Code of Conduct, for example, the global Public Population Project in Genomics (P³G; http://www.p3gobservatory.org), the European Network for Genetic and Genomic Epidemiology (ENGAGE) and the Centre for Health, Law and Emerging Technologies (HeLEX) in the EU.8

PLAN FOR ACTION It is clear that these advancements in PGx impact early drug and commercial strategy development. This calls for an early and thorough analysis of potential PGx implications even before Phase II development, and the development of appropriate plans for RWE generation.

These plans need to incorporate the co-development of RWE programs to collect, or enable a certain level of access to the complex patient-centric data required. This early anticipation is already implicit for “normal” product development, but takes on even greater significance with the introduction of PGx given the even greater complexity of the data requirements and the need for co-development of diagnostics and treatment interventions.

It goes without saying that industry must take partnered control of RWE to improve its access to and understanding of valuable information, even more so in PGx. Positive advancements have seen various different initiatives established in which the industry has a role to play. To a growing extent, data sharing is regarded as an ethical and scientific imperative that advances knowledge and thereby respects the contributions of the participants. Increased public trust, which is increasingly translated through broad consents and efforts in harmonization of data privacy are also positive trends. Perhaps the downside is that biobank and pharmacogenomic data access (and if feasible, linkages) will take much time investment in building relationships and establishing well-managed governance and access models which ensure platform quality and integrity and are in-line with data standards. Now is the time to start investing in these partnerships. •

This article partially draws on a recent MSc.Thesis “Is the pharmaceutical industry ready to make its choice for PGx?” by Jorien van Luling, Erasmus University, 2012, working under Dr Keja’s supervision.

1 Sim SC, Ingelman-Sundberg M. Pharmacogenomic biomarkers: New tools in current and future drug therapy. Trends Pharmacol Sci. 2011, Feb; 32(2): 72-81.

2 Sim SC, Altman R B, Ingelman-Sundberg M. Databases in the area of pharmacogenetics. Human Mutation. 2011, May; 32(5): 526-31. Epub 5 April 2011.

3 Garrison LP Jr, Finley Austin MJ. Linking pharmacogenetics-based diagnostics and drugs for personalized medicine. Health Affairs, 2006; 25(5): 1281-90.

4 Garrison LP Jr, et al. A review of public policy issues in promoting the development and commercialization of pharmacogenomic applications: Challenges and implications. Drug Metabolism Reviews, 2008; 40(2): 377-401.

5 Garrison LP. Will pharmacogenomics disrupt the U.S. Health Care System? No. Public Health Genomics, 2009; 12(3): 185-90.

6 Bernard S. The 5 Myths of Pharmacogenomics, Pharmaceutical Executive, 2003; Oct 1: 70-78.

7 McDonagh EM, Whirl-Carrillo M, Garten Y, Altman RB, Klein TE. From pharmacogenomic knowledge acquisition to clinical applications: The PharmGKB as a clinical pharmacogenomic biomarker resource.” Biomarkers in Medicine, 2011, Dec; 5(6): 795-806.

8 Knoppers BM, et al. Towards a data sharing Code of Conduct for international genomic research. Genome Medicine, 2011; 3: 46.

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PROJECT FOCUS | IMS CORE BUDGET IMPACT MODEL Sophisticated, user-centric modeling solutions are bringing new possibilities for uniformly analyzing the budget impact of technologies across multiple stakeholder settings The authors Julie Munakata, MS is Principal HEOR, IMS Health Jmunakata@us.imshealth.com Cheryl Prasad Ferrufino, MS is Senior Consultant HEOR, IMS Health Cferrufino@us.imshealth.com

Developing payer-relevant pharmacy budget impact analyses in OAB Budget impact analyses (BIA) are increasingly required by national regulatory agencies and managed care organizations to estimate the financial consequences of adopting and diffusing a new healthcare intervention within a particular setting of care. They may be planneutral (eg, nationally representative data in the US for an Academy of Managed Care Pharmacy dossier) or customized, based on a particular plan’s characteristics (eg, state-level commercial data for field-based discussions). By enabling critical insights into the impact of a drug or technology on a healthcare budget over time, they are a source of key information for healthcare decision makers.

Recent advancements in health economic modeling are now broadening the scope of these analyses to provide a consolidated solution for multiple stakeholders.

REQUIREMENT FOR STAND ALONE TOOL A leading pharmaceutical manufacturer based in the US, was interested in developing a stand-alone tool that would enable it to determine and communicate the pharmacy budget impact of adding and/or increasing the uptake of a previously launched treatment for overactive bladder (OAB) within a health plan’s formulary. OAB, a chronic and embarrassing condition characterized by urinary urgency with or without urge incontinence, is a considerable health concern with an estimated prevalence of 16%-17% among adults in the US.1 It is often under diagnosed and under treated – despite the availability of pharmacotherapy – and can significantly impact quality of life, making strategies to improve its management and outcomes important.

The proposed tool was primarily intended for use by the company’s field-based account managers and internal health outcomes specialists. It was further being considered as a possible leavebehind for clients. In order to be fit for purpose, it would need to fulfill several key criteria: • A streamlined, “uncluttered” user interface • Transparent and logical presentation of data inputs and calculations • Populated with data sourced from syndicated databases to promote company-wide consistency and familiarity in modeling approach, and create efficiencies for model updates and training • Functionality to allow custom input overrides and scenario analyses • Clear within-model documentation of methods, assumptions and references

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

IMS CORE BUDGET IMPACT MODEL | PROJECT FOCUS FIGURE 1: IMS CORE BUDGET IMPACT MODEL: LANDING AND RESULTS SCREENS

User Requirements • Therapy area • Products of interest

1

DATA EXTRACTION

• IMS benchmark • Medi-Span • First DataBank

2

• Geographic coverage • Method of payment • Etc…

CONFIGURATION

• IMS CORE Budget Impact Model • Custom features

3

DELIVERY • Targeted analyzer • Stakeholder bridge

ADVANCED MODELING SOLUTION

STAKEHOLDER-RELEVANT ANALYSES

In approaching IMS HEOR for help, the company found an expert team with proven capabilities in evidence-based and user-centric, advanced design modeling solutions. These were backed by in-depth market knowledge, insights from worldclass data assets and relevant stakeholder networks, and access to the IMS CORE Budget Impact Model.

IMS benchmark data permit a view of retail pharmacy utilization and cost trends at national, state, or local (Metropolitan Statistical Area) level based on the IMS National Prescription Audit™, the industry-standard source of national prescription activity in the US. In addition, drug and cost inputs for the model may be sourced from First DataBank and/or Medi-Span. Key metrics may be shown by method of payment (commercial, Medicare, Medicaid) in addition to geography, and include total prescriptions, average price per prescription and quantity, and patient copay averages. Such granularity offers the user an opportunity to configure targeted analyses for clients with similar underlying policy or demographic characteristics.

Developed in MS Excel and in accordance with local and national guidelines for BIAs, the IMS CORE Budget Impact Model is an interactive, flexible, multi-use and standardized framework enabling pharmacy budget impact analyses (Figure 1).

The model is designed to be an efficient turnkey modeling solution – packaged and delivered pre-populated with userspecified default values, such as therapy area and products of interest, geographic coverage, method of payment, etc.

All model screens are presented in a logical fashion and include informational, user-input (population, market share, drug prices and contracting), results and sensitivity analyses screens. Users are able to select default data sources and assumptions and override all inputs to perform exploratory scenario analyses.

BRIDGING A CRITICAL GAP Co-developed by IMS HEOR and the Payer Solutions unit of IMS Health, the IMS CORE Budget Impact Model has been specifically designed to be used by manufacturers and payers alike and is the first of its kind to bridge the critical gap between payers and manufacturers. Through their work with IMS, the client gained a simple, easy-to-use tool that could be custom-configured by geographic region and payment methods, enabling up-to-date, relevant and impactful analytics and insight to inform OAB therapy options within their targeted health plans. •

1 Stewart WF,

Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL. Prevalence and burden of overactive bladder in the United States.

World J Urol, 2003;20(6):327-336.

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PROJECT FOCUS | GLAUCOMA Country adaptations of economic models leveraging rigorous, best-practice methodologies are key to generating value arguments in diverse local settings The authors Laetitia Gerlier, MSC is Senior Consultant HEOR, IMS Health Lgerlier@be.imshealth.com Joe Caputo, BSC is Regional Principal HEOR, Asia Pacific, IMS Health Jcaputo@sg.imshealth.com

Modeling cost-effectiveness in glaucoma across multiple Asia-Pacific markets The increasingly global scale of product launches is driving new challenges for pharmaceutical manufacturers in generating a coherent value proposition across multiple diverse markets. More countries are formalizing an HTA process and strengthening their focus on treatment cost-effectiveness but, importantly, their requirements differ. Approaches that enable core evidence for a product to be modeled and adapted to individual healthcare settings play a key role in ensuring value messages that are locally relevant but consistent with global positioning. For one leading manufacturer of eye care products, the ability to demonstrate improved long-term outcomes leveraging rigorous, best-practice model adaptations proved critical to supporting preferential product use across ten Asia-Pacific markets.

IDENTIFYING LONG-TERM VALUE The company had recently launched a new treatment for primary open angle glaucoma (POAG) - a chronic eye disease characterized by damage to the optic nerve associated with increased intra-ocular pressure. The condition progresses through three stages of severity: ocular hypertension (OHT); early, moderate and advanced glaucoma; and blindness. Glaucoma is the second leading cause of blindness after cataract1 and is estimated to affect more than 60 million people worldwide.2 Although the loss of visual fields is irreversible, the progression of glaucoma can be slowed with medication, usually in the form of eye drops. These are typically preserved to allow multiple dosing from a single bottle. However, exposure to the commonly-used preservative benzalkonium chloride (BAK) has been linked to a higher incidence of ocular surface disease (OSD) as well as issues with post-surgical outcome in glaucoma. Marking an important step forward in treatment, the company had developed an alternative BAK-free formulation. This was expected to lower the risk of OSD, translating into fewer treatment changes, improved quality of life (QoL), better compliance and potentially reduced progression of disease.

The company was keen to complement existing data on the productâ&#x20AC;&#x2122;s clinical benefits with evidence of its health economic implications, particularly in terms of long-term cost and patient outcomes. This information would be pivotal for HTA submissions, reimbursement, and pricing negotiations during the planned launch roll-out in Europe and Asia Pacific, but would require advanced capabilities in modeling outcomes across countries with very different healthcare systems and HTA requirements. In IMS HEOR they found a coordinated, global team of in-market experts with extensive experience in developing core models and seamlessly adapting them to multiple geographic settings, supported by access to a strong network of local contacts and relevant patient-level data.

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GLAUCOMA | PROJECT FOCUS The key goal was to estimate the modeled effectiveness and cost-effectiveness of treating OHT/POAG patients with the new product compared to the original brand as well as a leading BAK-preserved competitor. A core model was developed in Europe and adapted to a cross-section of countries in Asia Pacific.

Leveraging the findings of a patient chart review which had been previously undertaken by IMS HEOR in Europe, and following a systematic literature search, IMS designed a transition-state Markov model so as to capture the effects of OSD on both the risk of treatment change and disease progression.

Country-specific data included mortality, discount rates, type and frequency of medical resources used and corresponding unit costs. Resource use and glaucoma costs from a cost-ofillness study were applied to populate the core model. Unit cost data for the country settings was collected by local IMS experts in each of the markets, with microcosting allowing for adaptation of the core model. Interviews with key opinion leaders (KOLs) were conducted in each of the focus AsiaPacific countries to account for local practice in terms of type and frequency of medical resource use.

Outcomes were measured over a 10-year horizon, enabling disease progression to be followed from OHT through to more advanced stages of glaucoma. These included: • Percentage of patients with OSD: reaching second- or third-line treatment; remaining in first-line treatment at model end; requiring eye surgery/laser • Drug cost • Total cost of glaucoma management • Final visual field defect • Quality-adjusted life years (QALYs) gained Extensive sensitivity analyses were conducted on all key parameters of the model.

SIGNIFICANT COST SAVINGS REVEALED The IMS analysis showed that despite its higher unit cost, use of the new formulation was consistently associated with lower total costs, better clinical outcomes and a modest but positive impact on QoL. Both the cost savings and clinical/ QoL improvements were directly attributable to a significantly reduced incidence of OSD (Figure 1) and higher rate of compliance and persistence observed with the product versus the comparators.

FIGURE 1: OSD DEVELOPMENT OVER TIME

70% 60%

% patients with OSD

FROM GLOBAL TO LOCAL

50.7%

50% 40%

34.4%

30% 20% BAK-free product BAK-preserved product Natural OSD

10% 0% 0

1

2

3

4

5

6

7

8

9

10

Year

Development of OSD in patients receiving the BAK-free formulation was slower than for the BAK-preserved product and similar to OSD progression expected in a normal aging population without glaucoma.

Probabilistic sensitivity analysis confirmed the significance of the clinical results when using distributions around the key model parameters. The findings paved the way for further comparative studies to more closely examine the effect of the BAK-free formulation on treatment persistence and on rate of disease progression.

IMPORTANT VALUE MESSAGES FOR KEY STAKEHOLDERS Through its work with IMS, the company gained a deep understanding of the real-world value of its new formulation in terms of long-term benefits and economic consequences within the context of disparate healthcare systems in Asia Pacific. In addition to informing market access decision making and serving as a vital tool for affiliate dialogue with local payers, the clinical and cost outcomes of the model were presented at a number of specialist international conferences. At a time of continued growth in the prevalence of glaucoma they have also enabled important value messages to physicians and KOLs, serving to increase prescriber awareness of the long-term impact of BAK on the rate of OSD in glaucoma. They continue to inform price negotiations in this rapidly expanding region and justify the presence of the product on formulary listings. •

1 Resnikoff 2 Quigley

S, Pascolini D, Etya’ale D, et al. Global data on visual impairment in the year 2002. Bulletin of the World Health Organization, 2004; 82:844-51 HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmology, 2006; 90: 262-267

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PROJECT FOCUS | METASTATIC COLORECTAL CANCER Retrospective cohort analyses of physiciansurvey data can enable value messages based on real-world evidence of current patterns of practice

The author Elise Pelletier, MS is Director HEOR, IMS Health Epelletier@us.imshealth.com

Informing optimal treatment strategies in advanced colorectal cancer in Europe Pharmaceutical manufacturers face a growing need to generate, analyze and apply real-world evidence (RWE) to support value demonstrations for their products and ensure optimal use in treatment protocols. This is particularly valid in crowded therapy areas like oncology, where scientific breakthroughs are expanding treatment options and the range of indications they can address, but where new agents must compete for inclusion in complex regimens, often involving multiple modalities, including surgery.

The ability to determine and demonstrate added value within the context of current and emerging practice patterns is key to ensuring optimal outcomes â&#x20AC;&#x201C; and successful product differentiation.

Anonymized patient-level databases, which track the treatment experience of large patient cohorts over time, afford unique glimpses into the real-world use of medicines and, importantly, the implications of attributes associated with different interventions.

When one leading biopharmaceutical manufacturer needed help in generating RWE in Europe for its new monoclonal antibody (mAB) for metastatic colorectal cancer (mCRC), the retrospective analysis of physician-survey patient-level data in IMS LifeLink Oncology Analyzer proved pivotal to identifying value differentiators based on the relative safety profile of its competitors.

UNDERSTANDING THE IMPACT OF ATTRIBUTES In Europe, CRC is the most common newly diagnosed cancer and the second leading cause of death from cancer.1 Between 15-25% of newly identified CRC patients present with metastatic disease, and up to 50% of all CRC patients will eventually develop metastases.2 Consequently, high numbers of patients seek treatment for mCRC, where prolonged survival/prevention of tumor progression, reduction of associated symptoms, and/or maintenance of quality of life are the key goals.3 After many years of limited therapeutic options for mCRC, recent advances in systemic approaches, including new combination chemotherapies and targeted treatment with mABs combined with chemotherapy, have significantly improved the ability to achieve these outcomes.

The company, a key player in oncology, wanted to explore the value of its mAB, which was indicated for second-line treatment of mCRC, but lacked sufficient post-launch experience to study the drugâ&#x20AC;&#x2122;s performance in the real world. However, by understanding the use of other targeted agents and the distribution of chemotherapy backbones, it could better determine the potential patient segment for a first-line indication. One significant adverse effect of a

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METASTATIC COLORECTAL CANCER | PROJECT FOCUS FIGURE 1: SURGERY BY PURPOSE: PATIENTS WITH AT LEAST ONE SURGERY FOR ANY PURPOSE AND FOR DIAGNOSTIC, CURATIVE AND PALLIATIVE PURPOSE, BY COUNTRY 45% 40%

38.4%

36.3%

35.6%

35.2%

35%

30.5%

30% 25% 20.5%

20% 15%

12.8%

14.1%

13.4%

11.5% 9.2%

10%

20.5%

19.4%

15.7% 8.4%

5%

10.8%

10.3% 7.3%

5.7%

7.2%

0% Germany France Total patients with at least 1 surgery for any purpose (curative, palliative, diagnostic)

Italy Spain UK Total patients with at least 1 surgery for curative purposes Total patients with at least 1 surgery for palliative purposes Total patients with at least 1 surgery for diagnostic purposes

Source: Zhao A, Pelletier E, Barber B, Bhosle M, Wang S, Klingman D, Gao S Major surgery in patients with metastatic colorectal cancer in Western Europe.

J Gastrointest Cancer, Epub 2011, Nov 29.

competing mAB was serious wound-healing complications, causing treatment discontinuation for a period of 5-8 weeks prior to surgery and 28 days after. Keen to understand the limitations this imposed and thereby better communicate the benefits of a product without this safety issue, the company approached IMS for help. Through the course of working with the HEOR team on several economic evaluations leveraging IMS LifeLink Oncology Analyzer, it had come to rely on the quality and rigor of the analyses and the power of the underlying data.

EXPLORING THE EVIDENCE Given the potential connection between surgical events and treatment for mCRC, and to better understand the implications of interruptions in therapy, the IMS team set out to establish the prevalence of major surgery following a diagnosis of mCRC. The retrospective cohort study used physician-survey data from the IMS LifeLink Oncology Analyzer database for mCRC patients in France, Germany, Italy, Spain and the UK. This includes information on patients with all types and stages of cancer treated by a panel of nearly 2,300 physicians at hospitals, private clinics and other cancer care centers across Europe, the US and Japan. Physicians provide case histories on a quarterly basis for the last 5-25 patients they have seen, without including the same patient’s details twice in any 12month period. The database records include full treatment history from diagnosis to current treatment, including all major surgical procedures (MSP), with patients segmented by

diagnosis, stage and line of therapy. Both physician recruitment and data collection meet exacting quality standards.

All patients aged 21 years and over at the time of mCRC diagnosis were included, and MSPs were examined descriptively by the purpose and location of surgery.

UNDERSTANDING THE IMPLICATIONS The study identified at least one MSP for any purpose in 30.5% (UK),35.2% (Germany), 35.6% (Spain), 36.3% (France), and 38.4% (Italy) of patients, indicating that major surgery is highly prevalent in the mCRC population, and thus has a significant role to play in meeting the goals of mCRC treatment (Figure 1).

KEY VALUE DIFFERENTIATOR The results of the analysis4 enabled the company to demonstrate, based on RWE, the importance of considering the role of pharmacological treatment options and their potential to interfere with both the use of surgery and surgical outcomes when evaluating treatment strategies for mCRC. With an additional study conducted by IMS indicating that nearly half of patients with mCRC in western Europe (with the exception of the UK) receive mAB therapy as part of their pharmacological treatment,5 the company was able to further quantify the implications of the results. The findings have been disseminated to the broader medical community in several peer-reviewed publications and at leading conferences. •

1 Ferlay

J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer, 2010:46(4):765-781.

HL, Shulman KL. Metastatic colorectal cancer. Curr Treat Options Oncol, 2001;2:459-71.

3 Van Cutsem E, Nordinger B, Cervantes A. Advanced colorectal cancer: ESMO clinical practice guidelines for treatment. Ann Oncol, 2010; 21 (Suppl 5):v93-7.

4 Zhao Z, Pelletier E, Barber B, Bhosle M, Wang S, Klingman D, Gao S. Major surgery in patients with metastatic colorectal cancer in Western Europe. J Gastrointest Cancer, Epub 2011, Nov 29.

5 Zhao Z, Pelletier E, Barber B, et al. Current chemotherapy and monoclonal antibody use patterns in metastatic colorectal cancer in Western Europe.

35th EMSO Congress, Milan Italy, 8-12 October 2010.

2 Kindler

ACCESSPOINT • VOLUME 2 ISSUE 4

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IMS HEOR | OVERVIEW

Enabling your real-world success IMS offers a spectrum of world-class expertise in Health Economics & Outcomes Research (HEOR) and real-world evidence (RWE) to deliver the local excellence you need.

In a future where healthcare efficiency and quality are measured through the lens of ‘real-world’ insights, external validity demands a focus on the right data sources, best-in-class research and actionable communication.

IMS is committed to helping you succeed: • Largest multi-disciplinary team of HEOR experts, based in 18 countries worldwide • Credible scientific voice and deep therapy area knowledge, captured in 200+ publications each year • Market leadership in developing and adapting robust economic models • Most advanced capabilities in RWE management and analysis • Proven expertise in generating and communicating RWE to advance stakeholder engagement at all levels

IMS is a leading independent provider of outcomes research, economic modeling, RWE and market access solutions leveraging relevant IMS proprietary and other key, third-party data assets.

Our unique, data-agnostic market position can help you develop and support the evidence required to engage global and local healthcare stakeholders, with deep insights into product safety, efficacy, cost, value for money and affordability.

PAGE 56

Outcomes Research • Evidence generation • Late-phase studies • Patient-Reported Outcomes (PROs) • Database studies • Epidemiology • Risk management

Real-World Evidence Solutions • Data sourcing & validation • Data integration & linking • Data management & curation • Platform development • Customized analytics & reporting • Evidence planning

Health Economic Modeling • Health economic evaluations • Core models & local adaptations • Budget impact • Meta-analyses • Indirect comparisons • IMS CORE Diabetes Model

Technology • Platform engines • Data warehouse/data marts • Encryption systems & linking technology • Meta-data repository • User interface & sophisticated analytics library • Electronic data capture

Market Access • Value development planning • Market access strategy • Core value dossiers & local adaptations • HTA readiness • Value communication • Reimbursement submissions

IMS LifeLink Largest collection of scientifically validated, anonymized patient-level data assets: • Health plan claims • Longitudinal Rx • Electronic medical records • Hospital disease • Oncology • Diabetes

TM

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

LOCATIONS | IMS

Global scope, local expertise IMS HEOR and RWE experts are located in 18 countries worldwide and they have published on projects completed in more than 50 countries on all continents.

YOUR PRIMARY CONTACTS: Dr. Xavier Badier Senior Principal HEOR IMS Health Doctor Ferran 25-27 08034 Barcelona Spain Tel: +34 93 749 63 00 Xbadia@es.imshealth.com

Dr. Jacco Keja Senior Principal HEOR IMS Health 210 Pentonville Road London N1 9JY United Kingdom Tel: +31 (0) 631 693 939 Jkeja@nl.imshealth.com

Adam Lloyd Senior Principal HEOR IMS Health 210 Pentonville Road London N1 9JY United Kingdom Tel: +44 (0)20 3075 4800 Alloyd@uk.imshealth.com

Dr. Michael Nelson Senior Principal HEOR IMS Health 1725 Duke Street, Suite 510 Alexandria, VA 22314 USA Tel: +1 703 837 5150 Mnelson@us.imshealth.com

IMS HEOR and RWE solutions office locations NORTH AMERICA REGIONAL HEADQUARTERS 200 Campus Drive Collegeville, PA 19426 USA Tel: +1 610 244 2000

EUROPE REGIONAL HEADQUARTERS 210 Pentonville Road London N1 9JY United Kingdom Tel: +44 (0)20 3075 4800

UNITED STATES 1725 Duke Street Suite 510 Alexandria, VA 22314 USA Tel: +1 703 837 5150

BELGIUM Medialaan 38 1800 Vilvoorde Belgium Tel: +32 2 627 3211

The Arsenal on the Charles 311 Arsenal Street Watertown, MA 02472 USA Tel: +1 800 783 6362 CANADA 303 Terry Fox Drive Suite 300 Ottawa K2K 3J1, Ontario Canada Tel: +1 613 599 0711 LATIN AMERICA REGIONAL HEADQUARTERS Insurgentes Sur # 2375 5th Floor, Col. Tizapan Mexico City D.F. - C.P. 01090 Mexico Tel: + 52 (55) 50 62 52 00 ext 5269

FRANCE 91 rue Jean Jaurès 92807 Puteaux cedex France Tel: +33 1 41 35 1000 GERMANY Erika-Mann-Str. 5 80636 München Germany Tel: +49 89 457912 6400 ITALY Viale Certosa 2 20155 Milano Italy Tel: +39 02 69 78 6721

SPAIN Dr Ferran, 25-27 08034 Barcelona Spain Tel: +34 93 749 63 00 SWEDEN Sveavägen 155/Plan9 11346 Stockholm Sweden Tel: +46 8 508 842 00 SWITZERLAND Theaterstr. 4 4051 Basle Switzerland Tel: +41 61 204 5071 UNITED KINGDOM 210 Pentonville Road London N1 9JY United Kingdom Tel: +44 (0)20 3075 4800 ASIA PACIFIC REGIONAL HEADQUARTERS 10 Hoe Chiang Road Keppel Towers #23-01/02 Singapore 089315 Tel: +65 6227 3006

AUSTRALIA Level 5, Charter Grove 29 - 57 Christie Street St Leonards, NSW 2065 Australia Telephone: +61 2 9805 6800 CHINA 7/F Central Tower China Overseas Plaza Jianguomenwai Avenue, Chaoyang District Beijing 100001 China Tel: +86 10 8567 4255 SOUTH KOREA 9F Handok Building 735 Yeoksam1-dong Kangnam-ku Seoul 135-755 S. Korea Tel: +82 2 3459 7307 TAIWAN 8th Floor No 2, Tun Hwa South Road Section 1 Taipei 10506 Taiwan ROC Tel: +886 2 2721 5337

FOR FURTHER INFORMATION: email HEORinfo@imshealth.com or RWEinfo@imshealth.com or visit www.imshealth.com/heor

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IMS | EXPERTISE

Expertise in depth IMS has one of the largest global teams of experts in HEOR, RWE and market access of any organization in the world.

We apply unrivalled experience and specialist expertise to help our clients meet the demands of an increasingly complex global, regional and local pharmaceutical landscape.

Our highly-qualified, multi-disciplinary consultants and researchers have proven skills and capabilities across all key therapy areas. Spanning industry, consulting, government and academia, their expertise reflects a global grasp, local experience and a unique, inside market perspective.

The strength of our ability to support clients in healthcare decision making for health economics, outcomes research, RWE and market access, is built on the quality of our global team.

Our senior team Renée J. G. Arnold, PHARM D • Dr. Renée Arnold is Principal HEOR at IMS Health with particular expertise in the use of technology to collect and/or model real-world data to facilitate rational decision making by healthcare practitioners and policy makers.

• Renée was previously President and CEO, Arnold Consultancy & Technology where she developed and oversaw outcomes research for the pharmaceutical, biotech and device industries as well as federal government programs. Her distinguished career in health economics and outcomes research includes roles as President and co-founder of Pharmacon International, Center for Health Outcomes Excellence and Senior VP and Medical Director at William J Bologna International.

• Founding member and former Chair of the Education Committee of ISPOR, Renée has several adjunct appointments and is the author of numerous articles on pharmacoeconomics and cost-containment strategies. She holds a Doctor of Pharmacy degree from the University of Southern California in Los Angeles.

Xavier Badia, MD, MPH, PHD • Dr. Xavier Badia is Senior Principal HEOR at IMS Health with extensive experience in all areas of outcomes research.

• A founder of Health Outcomes Research Europe, Xavier has extensive experience in consulting and research outcomes, patient-reported outcomes, and effectiveness and cost-effectiveness evaluations. A respected scientific speaker and member of EuroQol since 1993, he serves on several international advisory and editorial boards and has published over 150 peer-reviewed papers.

• Xavier holds an MD, a PhD in Medicine, and a Master’s in Public Health and Health Economics from the University of Barcelona.

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IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS

EXPERTISE | IMS Karin Berger, MBA • Karin Berger is Principal HEOR at IMS Health with a particular focus on outcomes research, patientreported outcomes, and cost-effectiveness evaluation analyses at a national and international level.

• Formerly Managing Director of MERG (Medical Economics Research Group), an independent German organization providing health economics services to the pharmaceutical industry, university hospitals and European Commission, Karin has more than 14 years experience in the health economics arena. She lectures at several universities, has published extensively in peer-reviewed journals, and regularly presents at economic and medical conferences around the world.

• Karin graduated as Diplom-Kaufmann (German MBA equivalent) from the Bayreuth University, Germany, with a special focus on health economics.

Christopher M. Blanchette, PHD, MS, MA • Dr. Chris Blanchette is Principal HEOR at IMS Health, with extensive experience in retrospective database research and observational studies with particular emphasis on respiratory diseases.

• Chris was previously Director of Clinical & Outcomes Research at the Lovelace Respiratory Research Institute, where he led a team of 50 people conducting clinical research, biostatistics, and outcomes research programs. He also spent time in market access and R&D health economics at GlaxoSmithKline, most recently as Director for Health Data Analytics, and was formerly a researcher at the Premier Hospital Alliance and Agency for Healthcare Research and Quality.

• In addition to serving in leadership positions for ISPOR and several respiratory disease associations, Christopher is on the editorial board of the Journal of Medical Economics and advisory board of Current Medical Research and Opinion. He holds a PhD in Pharmaceutical Health Services Research and an MS in Epidemiology from the University of Maryland, and an MA in Medical Sociology from the University of North Carolina.

Nevzeta Bosnic, BA • Nevzeta Bosnic is Principal at IMS Brogan, where she manages projects to meet the broad spectrum of client needs in the Canadian pharmaceutical market.

• Formerly Director of Economic Consulting at Brogan Inc, Nev has led many strategic consulting, policy and data analyses for pharmaceutical clients, government bodies and academic institutions in Canada. She has extensive knowledge of public and private drug plans across the country and in-depth expertise and experience on the drug reimbursement process.

• Nev holds a Bachelor’s degree in Business Economics from the School of Economics and Business at the University of Sarajevo, Bosnia-Herzegovina.

Joe Caputo, BSC • Joe Caputo is Regional Principal HEOR, Asia Pacific, at IMS Health leveraging more than 20 years experience in the pharmaceutical sector to help clients address the challenges of global reimbursement and market access throughout the drug development program. He has led numerous projects involving payer research, value dossiers, local market access models and HTA submissions.

• With a background that spans industry roles in drug development, sales & marketing and UK & global health outcomes, and consulting in health economics, Joe has wide-ranging knowledge of the drug development process at both local and international level and a unique understanding of evidence gaps in light of reimbursement and market access requirements.

• Joe holds a BSc in Applied Statistics and Operational Research from Sheffield Hallam University, UK. Frank-Ulrich Fricke, PHD, MSC • Dr. Frank-Ulrich Fricke is Principal HEOR at IMS Health and Professor for Health Economics, GeorgSimon-Ohm University of Applied Sciences, Nuremberg in Germany, with a focus on health economic evaluations, market access strategies and health policy.

• Formerly a Managing Director of Fricke & Pirk GmbH, and previously Head of Health Economics at Novartis Pharmaceuticals, Frank-Ulrich has conducted health economic evaluations across a wide range of therapeutic areas, developing a wealth of experience in pricing, health affairs and health policy. As a co-founder of the NIG 21 association, he has forged strong relationships with health economists, physicians and related researchers working in the German healthcare system.

• Frank-Ulrich holds a PhD in Economics from the Bayreuth University, and an MBA equivalent from the Christian-Albrechts-University, Kiel.

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IMS | EXPERTISE David Grant, MBA • David Grant is Senior Principal HEOR at IMS Health, specializing in reimbursement and market access, environmental analysis, prospective and retrospective data collection and communications for product support.

• A co-founder and former Director of Fourth Hurdle, David’s experience spans 10 years in health economics and outcomes research consulting, and 15 years in the pharmaceutical industry, including roles in clinical research, new product marketing and health economics in the U.K. and Japan.

• David holds a degree in Microbiology and an MBA from the London Business School.

Jacco Keja, PHD • Dr. Jacco Keja is Senior Principal HEOR at IMS Health, drawing on deep expertise in global market access, operational and strategic pricing, and health economics and outcomes research.

• Jacco’s background includes four years as global head of pricing, reimbursement, health outcomes and market access consulting services at a large clinical research organization and more than 13 years experience in the pharmaceutical industry, including senior-level international and global roles in strategic marketing, pricing and reimbursement and health economics.

• Jacco holds a PhD in Biology (Neurophysiology) from Vrije Universiteit in Amsterdam, a Masters in Medical Biology, and an undergraduate degree in Biology, both from Utrecht. He is also visiting Professor at the Institute of Health Policy & Management at Erasmus University, Rotterdam.

Mark Lamotte, MD • Dr. Mark Lamotte is Principal HEOR at IMS Health with responsibility for the content and quality of all health economic evaluations conducted by his team.

• A physician by training (cardiology), Mark spent a number of years in medical practice before joining Rhône-Poulenc Rorer as Cardiovascular Medical Advisor and later becoming Scientific Director at the Belgian research organization, HEDM. He has since worked on more than 150 projects, involving expert interviews, patient record reviews, extensive modeling and report writing across a wide range of therapy areas, and authored many peer-reviewed publications.

• Mark holds an MD from the Free University of Brussels (Vrije Univeristeit Brussel, Belgium) and is fluent in Dutch, French, English and Spanish.

Won Chan Lee, PHD • Dr. Won Chan Lee is Principal HEOR at IMS Health, specializing in prospective and retrospective health economics research.

• Over the course of his career, Won has completed numerous international economic evaluations employing a variety of analytical methods across a range of diseases and geographies. His expertise includes econometric database analysis, quality of life assessment and advanced economic modeling to establish the economic and humanistic value of new and existing therapeutic interventions.

• Won holds a Master’s in Economics from the University of Grenoble II, and a PhD in Economics from the Graduate Center of the City University of New York.

Claude Le Pen, PHD • Dr. Claude Le Pen is a member of the strategic committee of IMS Health and Professor of Health Economics at Paris-Dauphine University, providing expert economic advisory services to the consulting practice.

• A renowned economist, leading academic, and respected public commentator, Claude has served as an appointed senior member of several state commissions in the French Ministry of Health and is an expert for a number of parliamentary bodies, bringing a unique perspective and unparalleled insights into the economic evaluation of pharmaceutical technologies at the highest level.

• Claude studied Business Administration in HEC Business School in Paris and holds a PhD in Economics from Panthéon-Sorbonne University.

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IMS HEALTH & EVIDENCE OUTCOMESSOLUTIONS RESEARCH IMS HEOR AND ECONOMICS REAL-WORLD

EXPERTISE | IMS Adam Lloyd, MPHIL, BA • Adam Lloyd is Senior Principal HEOR at IMS Health, with a particular focus on economic modeling and the global application of economic tools to support the needs of local markets.

• A former founder and Director of Fourth Hurdle, and previously Senior Manager of Global Health Outcomes at GlaxoWellcome, Adam has extensive experience leading economic evaluations of prelaunched and marketed products, developing submissions to NICE and the SMC, decision-analytic and Markov modeling, and in the use of health economics in reimbursement and marketing in continental Europe.

• Adam holds an MPhil in Economics, and a BA (Hons) in Philosophy, Politics and Economics from the University of Oxford.

Charles Makin, MS, MBA, MM, BS • Charles Makin is Principal HEOR at IMS Health, focusing on naturalistic trials, adherence interventions, chart abstractions, patient-reported outcomes and other studies involving primary data collection.

• During a career that includes senior roles at the UnitedHealth Group and Wellpoint, Charles has led numerous studies involving database analyses, economic modeling, multi-country patient registries, systematic literature reviews and survey-based research.

• Charles holds a BS in Pharmacy from the University of Pune, India, an MS in Pharmacy Administration from Purdue University, Indiana, U.S. and an MBA in Marketing Management and a Master’s in Management, both from Goldey Beacom College, Delaware, U.S.

Frédérique Maurel, MS, MPH • Frédérique Maurel is Principal HEOR at IMS Health, with a particular focus on observational research and health economics studies.

• A skilled consultant and project manager, Frédérique has extensive experience in the economic evaluation of medical technologies gained in roles at ANDEM, Medicoeconomie, and AREMIS Consultants.

• Frédérique holds a Masters degree in Economics – equivalent to an MS – and completed a postgraduate degree equivalent to an MPH with a specialization in Health Economics at the University of Paris-Dauphine (Paris IX) as well as a degree in Industrial Strategies at the Pantheon-Sorbonne University (Paris I).

Joan McCormick, MBA • Joan McCormick is Principal at IMS Brogan, leading a team providing strategic advice to companies with new products coming to market and ongoing consultation on the rules for existing drugs post launch.

• Formerly Head of Price Regulation Consulting at Brogan Inc, Joan has supported many major pharmaceutical companies with the preparation of pricing submissions to the Patented Medicine Prices Review Board (PMPRB), gaining extensive insights into the operation of the Canadian pharmaceutical market.

• Joan holds a Bachelor’s degree in Life Sciences from Queen’s University in Kingston, Canada, and an MBA from the University of Ottawa, Canada.

Dana Morlet-Vigier, MD • Dr. Dana Morlet-Vigier is Principal HEOR at IMS Health, applying in-depth expertise and extensive experience in pharmaceutical pricing, reimbursement and market access to help clients meet the growing challenges of today’s increasingly complex product launch process.

• A medical doctor and INSEAD executive, Dana’s background spans 15 years in pharmaceuticals and includes roles in R&D, commercial, market access, strategy and government affairs at GlaxoSmithKline, Organon and 3M Pharma. She has worked on numerous pricing and reimbursement negotiations and designed and implemented national and international Phase II, III and IV studies across a wide range of therapy areas.

• Dana holds an MD from Bucharest Medical University, Romania and the Paris-Cochin Faculty, Paris, France.

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IMS | EXPERTISE Julie Munakata, MS • Julie Munakata is Principal HEOR at IMS Health, with a particular focus on global economic modeling, value development planning, and survey data analysis.

• An accomplished researcher and author of more than 25 original articles, Julie has extensive experience in managing clinical trials, health economic studies and decision analytic modeling work, gained in senior roles at ValueMedics Research LLC, the VA Health Economics Resource Center and Stanford Center for Primary Care & Outcomes Research, and Wyeth Pharmaceuticals.

• Julie holds an MS in Health Policy and Management from the Harvard School of Public Health and a BS in Psychobiology from the University of California, Los Angeles.

Michael Nelson, PHARM D • Dr. Michael Nelson is Senior Principal HEOR at IMS Health, with particular expertise in retrospective database research, prospective observational research, health program evaluation, and costeffectiveness analysis.

• During a career that includes leadership roles in HEOR at PharmaNet, i3 Innovus, SmithKline Beecham, and DPS/UnitedHealth Group, Mike has gained extensive experience in health information-based product development, formulary design, drug use evaluation, and disease management program design and implementation.

• A thought leader in health economics for more than 20 years, Mike holds a doctorate in Pharmacy and a Bachelor of Science degree, both from the University of Minnesota College of Pharmacy. He also served as an adjunct clinical faculty member at the University of Minnesota whilst in clinical pharmacy practice.

Olaf Pirk, MD, PHD • Dr. Olaf Pirk is Senior Scientific Consultant to IMS Health and previously Principal HEOR at IMS Health, with a particular focus on health technology assessment, healthcare system research, health policy and health economic modeling across a range of countries and therapeutic areas.

• Formerly a Managing Director of Fricke & Pirk GmbH, Olaf has considerable pharmaceutical industry experience gained in roles within health economics, pricing, health policy, marketing and clinical research. As a co-founder of the NIG 21 association, he has forged strong relationships with health economists, physicians and related researchers working in the German healthcare system.

• Olaf holds an MD and PhD in Medicines from the Medical University of Lübeck.

Jon Resnick, MBA • Jon Resnick is Vice President HEOR and Real-World Evidence Solutions at IMS Health, leading the company’s global real-world evidence (RWE) business, including the development of RWE strategy, offerings, collaborations and foundational technologies to meet the RWE needs of healthcare stakeholders.

• A former Legislative Research Assistant in Washington DC and member of the Professional Health and Social Security staff for the US Senate Committee on Finance, Jon has 10 years consulting experience at IMS. He was most recently responsible for leading the European management consulting team and global HEOR business teams of 300 colleagues, advising clients on a wide range of strategic, pricing and market access issues.

• Jon holds an MBA from the Kellogg School of Management, Northwestern University, with a major in Management & Strategy, Finance, Health Industry Management and Biotechnology.

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IMS HEALTH & EVIDENCE OUTCOMESSOLUTIONS RESEARCH IMS HEOR AND ECONOMICS REAL-WORLD

EXPERTISE | IMS Vernon Schabert, PHD • Dr. Vernon Schabert is Senior Principal HEOR at IMS Health, with a particular focus on the assessment and validation of patient-reported outcomes (PRO) instruments, retrospective analyses of claims and survey databases, and primary data collection surveys.

• A founder and former President of Integral Health Decisions, Inc, Vernon has extensive experience in conducting claims analyses, creating custom administrative databases, developing business intelligence software, and leading national quality research projects, gained in roles with Thomson Reuters, Strategic Healthcare Programs LLC, and CIGNA HealthCare. His expertise spans numerous disease areas and diverse topics including medication adherence, in-patient safety and outcomes in post-acute care.

• Vernon holds a PhD in Personality and Social Psychology from Stanford University and a BA in Psychology from Princeton University.

Núria Lara Surinach, MD, MSC • Dr. Núria Lara is Principal HEOR at IMS Health, with a particular focus on the design and coordination of local and international observational and patient-reported outcomes studies.

• A former practicing GP and clinical researcher, Núria’s experience spans roles in outcomes research at the Institute of Public Health in Barcelona and in Catalan Health Authorities, and consulting positions within the pharmaceutical and medical device industries focusing on medical regulatory and pricing affairs, pharmacoeconomics and market access strategies.

• Núria holds an MD (specializing in Family and Community Medicine in Barcelona), and a Master’s in Public Health from the London School of Hygiene and Tropical Medicine and London School of Economics.

Christian Thielscher, MD, MBA, PHD • Dr. Christian Thielscher is Principal HEOR at IMS Health and Professor for Health Economics at the FOM University in Germany, with expertise in clinical medicine, health economics, strategic consulting, business administration and innovative service development.

• Christian began his career in medical practice before moving into healthcare consulting at McKinsey, where he established one of the first disease management programs in Germany. He later founded GHX Europe where his work included developing the “health card” and the first German internet-based hospital guide.

• Founding president of the DGFM eV and editor of ‘Medizinökonomie’, Christian’s current research interests include quality in medicine and healthcare business management and marketing. He holds an MD from Bonn University, an MBA, and a PhD in Economics from the University of Frankfurt am Main, Germany.

Massoud Toussi, MD, MSC, PHD • Dr. Massoud Toussi is Medical Director HEOR at IMS Health with particular expertise in methodological and operational aspects of clinical research to assure the quality of interventional, observational and database studies.

• Previously Head of Global Clinical Research Operations at Cegedim, Massoud has also worked at the French High Authority for Health and various CROs as Project Lead, Scientific Manager and Operations Director. His experience includes defining and elaborating a new service process in drug safety signal detection and transmission.

• Massoud holds an MD from Mashad University in Iran, an MSc in Medical Informatics and Communication Technology from Paris IV, a PhD in Medical Informatics from Paris XIII University and a diploma in Transcultural Psychiatry from Paris Nord University.

Arnaud Troubat, PHARM D, MBA, MHEM • Dr. Arnaud Troubat is Principal HEOR at IMS Health. He has extensive consulting experience and special expertise in the development of registration dossiers and market access strategies across a large number of therapeutic areas.

• A pharmacist by training, Arnaud began his career at the French pharmaceutical industry association (LEEM), supporting members in understanding and interpreting the changing economical environment in France. He then spent a number of years in pharmaceutical affairs at ICI, leading regulatory work on registration submissions and reimbursement strategies, before subsequently moving into consulting. Most recently, he was Director at Carré-Castan Consultants, managing a team working for a wide range of pharmaceutical companies.

• Arnaud holds a Doctor of Pharmacy degree and an MBA from IAE Paris and a Master’s in Health Economics and Management from Paris-Dauphine University.

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IMS | MEETINGS

Conferences and events The global HEOR team at IMS Health play an active role in the HEOR community at events and conferences around the world and we look forward to meeting you and sharing our latest research at forthcoming meetings this year:

Conference

City

Country

Date

ASCO

Chicago

US

Jun 1-5

ISPOR

Washington

US

Jun 2-6

Mount Hood 2012 Challenge

Baltimore

US

Jun 7-8

American Diabetes Association (ADA)

Philadelphia

US

Jun 8-12

HTAi

Bilbao

Spain

Jun 23-27

ISPE

Barcelona

Spain

Aug 23-26

ISPOR

Taipei

Taiwan

Sept 2-4

European Association for Study of Diabetes (EASD)

Berlin

Germany

Oct 1-5

Society of Medical Decision Making (SMDM)

Phoenix

US

Oct 17-20

ISPOR

Berlin

Germany

Nov 3-7

Visit us online IMS HEOR and Real-World Evidence Solutions web pages are at www.imshealth.com/heor

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IMS HEALTH & EVIDENCE OUTCOMESSOLUTIONS RESEARCH IMS HEOR AND ECONOMICS REAL-WORLD

LIFELINK | IMS

Powering a patient perspective Pharmaceutical companies worldwide rely on LifeLink to power patient-centered decisions – from the first exploratory questions that drive clinical development to tactical sales planning for mature brands.

They are recognizing significant benefits, such as: • Better global decision making through consistent insights across all brands and across the product lifecycle • Improved internal alignment with consistent patient segments defined across Research & Development and Commercial functions • Enhanced communication with healthcare payers and other stakeholders through the use of a consistent patient view and common language • Faster and more accurate views across three key dimensions: patients, payers and prescribers • Confidence working with a partner who is committed to driving new metrics for new business models IMS has made extensive investments in anonymized patient-level data in markets around the world.

Today, we capture information for more than 300 million patient lives - for unparalleled real-world treatment insights.

Through the global IMS LifeLink™ program, we provide a powerful patient lens to drive focus and alignment across your business, deepening your understanding of critical patient, physician and payer dynamics. LifeLink allows you to identify the right patient segments early on, in order to gain competitive advantage in today’s complex environment.

We make a patient-centered perspective easy – by integrating patient-level intelligence into our industry leading offerings and giving you expert consultants who apply it to your key issues.

LifeLink provides the insights of primary research with the benefits of secondary: lower cost, repeatable, faster, larger sample size.

IMS LifeLink has everything you need to succeed in a patient-centered universe.

AN UNPARALLELED ARRAY OF ANONYMIZED PATIENT-LEVEL DATA WORLDWIDE CANADA

EUROPE

ASIA PACIFIC

• Longitudinal Rx

• Longitudinal Rx (Belgium, France, Germany, Italy, Netherlands, Sweden, UK)

• Oncology Analyzer (China, Japan, South Korea, Taiwan)

• Electronic Medical Records (France, Germany, Italy, UK)

• Longitudinal Rx (Japan, South Korea)

• Oncology Analyzer (France, Germany, Italy, Netherlands, Spain, Turkey, UK)

AUSTRALIA

• Drug Plan Claims (Oncology, hospital)

UNITED STATES • Longitudinal Rx • Health Plan Claims • Electronic Medical Records (Oncology, ambulatory) PLUS

• PharMetrics

• Hospital Charge Detail Master

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• Hospital Disease Database (Belgium)

• Longitudinal Rx

• Longitudinal Patient Database (Sweden)

Page 65 PAGE 65

IMS HEOR AND REAL-WORLD EVIDENCE SOLUTIONS is based in 18 countries worldwide with regional headquarters in: EUROPE & WORLDWIDE 210 Pentonville Road London N1 9JY United Kingdom Tel: +44 (0)20 3075 4800

THE AMERICAS 1725 Duke Street Suite 510 Alexandria, VA 22314 USA Tel: +1 (703) 837 5150

LATIN AMERICA Insurgentes Sur # 2375 5th Floor Col. Tizapan MĂŠxico D.F. - C.P. 01090 Tel: + 52 (55) 50 62 52 00

ASIA PACIFIC 10 Hoe Chiang Road Keppel Towers # 23-01/02 Singapore 089315 Tel: +65 6412 7365

HEORinfo@imshealth.com RWEinfo@imshealth.com www.imshealth.com/heor

ABOUT IMS IMS Health is the leading provider of information services for the healthcare industry around the world. The company draws on its global technology infrastructure and unique combination of in-depth, sophisticated analytics, on-shore and off-shore commercial services, and consulting platforms to help clients better understand the performance and value of medicines. With a presence in 100+ countries and more than 55 years of industry experience, IMS Health serves leading decision makers in healthcare, including pharmaceutical manufacturers and distributors, providers, payers, government agencies, policymakers, researchers and the financial community. Additional information is available at www.imshealth.com

Š2012 IMS Health Incorporated and its affiliates. All rights reserved.

Trademarks are registered in the United States and in various other countries.

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