IMS AccessPoint - May 2011

ACCESSPOINT IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

Volume 1, Issue 2 MAY 2011

News, views and insights from leading experts in HEOR

New priorities for HEOR? The U.S. reforms in focus

HTA moves center stage Taking an early, real-world view

Advances in medical adherence TM

Joshua Benner considers HEOR and the PageOUTCOMES 1 - Issue 1 U.S. reforms Page 6

Dr. Olaf Pirk Adam Lloyd discusses AMNOG examines country implications in adaptation of 1 Page IMS HEALTH ECONOMICS AND OUTCOMES RESEARCH Germany economic models Page 10 Page 22

ACCESSPOINT IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

News, views and insights from leading experts in HEOR

New priorities for HEOR? The U.S. reforms are reshaping the landscape and the outlook for health economics and outcomes research page 6

All change for market access in Germany The recent introduction of AMNOG is set to radically alter market access in this country page 10

Modeling for success in Canada Cost-effectiveness assessments must take account of the pricing that is possible within the rules of a powerful regulator page 18

From global to local Adapting economic models to local requirements is key to implementing value arguments in diverse markets page 22

Putting the P into Outcomes Research As the patient perspective becomes increasingly important, we consider a framework for its effective capture page 31

“2011 is signaling important developments in several key areas of healthcare”

WELCOME Welcome to the second issue of AccessPoint, a twice-yearly round-up of news and insights from the international team of HEOR specialists in the IMS Consulting Group – offering a timely outlook on the pivotal dynamics driving change, challenge and new potential for health economics and outcomes research.

In a year that is signaling important developments in several key areas of healthcare, we have already seen significant advancements across a number of fronts: in Germany, the recent drug reimbursement law (AMNOG) heralds a new era for market access in this country with far greater emphasis on demonstrating additional benefit (Page 10); in the U.S., innovations in patientlevel data and wider use of comparative effectiveness research have the potential to move HEOR to the forefront of reform efforts well into the future (Page 6); globally, collaboration in HTAs is gathering pace at the national and regional level (Page 14); and everywhere we see a patient-centered focus rising to the fore of outcomes research (Page 31).

Underpinning these trends is increasing recognition of the growing international need for more and better information comparing the clinical and economic value of medical technologies. IMS Health is committed to supporting the advancement of evidence-based healthcare with insights based on appropriate analysis of the best bespoke and available information – including our proprietary data assets. The recent launch of the IMS Institute for Healthcare Informatics, highlighted in this issue of AccessPoint (Page 2), further strengthens our resolve to accelerate understanding and innovation, and better serve the needs of patients worldwide through the stronger linkage of healthcare decisions and information.

IMS’ international team of more than 300 highly-qualified, multi-disciplinary researchers and consultants in HEOR and Pricing & Market Access is dedicated to generating the realworld evidence that enables more informed decision making. We continue to invest in new capabilities to ensure that our services leverage the very latest technological advances. Our new collaboration with BaseCase.com (Page 5) is already helping customers more clearly articulate economic value to a broad range of healthcare decision makers. Please stay tuned for more…

I hope you find our perspective on these exciting times for global healthcare both informative and enlightening. I would also like to thank our guest contributor Joshua Benner, of the Engelberg Center for Health Care Reform at the Brookings Institution, for his insightful take on the progress of the critical U.S. reforms (Page 6).

CONTENTS NEWS SECTION 2 IMS Institute for Healthcare Informatics 3 Five-level EQ-5D progresses 4 New analysis on treatment non-adherence 5 IMS collaboration boosts value communications INSIGHTS 6 U.S. HEALTH REFORMS Increased visibility for HEOR 10 MARKET ACCESS IN GERMANY Radical changes for pricing & market access 14 HTA CONVERGENCE Early focus on health economics key 18 COST-EFFECTIVENESS IN CANADA Working with a powerful regulator 22 GLOBAL TO LOCAL Country adaptation of economic models 26 MEDICAL ADHERENCE Advances from a decade of research 31 PATIENT-REPORTED OUTCOMES Capturing the patient perspective 36 IMS SYMPOSIUM Growing use of observational research PROJECT FOCUS 40 ACUTE RESPIRATORY FAILURE Modeling techniques add insight 42 HTA STRATEGY Past decisions help future submissions IMS OVERVIEW 44 IMS HEOR 45 Office locations 46 Our senior experts 53 IMS LifelinkTM: Longitudinal patient data TM

AccessPoint is published twice yearly by the Health Economics & Outcomes Research team of the IMS Consulting Group. ISSUE 2. PUBLISHED MAY 2011.

Jon Resnick VICE PRESIDENT AND GLOBAL LEADER, HEOR IMS CONSULTING GROUP JResnick@imshealth.com

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IMS HEALTH® 7 Harewood Avenue, London NW1 6JB, UK Tel: +44 (0) 20 3075 4800 • HEORInfo@uk.imshealth.com • www.imshealth.com ©2011 IMS Health Incorporated or its affiliates.

All Rights Reserved.

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NEWS | IMS INSTITUTE LAUNCH A new initiative from IMS Health underscores the company’s resolute commitment to advancing healthcare with transformational insights globally.

IMS Institute for Healthcare Informatics drives strong research agenda Marking an important milestone in a long history of supporting the advancement of evidence-based healthcare around the world, IMS Health has recently announced the launch of the IMS Institute for Healthcare Informatics. This major new initiative will leverage collaborative relationships in the public and private sectors to strengthen the vital role of information in accelerating the understanding and innovation that are critical to sound decision making and improved patient care.

UNIQUE, RELEVANT INSIGHTS At a time of immense challenges, but also tremendous possibilities, for technological innovation and healthcare advancement worldwide, the Institute will provide key policy setters and decision makers in the sector with unique and transformational insights into healthcare dynamics, derived from granular analysis of information. With access to unparalleled IMS data assets and analytics, and working in tandem with government agencies, academic institutions, the life sciences industry and payers, its research agenda will be dedicated to addressing the issues that impact healthcare in every country worldwide.

DEFINED FOCUS Led by Executive Director, Murray Aitken, the Institute will focus on five key areas of research: 1. Use of information by healthcare stakeholders globally to improve health outcomes, reduce costs and increase access to available treatments 2. Performance of medical care through a better understanding of disease causes, treatment consequences and measures to improve quality and cost of healthcare delivered to patients 3. Future global role for biopharmaceuticals, the dynamics that shape the market, and implications for manufacturers, public and private payers, providers, patients, pharmacists and distributors 4. Role of innovation in health system products, processes and delivery systems, and the business and policy systems that drive innovation 5. Advancement of healthcare agendas in developing nations based on information and analysis.

CLOSE LINKS WITH IMS HEOR Reflecting the extensive role of information in all key areas from healthcare policy and health economics and outcomes research, to healthcare reform and healthcare systems, the Institute will be working in close liaison with the IMS global team of experts in health economics and outcomes research.

Indeed, the Institute’s first comprehensive publication, HealthIQ – The Frontiers of Healthcare Advancement, which was released in March 2011, draws on their extensive work in value demonstration and evidence generation as well as other recently published research supported by IMS Health. Topics covered in this report include patterns and effects in the diffusion of innovation, the impact of regulatory advisories and guidelines on clinical practice, insights from research into medication adherence, and an overview of evolving techniques and approaches in comparative effectiveness research.

IMS CHINA INSTITUTE Given the critical and growing importance of China and its healthcare system in the global arena, the Institute has also now launched a branch in Beijing, where a team will collaborate with government agencies and institutions to enhance the role of information in policymaking and healthcare improvement. Within the overall objectives of the Institute, the local agenda will be tailored towards helping accelerate actions that are critical to China’s healthcare system, including support for the government's aggressive healthcare goals.

Among key priorities are the establishment of a China Health Services Research Network and a platform of professional training programs to support hospital executives, policy makers and healthcare industry executives. Several attendees at the launch in April have already expressed interest in exploring partnerships with the Institute, including the Director of the Department of Health Economics at Shanghai Fudan University.

LATEST RELEASE DELIVERS NEW INSIGHTS INTO U.S. PHARMACEUTICAL SPENDING At this critical juncture for U.S. healthcare, with the impact of reforms still playing out and the slowing growth trends of the previous decade reinforced in 2010, the Institute has just released a major new report placing the last year into context for healthcare decision makers. Featuring additional details on the U.S. pharmaceutical market, including top therapeutic continued opposite (bottom)

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

NEW VERSION OF EQ-5D | NEWS The EQ-5D™ is a standardized, broadly-used measure of health status.

Enhancements underway promise greater sensitivity in a range of diseases.

New five-level EQ-5D™ progresses through preliminary testing The EuroQol Group has been exploring ways of enhancing the tool’s sensitivity

First developed over twenty years ago by the EuroQol Group – a network of international, multilingual, multidisciplinary researchers – the EQ-5D is a standardized instrument for describing and valuing health-related quality of life1. Non disease-specific and measuring health using three levels of severity in five dimensions, it has been widely applied across a range of medical The selection of labels at approximately the 25th, 50th and 75th centiles yielded two alternative 5-level versions. Focus conditions.

FROM EQ-5D TO EQ-5D-5L In a move to improve the EQ-5D as a measure of health status in the clinical setting (randomized controlled trial or observational), a EurQol Group task force which includes Dr Xavier Badia, Global Leader Observational Outcomes Research and Senior Principal at IMS, has been exploring ways of enhancing the tool’s sensitivity and reducing ceiling effects – by increasing the number of severity levels. Three years on, the first results of these efforts have just been published online2, based on developing the working and concepts of the possible 5 levels.

In the study, which was conducted in the U.S. and Spain, severity labels were identified for 5 levels in each dimension, leveraging response scaling. The face and content validity of the new versions, including hypothetical health states generated from them, were tested in a series of focus groups.

group members showed a slight preference for the wording “slight-moderate-severe” problems, with anchors of “no problems” and “unable to do” in the EQ-5D functional dimensions. Similar wording was used in the Pain/Discomfort and Anxiety/Depression dimensions. The hypothetical health states were well understood although participants did stress the need for the internal coherence of health states.

With the development phase of the 5-level version now complete, the EQ-5D-5L will next undergo further testing to determine whether it does indeed improve sensitivity and lower ceiling effects. A EuroQol Group task force will also be working on the development of a methodology to obtain a set of societal values for the EQ-5D-5L.

1

http:/www.euroqol.org/euroqol-group/about-us.html. Accessed April 29, 2011.

2 Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res, 2011; Apr 9 [Epub ahead of print]

IMS Institute for Healthcare Informatics drives strong research agenda continued classes, products and dispensing locations, The Use of Medicines in the United States: 2010 Review reveals the key dynamics that are driving historically low levels in the volume of prescription medicines consumed.

FURTHER INFORMATION For further information on the IMS Institute for Healthcare Informatics or for copies of its published reports, contact Murray Aitken at MAitken@theimsinstitute.org or visit www.theimsinstitute.org. The website hosts an extensive array of resources on the Institute’s work, including news features, publications, topical webinars and podcasts on leading healthcare issues, the China IMS Institute and the opportunity to share feedback and proposals for collaboration, consistent with its research agenda.

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Celebrating the launch of the China Institute, from left, Davey Han, Director General, IMS China Institute; Sati Sian, President, IMS China; Zhao Yajun, Director General, China Center for Pharmaceutical International Exchange, SFDA; Deng Haihua, Deputy Director General, MOH General Office; and Murray Aitken, Executive Director, IMS Institute for Healthcare Informatics.

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NEWS | COST-EFFECTIVENESS IN ADHERENCE Treatment non-adherence has important economic and health implications.

Findings from IMS research bring new insights into cost-effective approaches.

IMS explores cost-effectiveness of adherence interventions at WHO self-care meeting Poor adherence with medical treatment both limits Understanding the relative the effectiveness of healthcare interventions as well as increasing disease burden. Despite cost-effectiveness of adherence extensive research, progress has been slow in interventions may guide achieving demonstrable improvements, particularly efficient programs in the case of chronic medications. Complexities abound, many findings cannot be generalized and A total of 22 eligible adherence-improving interventions were identified from 18 studies. A program with self-monitoring, patients differ in their attitudes and motivators.

Among a growing body of programs to improve adherence are efforts involving patient self-monitoring, self-education and self-report. However, these approaches are generally timeconsuming and expensive versus less intensive interventions such as patient reminders, while generally less expensive than clinician-directed methods such as pharmacist counseling. Recognizing that comparisons of programs for improving adherence may benefit from an analysis of costs alongside their results, IMS HEOR experts set out to compare the cost-effectiveness of different interventions that have been shown to improve adherence with antihypertensive and lipid-lowering therapy.

In April 2011, the results of this work formed part of a program of research presentations at a WHO meeting in Geneva1 exploring innovative approaches to helping people with non-communicable diseases better manage their own conditions. Self-care programs have the potential to improve outcomes as well as lower costs in this patient population.

COST-EFFECTIVENESS OF SELF-MANAGING ADHERENCE IN CARDIOVASCULAR DISEASE The analysis, led by Richard Chapman, PhD, Principal, HEOR in the IMS Consulting Group, focused on exploring the cost-effectiveness of adherence-improving interventions, including self-monitoring and self-education, for cardiovascular medications. The approach combined a burden of non-adherence model framework with literature-based data on adherence-improving interventions. Outputs from the model included life-years gained, direct medical costs and incremental costs per quality-adjusted life-year (QALY) gained. Costs were standardized to 12 months and adjusted to 2007 US$.

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reminders, and educational materials incurred total healthcare costs of $17,520 and compared with no adherence intervention had an incremental cost-effectiveness ratio (ICER) of $4984 per QALY gained. Pharmacist/nurse management incurred total healthcare costs of $17,896, and versus self-monitoring, reminders, and education had an ICER of $6,358 per QALY gained.

The results suggest that, among published interventions which have been shown to improve adherence, reminders and educational materials, and a pharmacist/nurse management program are cost-effective, and should thus be considered ahead of other approaches. Understanding the relative cost-effectiveness of adherence interventions may guide design and implementation of efficient adherence-improving programs, and allow comparisons of programs involving selfcare with those that require other external resources.

WHO RECOMMENDATIONS IN DEVELOPMENT Among other topics explored at the WHO meeting were the effectiveness of self-care interventions on morbidity and mortality, self-monitoring components in cardiovascular risk management, and self-care programs for non-communicable diseases in developing countries. The WHO is currently developing recommendations on the self-care of non-communicable diseases.

1

WHO Meeting on Self Care of Noncommunicable Diseases, Geneva, Switzerland, 19-20 April, 2011.

Jonothan Tierce, CPhil, considers a decade of research into medication non-adherence on Page 26 in this issue of AccessPoint.

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

VALUE COMMUNICATION | NEWS IMS value communications support drives clearer, more informed healthcare decision making worldwide. An exciting development adds a new cutting edge.

IMS HEOR and BaseCase.com collaboration takes value communications to a new level With the BaseCase platform, complex models can be effectively manipulated and communicated

Building on our extensive capabilities in evidencebased messaging and compelling articulation of product value to a range of healthcare decision makers, we are delighted to announce a major enhancement to our services. Leveraging the cutting-edge platform of BaseCase.com, this exciting development brings tremendous possibilities for communicating the output of Such instant functionality and clarity opens up new health economic (HE) models to both internal and dimensions for communicating health economic value to internal affiliates and commercial teams – as well as to our external stakeholders.

VISUAL, REAL-TIME, INTERACTIVE FORMAT BaseCase.com is an internet-based software platform developed by a team of health economists to deliver health economic data in a visual, real-time and interactive format.

It enables clear and effective manipulation and communication of complex HE model outputs for both technical and non-technical audiences.

With the BaseCase platform, complex models can be manipulated in real time using an online interface to immediately assess the impact of changes to model variables.

FIGURE 1: BUDGET IMPACT EXAMPLE ON BASECASE.COM – YOUR HE MODEL OR CORE VALUE DOSSIER IS EASY TO USE, DISTRIBUTE AND MAINTAIN INSIDE THE WEB BROWSER

clients’ key customers. Additionally, BaseCase supports the distribution and maintenance of interactive Core Value Dossiers via the internet.

KEY TOOL, FULL SUPPORT Working in collaboration with BaseCase, IMS will provide full global consulting support for this valuable communications resource. At any stage in the development of product evidence – whether core models and local adaptations have been completed or not – we will work with our clients to manage the installation of evidence into BaseCase and ensure maximum benefit is gained from the communications potential it can offer.

BaseCase and IMS are currently implementing an HEOR communication platform for a top 5 pharmaceutical client.

The platform delivers budget impact and cost-effectiveness models from global HQ to the worldwide affiliates. The format is intuitive, comprehensible and flexible so it can be adapted for immediate local usage by commercial teams. It further offers a real-time distribution mechanism for health economic models to any computer device including iPads, with full visibility for the global HQ over country adaptations (Figure 1).

For further details on this collaborative service please contact: IMS Consulting Group: Richard Mee (RMee@imshealth.com +447960 163 560), BaseCase.com: Gijs Hubben (G.Hubben@basecase.com +49 1522 3056714)

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INSIGHTS | INTERVIEW

A year has passed since the U.S. Health Reforms were enacted, along with other important legislative changes, all with the potential to significantly impact health economics and outcomes research (HEOR).

While many of these initiatives will roll out over time, others are taking effect more quickly. What has been their impact? And to what extent are they already redefining approaches to evidence generation?

The interviewees Joshua S Benner, PHARM D, SCD is Fellow at the Brookings Institution and Research Director at its Engelberg Center for Health Care Reform, Washington D.C. JBenner@brookings.edu

Michael Nelson, PHARM D is Regional Leader Americas, HEOR, IMS Consulting Group.

MNelson@us.imshealth.com

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

INTERVIEW | INSIGHTS

New priorities for HEOR? As major changes in U.S. health policy start to play out in the healthcare sector, Michael Nelson, Regional Leader Americas, HEOR at the IMS Consulting Group and Joshua Benner, Fellow at the Brookings Institution and Research Director at its Engelberg Center for Health Care Reform, discuss their take on the reforms so far and the key implications for health economics and outcomes research.

What are the main achievements of the reforms so far?

It is also important to remember that some key reforms were set in motion by the Recovery Act of 2009 (which contained provisions to expand the use of health information technology as well as a bolus of funding for comparative effectiveness research), the FDA Amendments Act of 2007 (which mandated the FDA to establish a new system for monitoring the safety of medical products), and other legislation. These elements are further along, laying a foundation for subsequent reforms by improving our capacity to develop better evidence and coordinate care.

path for development and approval of biosimilars, and the Independent Payment Advisory Board, among others.

JB: One year into the implementation of ACA, most of the focus has been on changes to the insurance market: children can now stay on their parents’ insurance until they reach the age of 26 years; individuals can no longer be denied coverage for pre-existing conditions; and lifetime coverage limits have been banned.Tax credits are available for small businesses that provide health Michael Nelson: How do you think the reforms insurance. The process of gradually closing the “donut are progressing, one year down the line? hole” coverage gap in Medicare Part D began with Joshua Benner: The Affordable Care Act of 2010 issuing $250 rebate checks for enrolees who reached the (ACA) – the major health reform legislation enacted coverage gap in 2010, and some preventive services such last year – includes significant steps in the areas of as mammograms and colonoscopies are now free to insurance market reforms and coverage expansion; Medicare enrolees. The Patient-Centered Outcomes demonstrations of new models for payment and delivery Research Institute (PCORI) has also been established to of care; and improving the evidence on which coordinate the national agenda on comparative healthcare decisions are made. Implementation of these effectiveness research. reforms is only just beginning, with some provisions not I think in the coming years we’ll learn more about the coming into effect until 2014, so it’s really still too early impacts of other planned reforms still to be implemented, to tell whether they will ultimately improve quality and including accountable care organizations, patientreduce avoidable costs. centered medical homes, the insurance exchanges, the

MN: The success of these changes seems to be heavily dependent on the generation and synthesis of better evidence on effectiveness and efficiency in support of optimizing decisions in healthcare.

This process of generating and synthesizing evidence has been variously referred to in global circles as health technology assessment (HTA), health economics and outcomes research, and comparative effectiveness research (CER). While one could debate subtle or more obvious MN: Yes, the previous legislation from 2007 and differences between these terms, CER seems to be 2009 and, one could argue, even legislation dating the focus of much of the recent legislation. How back to the 2003 Medicare Modernization Act, is its role evolving? established a foundation for comparative effectiveness research. The Affordable Care Act JB: More and better evidence on what works best in seems to go much further in that it also creates healthcare (referred to as “patient-centered outcomes an environment where the information generated research” in the health reform legislation of 2010) is from this research will be utilized in a more necessary to deliver more effective, individualized care. effective way by decision makers. These changes But it’s not enough to just do the research – the results also are being phased in over a number of years. have to be synthesized and disseminated to patients and

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INSIGHTS | INTERVIEW ...continued from previous page

consumers, healthcare providers, payers, and policy makers. Then we need incentives for that evidence to be applied in patient care and policy making. Ideally, enhanced quality measurement and reporting, performance-based payment systems, and value-based benefit designs will combine to encourage more evidence-based care.

MN: Several of the provisions in the 2009 Recovery Act and 2010 ACA refer to infrastructure and technology investments to support CER. While this likely extends to a range of potential innovations, there are specific initiatives mentioned and/or underway to support the implementation of electronic medical records and aggregation and analysis of secondary data. What sort of developments are you seeing in real-world data collection and management?

Healthcare reform legislation is shaping the landscape of health economic and outcomes research in the U.S. While recent changes represent a significant shift in the emphasis on effectiveness in decision making, other developments continue to influence the outlook.

evaluate different benefit designs, formularies, payment strategies, and other reforms.

MN:Yes, this is an important point. An increasing amount of data that will be available to decision makers will come from observational research.

There is clearly a need for applying appropriate JB: Electronic health information is becoming more research methods to analyzing data, but equally readily available, enabling the generation of much needed important will be an awareness among decision evidence on the safety, effectiveness, and costs of health makers of how to interpret these results. For care products and services. One of the exciting example, clinicians are well-versed in interpreting developments over the past three years has been randomized controlled clinical trials, but studies Mini-Sentinel, the FDA’s pilot system for post-market using observational methods are often foreign to surveillance of medical product safety. Mini-Sentinel uses them. Effective communication of research a distributed data network to remotely query databases including HEOR will be essential to achieve the held by participating health plans and delivery systems. intended improvements in quality and efficiency The model is appealing because it employs a common of healthcare in the U.S. Going forward, how do data format to facilitate consistent analysis at multiple you see the role of HEOR evolving? sites, and for most analyses, data can remain securely behind owners’ firewalls. A similar data network is being JB: As stakeholders demand more convincing evidence developed now in the Department of Health and Human of the safety, effectiveness and value of new medical Services (HHS) to make data from Medicare, Medicaid, technologies, the process of developing this evidence will and other payers available to qualified researchers for begin earlier in the product development cycle, comparative effectiveness research. The Agency for informing development decisions. Once approved, new Healthcare Research and Quality has also recently products will be subject to greater monitoring for safety awarded grants to support the development of this kind and comparative effectiveness in patient-care settings.

For some medical technologies, payers are beginning to of infrastructure. tie reimbursement to these endpoints. As we continue to MN: How are these developments likely to impact see innovation at the interface between payers and our ability to conduct outcomes research? manufacturers, the importance of data, methods, and experienced researchers will continue to grow. • JB: Large-scale data infrastructure investments improve our capacity to conduct observational outcomes research. However, for this research to have maximum impact, we also need to use the most appropriate methods. The risks of misclassification and selection bias in observational studies are well-documented, and so further work is needed to match the best methods to the available data. And ultimately, these data could be useful for measuring the outcomes of large experiments to

The process of developing evidence of safety, effectiveness and value will begin earlier in the product development cycle

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

INTERVIEW | INSIGHTS

Selected milestones in U.S. Health Reform IMPLICATIONS FOR HEALTH ECONOMICS AND OUTCOMES RESEARCH 2003 Medicare Modernization Act – The legislation which gave AHRQ a congressional mandate to support comparative effectiveness research (CER). Since 2003, AHRQ has supported CER and has established networks and research centers (Evidence-based Practice Centers, DEcIDE network) which support ongoing CER1.

2007 Food & Drug Administration Amendments Act (FDAAA) – Title IX of FDAAA provides FDA with additional authority with regard to both pre- and post-market drug safety including the authority to require post-market studies and clinical trials, safety labeling changes, and Risk Evaluation and Mitigation Strategies (REMS).

FDAAA requires increased activities for active post-market risk identification and analysis2.

2009 The American Recovery and Reinvestment Act of 2009 – Allocated $1.1 billion for CER with funding distributed between NIH, AHRQ, and HHS to establish CER infrastructure and studies1.

2010 Patient Protection and Affordable Care Act – Landmark U.S. healthcare legislation impacts the healthcare system in a variety of ways. Research and programs focused on quality and cost outcomes include3: • Patient-Centered Outcomes Research Institute (PCORI) –Establishes a private, non-profit institute to identify national priorities and provide for research to compare the effectiveness of health treatments and strategies.

• Quality Infrastructure – Additional resources provided to HHS to develop a national quality strategy and support quality measure development and endorsement for the Medicare, Medicaid and CHIP quality improvement programs.

2011 • Health Care Quality and Efficiency – Establishes a new Center for Medicare & Medicaid Innovation to test innovative payment and service delivery models to reduce healthcare costs and enhance the quality of care provided to individuals3.

2012 • Linking Payment to Quality Outcomes – Establishes a hospital value-based purchasing program to incentivize enhanced quality outcomes for acute care hospitals3.

• Reducing Avoidable Hospital Readmissions – Directs CMS to track hospital readmission rates for certain high-volume or high-cost conditions and uses new financial incentives to encourage hospitals to undertake reforms needed to reduce preventable readmissions, which will improve care for beneficiaries and rein in unnecessary healthcare spending3.

2013 • Administrative Simplification – Health plans must adopt and implement uniform standards and business rules for the electronic exchange of health information to reduce paperwork and administrative burdens and costs3.

• Fee for patient-centered outcomes research – Annual fee becomes effective on insured and self-insured plans to fund the patient-centered outcomes research trust fund3. It has been estimated that this fee will generate $500 million in funds annually to support PCORI1.

2014 • Quality Reporting for Certain Providers – Places certain providers, including ambulatory surgical centers, long-term care hospitals, inpatient rehabilitation facilities, inpatient psychiatric facilities, PPS-exempt cancer hospitals and hospice providers, on a path toward value-based purchasing by requiring the Secretary to implement quality measure reporting programs in these areas and also pilot test value-based purchasing for each of these providers in subsequent years3.

2015 • Continuing Innovation and Lower Health Costs – Establishes an Independent Payment Advisory Board to develop and submit proposals to Congress and the private sector aimed at extending the solvency of Medicare, lowering healthcare costs, improving health outcomes for patients, promoting quality and efficiency, and expanding access to evidence-based care3.

• Paying Physicians Based on Value Not Volume – Creates a physician value-based payment program to promote increased quality of care for Medicare beneficiaries3.

Sources: 1Sox

HC, Comparative effectiveness research: A progress report, Annals. org, August 2, 2010. http://www.annals.org/content/early/2010/08/02/0003-4819-153-7-201010050-00269.full?aimhp 2U.S. Department of Health and Human Services, Last updated 10/2/2009. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/Foodand DrugAdministrationAmendmentsActof2007/ucm184271.htm 3Committees on ways and means, energy and commerce, and education and labor, April 2, 2010. http://docs.house.gov/energycommerce/TIMELINE.pdf

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INSIGHTS | MARKET ACCESS IN GERMANY

The recent introduction of a mandatory benefit assessment process in Germany is set to radically alter market access in this country, with new stipulations for real-world evidence in clinical trials and a significantly altered pricing process based on discount negotiation.

The implications – both within and beyond Germany’s borders – are considerable.

The author Olaf Pirk, MD, PhD is a Principal HEOR, IMS Consulting Group, Germany.

OPirk@de.imshealth.com

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

MARKET ACCESS IN GERMANY | INSIGHTS

All change for market access in Germany On 1 January, 2011, the status of Germany as a fast-entry, 1. No additional benefit: If the drug is considered to offer no additional benefit, it will be given a reference premium-priced market changed with the introduction price in relation to the comparator used during the of AMNOG (law to restructure the drug market). In benefit assessment. Should that comparator belong to place of manufacturer-set prices – a feature this market an existing reference price group (Festbetragsgruppe) has shared with the UK for many years - is a system with the new drug will be classified immediately into that a benefit assessment-based discount negotiation during group if possible (this applies when the two products the first 12 months on the market. Figure 1 shows the are comparable on ATC level 4). If no reference price new process. group exists, the new drug will be discounted to set a EMPHASIS ON ADDITIONAL BENEFIT reimbursement price no higher than the reimbursed price of the comparator. This new price will be For every NCE, manufacturers are now required to effective from the beginning of month 13 after launch. submit a “benefit dossier” to the federal joint committee (Gemeinsamer Bundesausschuss: GBA) for assessment 2. Additional benefit: If the NCE is considered to offer an additional benefit then a discount will be negotiated either by the GBA itself or, alternatively, IQWiG. The based on the reimbursed price of the comparator and outcome (additional benefit/no additional benefit) will the additional benefit.The reimbursed price should be be published on the internet within three months. The as high as the comparator plus a surplus for the manufacturer and defined stakeholder groups will then additional benefit (the head association of the German have the opportunity to comment in a hearing. Over the sick fund thinks of the following algorithm: 10% next three months, the GBA will reach a decision, based additional benefit would equal 10% higher reimbursed on the results of the assessment. price.) The discount will be taken from the premium price set by the manufacturer. The new reimbursed price will be effective from month 13 after launch.

FIGURE 1: THE NEW GERMAN MARKET ACCESS PROCESS AS DEFINED IN SOCIAL CODE BOOK NO. 5 Institute for quality and efficiency in Health Care Benefit Assessment

Commission possible

Report

Dossier

Hearing

Additional benefit

Manufacturer

Federal Joint Commitee

Federal Joint Commitee

Market Launch

Benefit Assessment

Benefit Assessment

(Publication)

Market Launch

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6 months

Not accepted Arbitration panel

Head association of the SMI scheme

Decision (e.g. based on international prices)

Rebate Negotiations

Reference price not available

Reference price

3 months

Manufacturer

(Decision)

No additional benefit

Manufacturer’s price (set freely)

No agreement

Agreement

Discount

Decision

Retroactive

12 months

Institute Quality and Efficiency in Health Care Cost/benefit assessment

Discount

Valid until the end of the process

15 months

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INSIGHTS | MARKET ACCESS IN GERMANY ...continued from previous page

Healthcare politicians believe that current health economic assessments in Germany are virtually dead

REBATE NEGOTIATIONS All the pricing negotiations are conducted between the manufacturer and the head association of the German sick funds (GKV-SV) from months 7-12 post launch (ie after the GBA decision has been reached). Should negotiations fail, the reimbursed price will be set by an arbitration body between months 13 to 15, based on the international reference price.

This will come into force retroactively beginning with month 13 after launch.

BENEFIT DOSSIER The basis for the benefit assessment, as well as the negotiation process, is the benefit dossier which must be structured according to the GBA’s code of procedure (Figure 2).

The dossier consists of five modules, each of which forms the base for the module above. Module 1 is the executive summary of Modules 2-4. For each of the Modules there is at least one Word template defining the contents to be provided. The core of the dossier is Module 4 – the benefit dossier to be compiled by the manufacturer. This must prove additional benefit over the appropriate comparator, which is the cheapest drug to be used on label while treating a patient. If there are no drugs in the indication, the comparator might even be a non-drug treatment. The dossier is comparable to the kind of HTA formerly performed by IQWiG. Ideally, the additional benefit should be demonstrated on the basis of head-to-head trials with the appropriate comparator.

To facilitate the fulfillment of this goal, there are opportunities to consult with the GBA during the whole drug development process; ideally the manufacturer should approach the committee before commencing the Phase III program. The dossier should be based on all clinical trial data known to the manufacturer, including both published and unpublished data for aborted trials as well as for investigator-driven trials. In Module 4 publications are also requested. Even if only one trial is missing, the dossier will be judged incomplete and the additional benefit will not be shown.

LENGTHY PROCESS Since no one really yet knows how the process will work, the GBA has defined the period through 31 July 2011 as transitional. All benefit dossiers sent to the GBA during this time will be reviewed, whether they are complete or not and whether the comparator is appropriate or not. The manufacturer will then have the opportunity to adapt and resubmit the dossier within three months. Should the deadline be missed or omissions occur, the additional benefit will not be shown; in other words, the GBA will reach a “no additional

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

MARKET ACCESS IN GERMANY | INSIGHTS

benefit” decision, leaving the GKV-SV to set the reimbursement price.

If the manufacturer or GKV-SV is unhappy with the decision of the arbitration body, they can ask for a cost benefit analysis to be undertaken by IQWiG.This should be financed by the company, completed within three years, and be based on a prospective, non-interventional study, according to GBA specifications. Time wise, manufacturers must therefore plan for 6 months MODULE 1 • Administrative information • Summary of statements in the dossier

List of approved indications

negotiation with the GBA, 3 years study duration, and 2 years for the IQWiG assessment – with results available at the earliest 7 years post-launch.

Healthcare politicians believe that current health economic assessments in Germany are virtually dead: instead of requesting a cost benefit analysis, manufacturers should take the opportunity to initiate a new benefit assessment using new data after one year, since by law the process can be repeated annually. • FIGURE 2: THE ORGANIZATION OF THE BENEFIT DOSSIER AS DEFINED BY THE GBA

MODULE 2 • List of approved indications • General information about the medicinal product

General info. about the medicinal product Appropriate comparative therapy Patients with therapeutically meaningful additional benefit Cost of therapy for SHI

MODULE 3 (A-Z by indication) • Indication of the appropriate comparative therapy • Number of patients for whom there is a therapeutically meaningful additional benefit • Cost of therapy for statutory health insurance • Requirements for quality-assured application

Requirements for quality-assured application Methodology for determining the medical benefit and additional medical benefit Results regarding the medical benefit and the additional medical benefit Patient groups with therapeutically meaningful additional benefit

MODULE 4 (A-Z by indication) • Systematic overview regarding the medical benefit and additional medical benefit (description of the methodology and results) • Indication of the patient groups for whom there is a therapeutically meaningful additional benefit

Full text of quoted resources

Study reports

Assessment report of the regulatory agency

Files documenting the procurement of info.

CTD sections 2.5, 2.7.3, 2.7.4

Checklist for formal completeness

MODULE 5 • Full text of the quoted sources • Files documenting the procurement of information • Reports on all studies of the pharmaceutical entrepreneur

• Essential common technical documents (CTDs) • Assessment report of the regulatory agency • Checklist for formal completeness verification

AMNOG in a nutshell • Since the beginning of 2011, each NCE must be supported by a benefit dossier defining the additional benefit of the drug in relation to the appropriate comparator.

• If a benefit is shown, the new reimbursed price after one year on the market will be a surplus on the reimbursed comparator price, according to the additional benefit. If no additional benefit is shown, the reimbursed price after one year may not be higher than that of the appropriate comparator.

• The decision is based on a dossier submitted by the manufacturer, which draws on all the available clinical trials. An incomplete dossier means no additional benefit is shown, in which case the reimbursement price will be set and/or negotiated by the head association of the sick funds.

• If the negotiation fails, an arbitration body will determine the reimbursed price on the basis of international reference prices. No health economic data are requested during the entire process. The negotiation is based on the drug price accruing for the sick funds plus extra costs, based on additional resources used as mentioned in the physician’s information leaflet.

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INSIGHTS | HTA CONVERGENCE

After years of focusing first and foremost on clearing the traditional hurdles to market, companies now face a growing need to place health economics and the payer view at the center of their development activities.

Jacco Keja, PhD is Regional Leader EMEA, HEOR, IMS Consulting Group.

JKeja@nl.imshealth.com

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

HTA CONVERGENCE | INSIGHTS

HTA moves center stage EARLY FOCUS KEY TO FUTURE SUCCESS For many years, drug development was very much a staged affair, primarily geared towards regulatory approval and the three traditional clinical hurdles of quality, efficacy and safety. Value was based on retrospective review of the Phase III trial program; drugs were targeted at the widest indication and highest line of therapy possible; and pricing & reimbursement (P&R) was essentially a one-step affair, centered on a dossier submission. Only then, or at best in parallel, was the HTA and payer view drawn into the mix.

KEY DRIVERS Within the broader context of ongoing change and increasing complexity in the global healthcare arena, the shift towards outcomes and value for money is being spurred by a number of developments and trends in several of the major markets:

• France: In France, the fall-out from the safety scandal involving Servier’s Mediator (benfluorex) has placed drugs and their assessment under greater scrutiny than ever. Withdrawn from the market in 2009, the drug Today, a new model is emerging. One where product has since been alleged to have caused 500-2000 deaths value is defined as much by health economic endpoints during its 30+ years on the market. Amid reports of a - clinical outcomes, patient-related outcomes and quality promise to reform the French pharmaceutical of life - as harder clinical endpoints; where payers have regulatory system, six multi-stakeholder groups have started segmenting patients into populations that will been established by the Ministry of Health, charged benefit most from a product or where its use will be most with reviewing drug evaluation at every stage of the cost-effective; and where protocols that were traditionally process: from licensing, pharmacovigilance and offdesigned for regulatory and drug approval studies, label use to information, organizational aspects and based on a review of trial data and validation by medical devices. Reports detailing their findings are KOLs, now require complementary insights - from expected to result in recommendations for legislative prescribers, patients and real-world data (Figure 1). All change by mid-2011. these parameters must be identified, investigated and understood well in advance, in order to frame clinical • Germany: As a consequence of budget strains and a general perception that few new products are bringing programs accordingly. The key point is this: that additional benefits, pharmaceutical companies generating real-world evidence for health technology launching a new chemical entity in Germany are now assessments (HTAs) must begin even before Phase II.

Regulatory focus

HTA and real-world data centric

Internal study validity

External validity

Literature review

KOLs/ad board

Endpoint design

Protocol validation

KOLs

Regulatory agency

Real-world data

Prescribers & KOL

HTA insights

Literature review

KOLs/ad board

Endpoint design

Protocol validation

Patient insights

Regulatory agency

Payers

FIGURE 1: TODAY’S ENDPOINT DESIGN IS MOVING FROM REGULATORY TOWARDS HTA FOCUS

AccessPoint - Issue 2

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INSIGHTS | HTA CONVERGENCE ...continued from previous page

There are moves towards stronger regional and global collaboration in HTAs focused on greater coordination and the sharing of information

required to submit an early “benefit dossier” showing a medicine’s added value over the most appropriate comparator (see article in this issue on page 10).

Although pricing freedom is still allowed at launch, in the event that a subsequent GBA/IQWiG review completed within 6 months concludes that the product fails to show an additional benefit, then direct reimbursed price restrictions will be imposed. With a deemed “no added value”, pharmaceutical companies will be forced into secondary negotiations to set a rebate level from the list price at launch on the basis regional and even global collaboration in HTAs with networks of agencies such as EUnetHTA and INAHTA of this benefit assessment. focused on greater scientific coordination and the • UK: In the UK, the long-established PPRS pricing sharing of reliable, transferable information to improve process, built around the concept of profit control, is technology assessments. set to be replaced by a new value-based system of pricing pharmaceuticals by 2014. Intent on improving These goals are further underscored by the objectives laid access to medicines, based on assessing the outcomes out in the European Medicine Agency’s strategic they achieve, this is driving much greater emphasis on roadmap to 2015 in its efforts to facilitate access to overall value and is already the basis for a number of medicines and meet the challenges of drug development into the future2. These embrace the need for increased risk-sharing agreements or rebates to the NHS. interaction at stakeholder level with optimal flow of Alongside these important developments is growing unrest information between the EMA, the industry, patient at the continued decrease in patient access to medicines in groups and HTA bodies.

Europe, highlighted in the latest Patients W.A.I.T Indicator report (EFPIA, 2010). Long delays in accessing treatments Other ongoing initiatives in European HTA abound, with the rate of availability to patients down in collaboration include project-based joint actions between most of the countries included in the survey compared the European Commission and EUnetHTA to further with the previous period studied (2004-2007).Average time develop “Core HTA” methods, with an emphasis on elapsing between EU market approval and accessibility early dialogue between major players and the varies from 88 to 392 days, meaning that in some countries establishment of an information system and long-term patients are waiting for more than a year before they can business model. Proposed directives for the future further benefit from new technologies being prescribed elsewhere1. strengthen these trends, with a move from project-based Much of this can be attributed to the wide and strong to permanent cooperation on HTA. fragmentation at the national and sub-national level.

Just how these aims will translate into new ways of working, Nor is this broad trend unique to the EU: In the U.S. new interactions and some element of standardization more than 5 years ago requests from the FDA included remains to be determined. However, they clearly statistically significant functional outcomes as a underscore the growing perception that EU cooperation co-primary endpoint as context for the more typical in HTAs offers clear benefits, pooling expertise and endpoints. More recently, research into comparative minimizing duplication of effort, and that all stakeholders effectiveness has become an important element of the will need to find ways of working together to achieve this. country’s healthcare reform in an effort to drive more TRANSATLANTIC HARMONIZATION informed decision making.

The move towards harmonized approaches has also INCREASING MOVES TO INTERNATIONAL seen a notable increase in collaborative activities between COLLABORATION the EMA and FDA in recent years, including the Against this background, and with more countries turning “Transatlantic Administrative Simplification Action Plan”, to HTAs as the basis for healthcare decision making, focused on ensuring greater access to innovative products the need for more unified, consistent approaches to on both sides of the Atlantic. Sharing of clinical trial health economics and outcomes research has become inspections and a bilateral good clinical practice initiative increasingly apparent. Growing recognition of this to ensure that “clinical trials submitted in drug marketing imperative is already driving moves towards stronger applications in the U.S. and Europe are conducted Page 16

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

HTA CONVERGENCE | INSIGHTS

PRECLINICAL R&D • Epidemiology (prevalence, incidence) • Medical care practice • Target population • Early indicators of outcome and benefits • P&R landscape for therapy area

CLINICAL DEVELOPMENT

REGULATORY SUBMISSION

PHASE I PHASE II PHASE III

Observational Research for Pre-Launch Market Insight • Burden of disease • HE models (treatment cost and cost-effectiveness studies); Budget impact models • Guide/oversee quantitative price value studies • Value demonstration studies (eg, QoL) • Develop key value proposition for HTA/payers and finalize strategy implementation planning • Test value message for payers/physicians/patients

POST-APPROVAL LIFECYCLE P&R MANAGEMENT

Post-Launch Observational Research • Safety commitment/Requirement studies; estimate of the evolving risk-benefit profile • Comparative effectiveness real-life studies in clinical practice vs. efficacy data in clinical trials • Comparison of multiple alternative interventions to inform optimal therapy strategy • Joint population • Drug use in clinical practice (indication, dosage, treatment period, compliance, adherence, QoL, etc) • Ongoing P&R optimization & price management

FIGURE 2: COMPANIES MUST MEASURE AND ARTICULATE PRODUCT VALUE EARLY BY DEVELOPING METRICS AND SYSTEMS TO COLLECT SUPPORTING DATA

uniformly, appropriately and ethically”3 have paved the way for further areas of potential harmonization to be explored (eg biomarkers, trial design and comparators).

Among proposed projects in the transatlantic plan are an invitation to the pharmaceutical industry to compare the EU and U.S. approaches to risk management formats (eg, E2E, Volume 9a RMP guidance, REMS, etc.) and identify opportunities for convergence, as well as intensifying bilateral discussion on proposed specific risk management initiatives4.

BUSINESS IMPERATIVES For the industry, these developments have major implications. Companies must prepare for a world where regulatory bodies are increasingly focused on value-based issues, where national payers are increasingly adept at conducting HTAs, and where networks of agencies are coming together in a more intense, collaborative way. To succeed, they will need to: 1. Forget about old and current regulatory “pathways” to obtain product registration. At best these will result in a “me too” and they will fail with the HTA bodies and payers. Early development and articulation of value, leveraging metrics and systems to collect supporting data is key (Figure 2).

2. Focus on early and deep patient-level segmentation potentially leveraging growing knowledge in the field of pharmacogenomics, and use the conclusions from this analysis to drive the agenda AccessPoint - Issue 2

for regulatory approaches. There is little point, for example, in registering a product in primary insomnia and onset of sleep if chronic (secondary) insomnia and restorative sleep is what the market needs.

3. Understand the patient beyond claims analyses and optimize trials accordingly, recognizing the somewhat different RWE data dimension and needs for late development products. This is especially relevant in the fields of CNS/psychiatry, pain and behavioral disorders as well as others such as somatized diseases, where current approaches involving (administrative) claims analyses and often noninterventional studies quickly meet their limitations.

Both sources, in their current form, can have questionable validity and often lack the level of detail needed to quantify unmet needs, burden of disease and comparative effectiveness. In this case, it is important to understand signals of improvement and characterize patient groups often at the level of symptom, cognition, etc and be able to relate improvements to functional and economic advantages. •

1

http://www.efpia.org/Content/Default.asp?PageID=517 http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011 /01/WC500101373.pdf 3 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1 74983.htm 4 http://ec.europa.eu/health/files/international/doc/eu_fda_action_plan_20 0806_en.pdf 2

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INSIGHTS | ROLE OF REGULATORS IN CANADA

One of the unique features of the Canadian market is the existence of a powerful federal regulator charged with ensuring that pharmaceutical prices are not “excessive”.

Already responsible for multi-million dollar repayments, the Patented Medicine Prices Review Board (PMPRB) cannot be overlooked.

Cost-effectiveness assessments in Canada will be significantly enhanced by considering the pricing that is possible within the PMPRB rules.

The author Joan McCormick, MBA is a Principal, IMS Brogan, Canada.

JMccormick@ca.imsbrogan.com

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

ROLE OF REGULATORS IN CANADA | INSIGHTS

Modeling for success in Canada UNDERSTANDING THE ROLE OF THE PMPRB Cost-effectiveness modeling for a Canadian launch can be effective in having government payers reimburse a new drug product. However, regardless of the findings of a cost-effectiveness study, the product’s price must be compliant with the rules set out by the Patented Medicine Prices Review Board (PMPRB).

The Board interprets the definition of patent and medicine very broadly. Indeed, any patent pertaining to a product means it falls under PMPRB jurisdiction.

Companies should consider the implications of filing applications for patents that offer no intellectual property protection before filing in Canada.

The PMPRB is a federal regulatory agency, established in 1987, which reviews the prices of all patented drugs sold in Canada – including purchases by both the private and public sectors – to ensure they are not excessive.

Complying with PMPRB rules early in the development of health economics evidence is therefore of the utmost importance, particularly because cost-effectiveness results which are modeled into the future are heavily influenced by drug price.

The PMPRB is certainly a powerful force, yet companies have been successful in achieving reasonable prices and this regulatory hurdle need not dissuade a company from entering the market.

HIGH-PRICE COUNTRY At the time of the Board's creation, Canadian prices were well above the median international price, based on a comparison against the list of 7 countries (6 European countries and the U.S.) defined in the Patented Medicines Regulations, (the "Regulations"). From 1987 to 1998 Canadian prices declined to an average below the international median (Figure 1).

STRICT GUIDELINES BUT SUCCESS ACHIEVABLE The PMPRB has established a set of guidelines that allow for assessment of a range of potential pricing outcomes.These take into account the scientific evidence concerning the safety and efficacy of the new drug, the pricing of comparators, international prices (for 7 countries) and potential changes in the market ahead of first sales.

According to data from the PMPRB, Canada has now returned to being a high-priced country, on average falling behind only the U.S. and Germany (Figure 2).

Arguably, taking purchasing power into account, Canada may even surpass Germany.

FIGURE 1: CANADIAN PHARMACEUTICAL PRICES DECLINED TO AN AVERAGE BELOW THE INTERNATIONAL MEDIAN BETWEEN 1987-98 Source: PMPRB Annual Report, 2009

Average Ratio of Median International Price to Canadian Price of Patented Drug Products, 1987-2009 Ratio 1.2 1.0 0.8

0.81 0.85

0.94 0.93 0.89 0.88 0.90

1.01

1.08 1.11 1.12 1.14 1.12 1.09 1.05

1.01

1.05 1.10 1.09 1.02 0.98 0.97 0.98

0.6 0.4 0.2 0 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Year

AccessPoint - Issue 2

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INSIGHTS | ROLE OF REGULATORS IN CANADA ...continued from previous page

International pricing is one of the criteria used to restrict prices in Canada in a process that is designed to harmonize Canadian pricing into global standards. A rule introduced by the Board FIGURE 2: CANADA HAS RETURNED TO BEING A HIGH-PRICED COUNTRY Source: PMPRB Annual Report, 2009 Average Foreign-to-Canadian Bilateral Price Ratios at Market Exchange Rates,1998, 2003, 2009

1.60 1.75 1.71

2.0 1.8 1.6

1.00 1.00 1.00

1.09 1.01 1.08

1.08 0.94 0.93

1.07 1.07

France

0.90

Italy

1.18 1.11 0.98

0.8

0.92 0.84 0.84

1.2 1.0

1998 2003 2009

1.4

0.86 0.80 0.80

The expectation is that the PMPRB will effect change by reducing the complexity of some of the rules; decreasing the amount of enforcement activity but increasing the strictness of adherence to the rules that are still in place

Switzerland

Canada

Germany

0.6 0.4 0.2 0 UK

Sweden

US

Year

in 1994 stipulated that the Canadian price could not exceed the highest price of the product among the 7 countries listed in the Regulations. Furthermore, the international median price is used as a price test for the review of select new products as outlined below.

INTRODUCTORY PRICE TESTS For new chemical entities entering an established therapeutic class, and which do not offer moderate or substantial improvement, the price will be limited to that of the highest priced comparator in the class.This is known as the Therapeutic Class Comparison (TCC) test. For products where there are no therapeutic comparators, the rules permit the price to be as high as the international median.

Products offering a substantial improvement in therapy, for which the threshold is very high, will be permitted to price at the level of the higher of the international median or the TCC test. In 2010, a new category – moderate improvement – was introduced. In this case, relevant products are permitted to price at the level of the mid-point between the international median and the TCC - thus offering half of the premium which would be granted to a breakthrough medicine or one offering substantial improvement. This, of course, assumes that the median international price is, in fact, a premium price.

Where the median price is lower than the TCC, a drug offering moderate improvement is permitted to price at the level of the TCC, the same price as a medicine offering slight or no improvement.Table 1 summarizes the relationship between the level of therapeutic improvement and the introductory price tests applied.

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

ROLE OF REGULATORS IN CANADA | INSIGHTS

TABLE 1: RELATIONSHIP BETWEEN LEVEL OF THERAPEUTIC IMPROVEMENT AND INTRODUCTORY PRICE TESTS

Slight/No Price Test Improvement

Slight/No Improvement

Moderate Improvement

Substantial Improvement

HIGHER OF

HIGHER OF

Breakthrough

Slight/No Test 1 Improvement

Highest in Therapeutic Class

Highest in Therapeutic Class

Highest in Therapeutic Class

International Median

Slight/No Test 2 Improvement

N/A

Mid-point between therapeutic class and international median

International Median

N/A

Never higher than the highest international price Regardless of which test is used, no price in Canada can exceed the highest international price (i.e., the highest price among the 7 countries monitored by the Board). If launch sequence or exchange rate fluctuation result in the Canadian price exceeding the highest international price, it will be required to roll back and a penalty may be imposed. However, the level of transparency provided by the PMPRB in publishing its rules has resulted in relatively limited enforcement interventions.

At the PMPRB the leadership influence stems from two sources: 1. Board Staff, led by an Executive Director, who conducts the day-to-day operation of the price review process.

2. Board, led by a Chair, who directs policy decisions and sit at hearings.

In August 2010, a new Executive Director, Michelle Boudreau, joined the Board staff, followed in March 2011 by the appointment of a new Chair of the Board, Mary A DEGREE OF FLEXIBILITY Catherine Lindberg, the former Vice-Chair since June The Board appears to recognize that strict 2006. Board members can be appointed for up to two interpretation of a regulatory framework does not 5-year terms. This means the new Chair will be eligible result in appropriate results in all cases. An example for renewal later in 2011, potentially serving on the of this is Faslodex (fulvestrant) for breast cancer. Board until 2016.

Under the PMPRB guidelines the price of this product would have been restricted to that of existing The expectation is that this new leadership team at the agents used in the same place in therapy - about one PMPRB will effect change by reducing the complexity third of the lowest price in any of the comparator of some of the rules; decreasing the amount of countries. In the event, the PMPRB took into account enforcement activity but increasing the strictness of the premium over Arimidex (anastrozole) afforded in adherence to the rules that are still in place. It remains to each of the comparator countries. The resulting be seen how this prediction bears out over the coming years.

Faslodex price was several times higher than the The PMPRB continues to play a substantive role in the guidelines had proposed but Canada in this case Canadian pharmaceutical landscape. Cost-effectiveness remained the lowest priced country at a discount of 15% modeling for this market is enhanced when the PMPRB below the lowest priced country in the basket. rules are layered into the analysis to understand The opportunity to resolve the Faslodex case outside the compliance status of prices being studied. • framework of the standard introductory review process is a reflection of the discretion allowed by leadership.

AccessPoint - Issue 2

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INSIGHTS | HEALTH ECONOMIC MODELING

Implementing value arguments in diverse markets requires flexibility to meet country needs within a global positioning and value strategy. Adapting economic models to local requirements is a key part of this process, providing critical support for product launch. Here we consider the issues involved and an approach to achieving best practice.

The authors Adam Lloyd, MPhil, BA is Global Leader Health Economic Modeling, and Senior Principal HEOR, IMS Consulting Group, U.K. ALloyd@uk.imshealth.com

Yumiko Asukai, MSC is an Engagement Manager HEOR, IMS Consulting Group, U.K. YAsukai@uk.imshealth.com

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HEALTH ECONOMIC MODELING | INSIGHTS

From global to local COUNTRY ADAPTATION OF ECONOMIC MODELS need to rapidly gain skills and understanding around the value of a new intervention. Coordination of value delivery allows the local markets to get to grips with and benefit from global strategic thinking.

2. Facilitate a coherent global strategy Market variations in comparators and treatments can give rise to tensions between individual country versus central priorities.The strategy must thus be sufficiently flexible to accommodate market needs, while allowing for consistency in the product value story across countries. Coordination between global and local functions allows the strategy to WHY THE NEED FOR ADAPTATION? be clearly communicated to the markets, and decisions Economic analysis is a component of market access in a about local variation in approach to be taken after growing number of countries. Crucially, however, the exact considering implications for other countries. requirements differ: analysis conducted in the U.K., for 3. Provide affiliate support with technical skills example, may not be relevant in France, Korea or elsewhere.

Not all country organizations who will use economic Prices, patient characteristics, treatment practices and information during a launch will have the relevant in-house methods of measuring value vary between countries or expertise to conduct or commission the necessary work. regions. That said, the core package of evidence supporting A harmonized approach allows central expertise to be made a product is usually the same across geographies, and the available to meet local needs. intent is a coherent international value strategy.The purpose of model adaptation is to balance the need for arguments WHAT COUNTRIES ARE TYPICALLY INVOLVED? that support local requirements against the needs of Based on our experience at IMS, while model companies to generate a consistent strategy. adaptations do take place in the Asia Pacific, Australia, Canada and the U.S., the majority are conducted in Model adaptation may meet several goals: Europe, with the Nordic and CEE countries well1. Transfer expertise from the center to the markets represented. Figure 1 shows the geographic spread of This is particularly important in the peri-launch period models adapted by IMS for eleven projects in four key when most knowledge about a new product lies within therapy areas. Requirements vary between molecules the central functions of a company, but when affiliates and companies.

Model adaptations refer to the process of taking a health economic model and amending or adapting the inputs in a way that enables their application to different settings.

Adaptations are characterized by: • A model that assesses or describes the impact of an intervention that needs to be applied to different settings • A set of common assumptions that are consistent across analyses • Some coordination of the applications between different settings

Countries Included

Therapy area

CV/metab Oncology CV/metab CV/metab Oncology Respiratory Respiratory CV/metab CV/metab Oncology Anti-infective

x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x

x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x

x x x x x x x x x x x x x x

x x x x x x x x x x x x x x

x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x

FIGURE 1: RECENT MODEL ADAPTATIONS ACROSS VARIOUS DISEASE AREAS COVERED A MAGNITUDE OF COUNTRIES, ALSO IN EMERGING MARKETS

AccessPoint - Issue 2

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INSIGHTS | HEALTH ECONOMIC MODELING ...continued from previous page

Model adaptations enable companies to leverage evidence smoothly into country settings in support of affiliate needs

ISSUES TO CONSIDER IN ADAPTATION PROJECTS 1. When do we start?

Model adaptations can start sooner (eg, 18 months pre-launch) or later (eg, 6 months pre-launch). Each timing has its own pros and cons as shown in Figure 2.

Advantages Early, say 18 months pre-launch

Later, say 6 months pre-launch

Disadvantages

• Early results input to global strategy

• Starting too soon limits affiliate ability to invest

• Data available to help affiliates plan local access

• Phase III results often surprise

• Can move data collection off critical path

• Need to update final deliverables before use

• Affiliates are engaged and resourced to participate

• Models get crowded out in the busy pre-launch period

• Lower risk of product failure

• We need to prioritize, usually putting countries into waves

• Much more focused projects

• Unexpected events can lead to e x t r e m e l y intense needs for manpower

FIGURE 2: WHEN DO WE START?

2. Who collects the local data?

Local data collection – evaluating prices, guidelines and treatment practice, and interviewing local clinicians – is a key part of model adaptation. Understanding where to source local expertise is important.

Again, there are important issues to consider: Organizing data collection centrally with a single core vendor can be expensive but ensures accountability; sub-contractors extend potential coverage but imply some loss of relationship control; and contracting data collection locally may be lower cost but could also result in variable quality (Figure 3).

Advantages Core vendor

Disadvantages

• Accountability

• Can be expensive

• Internalize admin costs

• Limited by coverage

• Extends our coverage Vendor sub-contracts • Can work with local experts

• When things go wrong lose control over relationship

Countries

• Apparently lower cost

• Quality variable

• User owns local data

• QC still needed so unexpected costs occur

FIGURE 3: WHO COLLECTS THE LOCAL DATA?

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

HEALTH ECONOMIC MODELING | INSIGHTS

3. Who pays for adaptations?

Model adaptations can be either funded centrally or by local country affiliates themselves. Central financing ensures core control of strategy but runs the risk of poor local buy-in.

Conversely, resourcing at the country level may ensure greater follow-through but has the potential for increased congestion and a higher administrative burden (Figure 4).

A rigorous focus on consistency, timing and data collection is pivotal to achieving best practice

2. Timing • A central model can be created before first Phase III Advantages Disadvantages data is available (>18 months before launch) to move • The budget is there • Risks lack of buy-in Centre this task off the critical path.

• Maintain control of strategy • Scope creep • A structured program of country adaptations that • We can start early • Blame transfer starts once Phase III data is known. Countries • We can prioritize appreciate early warning of likely value arguments to • Loss of control over strategy Countries • Local buy-in and allow planning of local activities. engagement • Local budget available later • A process should be in place to respond to late • Payer is the user • Congestion arriving trial data, unexpected events, and • More likely to follow through • Administrative burden competitor activities.

• Adequate resource from both vendor and client FIGURE 4: WHO PAYS FOR ADAPTATIONS? company is essential for timely delivery.

3. Local data collection BEST PRACTICE APPROACH • There are significant advantages to having model A rigorous focus on three key areas – consistency, timing, development and data collection run by the same and data collection – is pivotal to achieving best practice company: collecting data is quicker and more reliable in the adaptation of economic models. and, importantly, if problems do occur there is clear 1. Ensuring consistency between countries accountability for addressing them.

• Incorporating affiliate input into the design of central • Vendors will have to sub-contract in smaller markets. cost-effectiveness models from the start increases buyPriorities for a sub-contractor should be technical in and shares ownership of the final strategy. Affiliates experience rather than perceived influence. It is also can be approached selectively – not necessarily simply helpful to have clear ownership of the relationship choosing the largest countries – as an economical with the sub-contractor. way of gaining input from engaged individuals.

• Company data collection imposes additional • Central control of financial support for technical work requirements on the commissioning firm, to ensures adequate funding and strategic coherence and coordinate affiliate involvement to protect timelines, minimizes the administrative burden. Countries and to QC data that is delivered. can be cross-charged if buy-in to the project or EFFECTIVE APPLICATION OF EVIDENCE deliverables is doubtful.

Model adaptations enable companies to leverage • Adaptation plans can include a set of core analyses that evidence smoothly into country settings in support support a clearly articulated global positioning, but of affiliate needs. Done well, based on good also a fall-back strategy for exceptions/challenges. communication, flexibility and adequate time and • Clear channels of communication within the client resource, they can ensure better consistency with global company are needed to resolve issues and to allow the strategy and smoother delivery of critical value messages strategy to adapt as market feedback solidifies. This to relevant local audiences. • requires a strong central project manager with time available to support the adaptation.

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INSIGHTS | MEDICATION ADHERENCE

It is well known that many patients fail to take their medication doses while some never even fill their prescriptions. All stakeholders can agree on the importance of addressing this critical issue. Progress has been slow, but advances are being made, as Jonothan Tierce explains.

The author Jonothan Tierce, CPHIL is a Senior Scientific Consultant to IMS in the U.S. JTierce@us.imshealth.com

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MEDICATION ADHERENCE | INSIGHTS

Getting to grips with medication adherence A DECADE OF RESEARCH INSIGHTS

Over the last few years, a significant body of research has been created – much of it using IMS or other administrative data – to understand the parameters of medication non-adherence, determine some of its causes and point the way to improvements. Taken together, this decade-long effort – involving many well-known clinical and health services research experts and many types of health informatics resources – begins to paint a corner of the vast adherence landscape.

Here we consider the progress that has been made and the insights that can be drawn from the findings published in four key areas of adherence research: 1. Adherence research methods 2. Patterns and predictors of poor adherence 3. Impact of non-adherence

and persistence with medications across 6 chronic medication areas, with rates continuing to decline over the two-year study period – findings which offer a useful baseline for the development of initiatives to improve the quality of drug therapy management2.

Insights from many of these studies involve cardiovascular (CV) agents, particularly longer-term use of antihypertensive agents and statins – both important targets for their poor rates of adherence. Adherence with CV medications has wide applicability to other treatment areas that share some or all of these characteristics: chronic daily treatment; therapy for life, often consisting of multiple pills; symptoms that are undetectable by the patient; some level of side effects; and a range of patient factors.

Among the key insights from a decade of CV adherence research are:

4. Adherence improvement

1. Adherence with CV medications is remarkably low using the newer approach ADHERENCE RESEARCH METHODS In an early study by Benner, persistence with statin Research by Benner in the early 2000s provided an therapy was shown in an elderly (65+) population of improved “repeated measures” methodology for patients to decline substantially over time, with the understanding patterns and predictors of adherence in greatest drop occurring in the first six months of administrative databases. In part the basis for overcoming treatment. Despite slightly better persistence among some of the limitations of research relying on patient selfpatients who began treatment in recent years, longreported adherence, this new approach has impacted our term use overall remained low.The mean Proportion ability to use and interpret adherence study results and of Days Covered (PDC) was 79% in the first three has since been employed by other researchers. months of treatment, 56% in the second quarter, and 42% after 12 months. Only one patient in four Subsequent insights from Wang, Benner and colleagues1 maintained a PDC of at least 80% after five years3. showing that patients “markedly overstated” adherence, led to the use of other approaches to understanding this 2. Adherence is a particular problem in people issue, and, somewhat later, improvements in the methods with dual CV disease for querying patients about their medication-taking In a large retrospective study of patients in a U.S. behaviors. These involved correlating questions about managed care plan, Chapman and colleagues showed health knowledge, attitudes and behaviors with that adherence with concomitant antihypertensive prescription or other medical claims data, and and lipid-lowering therapy is poor: only one in three drug-cap devices to measure the time and frequency of patients is adherent with both medications at six pill-bottle openings. months4. In a further analysis of the same population, the authors demonstrated that adherence to PATTERNS AND PREDICTORS OF POOR ADHERENCE concomitant antihypertensive and lipid-lowering Researchers have conducted numerous so-called therapy among older adults is poor. Modifiable factors “patterns and predictors” studies across many therapeutic that may improve this in Medicare-eligible patients areas. One recent analysis of a managed care health plan include initiating therapy concurrently and reducing found differential, but uniformly suboptimal, adherence overall pill burden5.

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INSIGHTS | MEDICATION ADHERENCE ...continued from previous page 3. The greater the pill burden, the greater the risk of non-adherence Among patients in a large managed care database taking antihypertensive and lipid-lowering medications, “adherence to those regimens became less likely as the number of prescription medications increased.The reduction in adherence with additional prescription medications was greatest in patients with the fewest pre-existing prescriptions”6.

4. Early adherence behavior with CV medications leads to long-term adherence In a recent study of Medi-Cal patients, those either fully adherent or non-adherent with both lipid-lowering and antihypertensive drugs at baseline were more likely to maintain their adherence status. Race, insurance coverage and type of lipid-lowering medication were significantly associated with transitioning from any adherence status to non-adherence7.

5. Physician interaction early in treatment is key to down-stream adherence In a unique study of a health plan claims database, the authors found that early and frequent follow-up by physicians, especially lipid testing, was associated with improved adherence to lipid-lowering therapy. They hypothesized that the role of the physician in reinforcing the need for, and value of, the treatment was a key factor in this association, although further testing would be needed to determine if this was causative8.

6. Early success with statin therapy is associated with greater adherence The authors of this study of the short-term effectiveness of statins and long-term adherence to lipid-lowering therapy found that patients who had early treatment success (in terms of lowered cholesterol) were more likely to be adherent to treatment9.

7. Therapeutic substitution of statins is more likely to destabilize therapy than generic substitution In a large study of CV patients in over 90 health plans using the health plan data, therapeutic substitution

The best results were seen from adherence programs involving medical professional-to-patient contact on a regular basis Page 28

was more likely to involve a subsequent disruption to statin therapy than generic substitution. The authors conclude that “therapeutic substitution could potentially lead to adverse impacts on patients' outcomes, and should be studied further”10.

8. Single-pill combinations lead to better adherence than 2-pill regimens Using the health plan data in a propensity-matched cohort of patients prescribed amlodipine who switched to amlodipine/atorvastatin or added a statin to their amlodipine regimen, the authors found that hypertensive patients who initiated statin therapy via a single-pill (amlodipine/atorvastatin) were more likely to remain adherent to their statin than patients adding a separate statin to their antihypertensive regimen11. Similarly, a large retrospective study using the health plan data confirms previous observations that a single-pill CV treatment regimen can help improve adherence versus two-pill regimens. The authors noted, however, that “greater improvements in adherence are likely to be observed in patients with prior experience of either calcium channel blocker or statin therapy than in those either naive to, or experienced with, both therapies”12.

IMPACT OF NON-ADHERENCE Studies evaluating the clinical and/or economic impact of non-adherence have also focused primarily on patients with CV disease. Among noteworthy insights are findings to suggest that in the specified population: 1. The costs of improving adherence are justified In a study using the 1999-2002 National Health and Nutrition Examination Survey, the authors estimated 15.2 million cases of uncontrolled hypertension, of which 84.8% had low/moderate cholesterol levels and 16.7% had >/=3 additional risk factors with no history of CHD. On that basis, nearly 200,000 coronary events are expected to occur within four years, generating more than $2.5 billion in direct medical costs. It was further estimated that 64% of 4-year risk was attributable to uncontrolled blood pressure and lipids13. The adverse outcomes and high costs associated with uncontrolled CV disease would thus appear to justify the costs of improving adherence with lipid-lowering and antihypertensive medications.

2. Statins may be clinically valuable in the presence of other CHD risk factors Using the health plan data, a study of patients beginning antihypertensive treatment found that those with established CHD or CHD risk factors IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

MEDICATION ADHERENCE | INSIGHTS

were more likely to receive statins. However, a substantial fraction did not fill any statin prescription, suggesting a treatment gap and excess, modifiable CV risk. The authors concluded that “the increased use of statin therapy could benefit many hypertensive patients with additional CHD risk factors”14.

3. Non-adherence reduces clinical trial benefit by 50% Applying an innovative modeling technique, this study simulated patient characteristics, matched those of participants in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Lipid-Lowering Arm, and calculated event probabilities with Framingham Heart Study risk equations. The authors estimated that patients taking antihypertensive and statin therapy at real-world adherence levels would receive approximately 50% of the potential benefit seen in clinical trials. This adds to the body of evidence suggesting that adherence-improving programs may well be cost justified as well as clinically necessary15.

We can see that the frontier of research in this area lies in a deeper understanding of the multiple factors that impact adherence • Typically, the higher-cost adherence-improving interventions, the ones that involve frequent contact with medical professionals, were the most effective17.

• Lower-cost interventions, such as reminders and educational materials, and a pharmacist/nurse management program, can provide some benefit and may be cost-effective as a first attempt to improve adherence18.

Adherence research in a number of specific disease areas found potential value in interventions that focused on the role of the physician, patient behavior modification, pill size, and a nurse-based management program:

ADHERENCE IMPROVEMENT Researchers have also been striving to understand what can be done to improve medication adherence. The results of a 30-year literature review (1972-2002) • Cardiovascular: A physician-implemented CHD risk conducted by IMS researchers show that relatively few evaluation/communication program was able to interventions designed to improve compliance with improve patients' modifiable risk factor profile and antihypertensive or lipid-lowering medications have been lower predicted CHD risk compared with usual care. studied in a scientifically meaningful way: only 62 studies By combining this strategy with more intensive describing 79 interventions were identified. Overall, 56% treatment to reduce residual modifiable risk, the of interventions were reported to improve patient authors suggest that substantial improvement in compliance.When only those studies meeting minimum CV disease prevention could be achieved in criteria for methodological quality were considered, clinical practice19,20.

22 interventions remained and a scant 12 were • Overactive bladder: Patient support of medication recommended, because they demonstrated a significant adherence may be enhanced by simultaneously improvement in compliance. supporting the use of non-pharmaceutical lifestyle Best results involve regular medical contact modifications and behavioral interventions21.

The best results were seen from adherence programs • Valproate usage: Patients taking valproate would involving medical professional-to-patient contact on a prefer a formulation that is easier to swallow, even regular basis. Other approaches, such as medication if it needs to be taken twice per day. The authors reminders, only demonstrate modest benefits. Those conclude that physicians choosing between recommended include fixed-dose combination drugs; medications with similar efficacy and safety may once-daily or once-weekly dosing schedules; unit-dose consider patient preferences to optimize conditions packaging; educational counseling by telephone; case for medication adherence22. management by pharmacists; treatment in pharmacist- or nurse-operated disease management clinics; mailed refill • Hepatitis-C: A retrospective cohort analysis demonstrated that hepatitis-C patients in a reminders; self-monitoring; dose-tailoring; rewards; and telephone-based, nurse drug management program various combination strategies16. refilled significantly and progressively more injections Based on an updated literature search (up to 2007), two than did controls when measured at 12 weeks, follow-on analyses to determine what types of interventions 24 weeks and 48 weeks23. were the most effective and cost-effective found that: AccessPoint - Issue 2

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INSIGHTS | MEDICATION ADHERENCE ...continued from previous page NEXT FRONTIERS Research has generated many useful and actionable insights into adherence and persistence with medication and other treatment. Many of these efforts are still underway as other important clinical, behavioral and scientific issues continue to be discovered and addressed.

As we move into the second decade of the 21st century, and IMS and others continue to enhance their databases with clinical, patient preference and behavioral information, we can expect these studies to yield deeper and more useful results. But at the same time we can also see that the frontier of research in this area lies in a deeper understanding of the multiple factors that impact adherence: physician and other provider/patient interactions; patient (and perhaps caregiver) knowledge, attitudes and behaviors; and finally external factors (insurance coverage, patient finances, etc). •

1

Wang PS, Jenner JS, Glyn RJ, Winkelmayer WC, Mogun H, Avorn J. How well do patients report noncompliance with antihypertensive medications?

A comparison of self-report versus filled prescriptions. Pharmacoepidemiol Drug Saf, 2004; 13(1):11-9.

2

Yeaw J, Benner JS, Walt JG, Sian S, Smith DB. Comparing adherence and persistence across 6 chronic medication classes. J Manag Care Pharm, 2009; 15(9): 728-40.

3

Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long-term persistence in use of statin therapy in elderly patients. JAMA, 2002; 228:445-61.

4

Chapman RH, Benner JS, Petrilla AA, Tierce, JC, Collins R, Battleman DS, Sanford Schwartz J. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med, 2005;165(10):1147-1152.

5

Chapman RH, Petrilla AA, Benner JS, Schwartz JS, Tang SS. Predictors of adherence to concomitant antihypertensive and lipid-lowering medications in older adults: A retrospective cohort study. Drugs Aging, 2008;25(10): 885-92.

6

Benner JS, Chapman RH, Petrilla AA, Tang SS, Rosenberg N, Schwartz JS. Association between prescription burden and medication adherence in patients initiating antihypertensive and lipid-lowering therapy. Am J Health Syst Pharm, 2009; 66(16):1471-7.

7

Nichol MB, Knight TK, Wu J, Tang SS, Cherry SB, Benner JS, Hussein M. Transition probabilities and predictors of adherence in a California Medicaid population using antihypertensive and lipid-lowering medications.Value Health, 2009; 12(4):544-50.

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8

Benner JS, Tierce JC, Ballantyne CM, Prasad C, Bullano MF, Willey WJ, et al. Follow-up lipid tests and physician visits are associated with improved adherence to statin therapy. Pharmacoeconomics, 2004; 22 (Suppl 3): 13-23.

9

Benner JS, Pollack MF, Smith TW, Bullano MF, Willey VJ, Williams SA. Association between short-term effectiveness of statins and long-term adherence to lipid-lowering therapy. Am J Health Syst Pharm, 2005; 62: 1468-75.

10

Chapman RH, Benner JS, Girase P, Benigno M, Axelsen K, Liu LZ, Nichol MB. Generic and therapeutic statin switches and disruptions in therapy. Curr Med Res Opin, 2009; 25(5): 1247-60.

11

Chapman RH, Pelletier EM, Smith PJ, Roberts CS. Can adherence to antihypertensive therapy be used to promote adherence to statin therapy?

Patient Prefer Adherence, 2009; 3: 265-75.

12

Hussein MA, Chapman RH, Benner JS, Tang SS, Solomon HA, Joyce A, Foody JM. Does a single-pill antihypertensive/lipid-lowering regimen improve adherence in US Managed Care enrolees? A non-randomized, observational, retrospective study. Am J Cardiovasc Drugs, 2010; 10(3):193-202.

13

BennerJS, Smith TW, Petrilla AA, Klingman D, Goel S, Tang SS, Wong ND. Estimated prevalence of uncontrolled hypertension and multiple cardiovascular risk factors and their associated risk of coronary heart disease in the United States. J Am Soc Hypertens, 2008; 2(1):44-53.

14

Chapman RH, Petrilla AA, Berman L, Benner JS, Tang SS. Are high-risk hypertensive patients being prescribed concomitant statin therapy? A retrospective cohort study. Am J Cardiovasc Drugs, 2009; 9(5): 299-308.

15

Cherry SB, Benner JS, Hussein MA, Tang SS, Nichol MB. The clinical and economic burden of nonadherence with antihypertensive and lipidlowering therapy in hypertensive patients.Value Health, 2009; 12(4): 48997. Epub 2008, Sept 9.

16

Petrilla AA, Benner JS, Battleman DS, Tierce JC, Hazard EH. Evidencebased interventions to improve patient compliance with antihypertensive and lipid-lowering medications. Int J Clin Pract 2005; 59(12): 1441-1451.

17

Chapman RH, Ferrufino CP, Kowal SL, Classi P, Roberts CS. The cost and effectiveness of adherence-improving interventions for antihypertensive and lipid-lowering drugs. Int J Clin Pract, 2010; 64(2): 169-81.

18

Chapman RH, Kowal SL, Cherry SB, Ferrufino CP, Roberts CS, Chen L. The modeled lifetime cost-effectiveness of published adherenceimproving interventions for antihypertensive and lipid-lowering medications.Value Health, 2010; 13(6):685-94.

19

Benner JS, Cherry SB, Erhardt L, et al. Rationale, design and methods for the risk evaluation and communication health outcomes and utilization trial (Reach out). Contemp Clin Trials, 2007;28(5): 662-73. Epub 2007 Mar 15.

20

Benner JS, Erhardt L, Flammer M, et al. Reach out investigators. A novel programme to evaluate and communicate 10-year risk of CHD reduces predicted risk and improves patients’ modifiable risk factor profile. Int J Clin Pract, 2008; 62(10): 1484-98. Epub 2008, Aug 7.

21

Schabert VF, Bavendam T, Goldberg EL, Trocio JN, Brubaker L. Challenges for managing overactive bladder and guidance for patient support. Am J Manag Care, 2009; 15 (4 Suppl): S118-22.

22

Bhosle M, Benner JS, Dekoven M, Shelton J. Difficult to swallow: Patient preferences for alternative valproate pharmaceutical formulations. Patient Prefer Adherence, 2009; 3:161-71.

23

Hussein M, Benner JS, Lee D, Sesti AM, Battleman DS, Brock-wood C. Propensity score matching in the evaluation of drug therapy management programs: An illustrative analysis of a program for patients with hepatitis C virus. Qual Manag Health Care, 2010; 19(1): 25-33.

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

PATIENT-REPORTED OUTCOMES | INSIGHTS

Putting the P into Outcomes Research Growing emphasis on real-world data as a key element of treatment comparisons and decision making has opened up new opportunities for outcomes research, including the ability to incorporate relevant patient-reported measures. As the patient perspective becomes increasingly important, we consider a framework for its effective capture within the broader context of outcomes research.

The authors Xavier Badia, MD, MPH, PHD is Global Leader Observational Outcomes Research, and Senior Principal HEOR, IMS Consulting Group, Spain.

XBadia@es.imshealth.com

Christina Donatti, BSC, MSC, CLIN PSYD is a Senior Consultant HEOR, IMS Consulting Group, U.K. CDonatti@uk.imshealth.com

Charles Makin BSPharm, MS, MBA, MM is a Principal HEOR, IMS Consulting Group, U.S. CMakin@us.imshealth.com

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Putting the P into Outcomes Research THE INCREASING RELEVANCE OF PROs

Outcomes Research (OR) is a commonly-used term and WHAT PROs ARE OF GREATEST INTEREST TO KEY longstanding concept which focuses on improving the STAKEHOLDERS? practice of medicine as applied to patients treated outside a • Regulatory: From a regulatory perspective, the clinical trial1.The key feature that sets it apart from clinical FDA requests PRO data to be collected within a research is the emphasis on effectiveness rather than efficacy, clinical trial program – but with a focus primarily reflecting the attempt of outcomes researchers to identify on symptom-based PRO labelling claims2. The the effect of an intervention as applied to a broad European Medicines Agency (EMA) provides broad population which most reflects the ‘real world’. recommendations on the use of PROs along with a The three main areas of OR are clinical, economic and Biomarker’s Qualification program to provide a formal patient-reported, which together provide evidence for mechanism for ratifying clinical trial endpoints, comparative effectiveness and economic evaluation: including new and existing PROs3.

1. Clinical: Most of the data from Phase III trials is • HTA/Reimbursement Authorities: Health clinical in focus (eg, blood pressure, symptom relief, Technology Assessment (HTA) and reimbursement overall survival). authorities broadly recommend quality of life measurement as part of their evaluations (eg, NICE, 2. Economic: Economic outcomes focus on PBAC, PMPRB). And, while the U.S. does not have a medical and non-medical resource utilization and formal HTA agency, there has been growing interest associated costs. in comparative effectiveness research4.

3. Patient-reported outcomes (PROs): PROs report • Clinical: PROs can be used to better understand the on a health condition and the benefits of treatment disease experience from a patient’s perspective, on a patient’s health-related quality of life (HRQoL), including satisfaction with treatment. In addition to symptoms, treatment satisfaction, medication providing a framework for assessing interventions from adherence and functional status, as reported by a clinical point of view, a patient perspective is essential the patient. to understanding how a treatment affects quality of life Thus OR essentially describes, interprets, and predicts in a broader context, beyond the obvious impairments the impact of various influences, especially interventions, and activity limitations assessed by HRQoL. on final endpoints – ranging from survival to satisfaction Despite the fact that the FDA currently focuses on with care – which matter to decision makers, including demonstrating symptom improvement, ultimately this patients and society at large. will not be sufficient as patient views become incorporated into pricing models of healthcare.

GROWING AUDIENCE FOR PROs Moreover, while the use of generic scales such as the EQ PROs have developed out of a growing trend to 5D or SF 36 provides a broad picture of a patient’s demonstrate the effectiveness of health care interventions; perception of their quality of life, it does not afford policy makers, health technology assessment (HTA) sufficient information on their perception of the direct authorities, physicians and patients all play a part in impact of the specific health condition or the treatment. determining both the availability and pricing of Issues such as disease-specific impact on productivity loss, medicinal products. This increasing number of stakeholders has resulted in a broad audience with an caregiver burden and broader quality of life dimensions, will be crucial in identifying the competitive advantage interest in PROs today. that lies with PRO outcomes and in communicating PRO value propositions.

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PATIENT-REPORTED OUTCOMES | INSIGHTS

REAL-WORLD EFFECTIVENESS The key to OR is to demonstrate in the real world (as opposed to a clinical trial) that a product or device has a benefit to the patient above and beyond effectiveness in a controlled setting.

It addresses such important issues as whether an intervention improves adherence and therefore outcomes (eg, mortality, remission or cure), whether it increases patient satisfaction (eg, by reducing side effects), or whether it leads to an improvement in HRQoL. Unless an intervention is completely ‘novel’ the ability to prove a statistically significant improvement in effectiveness over existing treatments is challenging. In which case, how do you differentiate your intervention from your competitor? By using real-world evidence/outcomes research to demonstrate significant, real-world benefits to patients, clinicians, payers and other stakeholders.

More and more, manufacturers and stakeholders are required to show that their intervention works in the real world and has a patient benefit. Data is collected in actual practice (rather than in theory or an artificially-imposed environment) for many purposes and applied to prove or disprove a hypothesis.

PATIENT-REPORTED OUTCOMES It is important to remember that the umbrella term of “patientreported outcomes” (PROs) includes functional status, quality of life (QoL) and health-related quality of life (HRQoL). It covers all health data reported by the patient and can include more than just the effects of health on wellbeing (Figure 1). For the measure of QoL to be related to health, there is a need to focus more specifically on health-related quality of life (HRQoL), which is health-related, subjective, self-assessed (or caregiver/parentreported) and multi-dimensional. The PRO definition enables a broad measure of patient perception at different points of both the disease and treatment burden spectrum.

Preference to treatment

Burden of symptoms – eg pain

Treatment or health service satisfaction

HRQoL

Adherence to treatment

More and more, manufacturers and stakeholders are required to show that their intervention works in the real world and has a patient benefit

FIGURE 1: PROs COVER ALL PATIENT-REPORTED HEALTH DATA

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INSIGHTS | PATIENT-REPORTED OUTCOMES ...continued from previous page

FIGURE 2: A FRAMEWORK FOR CAPTURING EXPLICIT PATIENT-REPORTED OUTCOMES

PRO Framework Symptoms

Functioning

Participation

HRQoL (Health status)

Needs-based QoL

Constructs assessed

Impairments

Activity limitations

Participation restrictions

Impairment, disability & some QoL

Needs-based QoL

Determines impact primarily from...

Clinical perspective

Clinical/social perspective

Social perspective

Clinical/social perspective

Patient perspective

Type of PRO measure

Patient perspective Clinical perspective

PRO framework • Assessing the reliability, validity and ability of the PRO The PRO questionnaire should be designed to inform questionnaire to detect changes on explicit patient-reported concepts such as HRQoL, • Modifying the questionnaire where necessary to symptoms or functional status, as well as meet key quality ensure that it targets the right patient concept in a standards (Figure 2). particular health condition.

PROs, if designed well and in accordance with standard It is clear from the EMA and FDA that patient perception practice will for the most part, ‘behave’ quite logically. In of treatment and outcome is a key focus – a perspective other words, patients or groups with better health will best measured by using PROs5. With the right skills, tend to have higher mean scores. A good instrument expertise and analytical support, patient perception of a registers increases in mean scores for patients and groups treatment (or procedure) on a disease can be gathered: with truly improved health. However, as always, the quality of the results from the analysis of PRO • At the start of the clinical pathway: For example, to determine the ability of pre-treatment PRO scores instruments can only be as good as the quality of the data to predict overall survival and, to some extent, the that is collected. response of a patient's cancer to treatment6,7.

To this end, it is essential to ensure that the choice and development of a PRO to measure a patient-reported concept is completed to the highest scientific standards.

As part of a detailed, systematic process (Figure 3), this involves: • Identifying the concepts and developing the conceptual framework that are required to select the patient group • Creating a PRO questionnaire, generating items, choosing the method of administration (paper or electronic) and piloting the draft instrument Page 34

Essentially, the use of PROs is intended to understand which medication or treatment pathway works better from a humanistic perspective

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

PATIENT-REPORTED OUTCOMES | INSIGHTS

Conceptual framework

Literature review

These two steps define the contents of the tool.

Generate items: Physicians and patients in-depth interviews

Create instrument Qualitative analysis

Through in-depth interviews with experts and patients and the subsequent qualitative analysis, tool items are determined.

Pilot study (small sample size)

Preliminary measurement properties

The objective of the pilot study is to identify and exclude those items ‘not applicable’ to the target population (rasch analysis) and to assess the questionnaire’s preliminary measurement properties (reliability and validity) before its administration to a higher sample of patients.

FIGURE 3: A SYSTEMATIC PROCESS FOR PRO CREATION AND DEVELOPMENT

• Through to Phase II and III: Changes in PROs during treatment may presage disease recurrence or failure to respond to treatment. In one particular cancer study where patients were receiving adjuvant chemotherapy for breast cancer, changes in physical wellbeing and nausea/vomiting significantly predicted recurrence8.

• Post-submission: For example, to determine longterm adverse events and fulfil other post-marketing study requirements.

ENABLING CHOICE OF EFFICIENT TREATMENT Essentially, the use of PROs is intended to understand which medication or treatment pathway works better from a humanistic perspective, thus enabling selection of the most efficient and “high-value” or “high net-benefit” treatments. PROs can assist in persuading clinicians, payers, sponsors and other stakeholders that a switch should be made from treatment A to treatment B. This requires an a priori hypothesis and a methodology that can determine the clinically important difference between these two treatments. Thus, going back to the beginning, this ‘real-world’ evidence calls for consideration of the effects of treatment on HRQoL in very specific and measurable terms. •

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1

Lee S, Earle C, Weeks J. Outcomes Research in Oncology: History, Conceptual Framework and Trends in the Literature. Natl Cancer Inst., 2000; 92:195-204.

2 Caron M, Emery MP, Marquis P, Piault E, Scott J: Recent trends in the inclusion of patient-reported outcomes (PRO) data in approved drugs labelling by the FDA and EMA. Patient Reported Outcomes Newsletter, 2008; 40:8-10.

3 EMA (Committee for Medicinal Products for Human Use (CHMP)): Reflection paper on regulatory guidance for the use of Health Related Quality of Life (HRQL) measures in the evaluation of medicinal products.

2005. Doc. Ref. EMA/CHMP/EWP/139391/2004. London & EMA (Consultation committee for medicinal products for human use (CHMP)): Draft biomarkers Qualification: Guidance to applicants. 2008. Doc. Ref. EMA/CHMP/SAWP/72894/2008. London.

4 Brixner D: Comparative Effectiveness: What Are We Comparing? http://www.ispor.org/News/articles/Mar08/president.asp] ISPOR Connections 2008. Accessed 8th April, 2011.

5 FDA Definition: “A PRO is any report of the status of a patient’s 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 (…)” http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryIn formation/Guidances/UCM193282 EMEA Definition: “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)”. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_gui deline/2009/09/WC500003637.pdf 6 Montazeri, A. (2009) Quality of life data as prognostic indicators of survival in cancer patients: an overview of the literature from 1982 to 2008. Health Qual Life Outcomes 7: 102.

7 Gotay, C.C., Kawamoto, C.T., Bottomley, A. and Efficace, F. (2008) The prognostic significance of patient-reported outcomes in cancer clinical trials. J Clin Oncol 26: 1355–1363.

8 Kenne Sarenmalm, E., Odén, A., Ohlén, J., Gaston-Johansson, F. and Holmberg, S.B. (2009) Changes in health-related quality of life may predict recurrent breast cancer. Eur J Oncol Nurs 13: 323–329.

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INSIGHTS | IMS SYMPOSIUM

An IMS Symposium at the 13th Annual European Congress of ISPOR considered the growing use of observational studies and their challenges in design, execution and appropriate use by decision makers. With all signs pointing to an even greater role for observational research in future, these are increasingly important issues.

The authors Jorge Arellano, MSC, MPHIL is Director IHE, Evidence Generation, Amgen UK. jorge.arellano@amgen.com

Jonothan Tierce, CPHIL is a Senior Scientific Consultant to IMS in the U.S. JTierce@us.imshealth.com

Jacco Keja, PhD is Regional Leader EMEA HEOR, IMS Consulting Group.

JKeja@nl.imshealth.com

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

IMS SYMPOSIUM | INSIGHTS

Addressing the challenges of real-world observational studies The growing global need for more useable information comparing the relative clinical and economic value of medical technologies and treatment approaches has seen a corresponding rise in the number of observational studies (OS) attempting to meet this demand. With their greater focus on functional outcomes (patient-reported, resource use and costs) and on following rather than driving medical practice, observational studies provide a key link between clinical trials, where there is strong internal validity, and the “real-world” use of a medical technology, where the goal is to provide external validation among other available products, treatment programs and diagnostic approaches.

pharmacoepidemiology groups.There are many different owners in RWE generation, with different SOPs, different standards, different backgrounds and also different power within the organization. This is a complex field with numerous interpretations of RWE and its associated stakeholders.

In moving towards a better understanding of the issues involved in developing RWE, the results of some recent primary research to explore the need for observational research (OR) and obstacles hindering its development, are enlightening. The survey among pharmaceutical companies, government and academic institutions, CROs Increasingly aggressive post-marketing surveillance, the and consultancies in Europe yielded feedback from more continued importance of value messages and growth of than 80 respondents, most from within the industry, and mandatory risk-management programs are likely to witness offers several key insights into perceptions of OS, relevant an even greater role for observational research in future. guidelines, and the need for improved harmonized/ However, these studies present their own rigor and international guidance: challenges that are different from traditional clinical trials, • Late-stage focus: Typically, among individuals who with emphasis on providing evidence of value to a broad were heavily involved with RWE and OR, this was for range of decision makers - who themselves may not be planning development purposes, and late-stage for familiar with interpreting and incorporating this kind of assessment, review and execution of studies. At the data into their decision making. same time, most RWE was generated not for market Understanding the issues involved in designing, executing, segmentation studies or for identifying the ideal and delivering so-called “real-world” observational studies patient population but rather to fulfill post-launch is essential to having them appropriately interpreted and obligations: collecting effectiveness data, meeting P&R utilized for healthcare decision making. Key among these commitments, and also to some extent addressing the are the internal organizational hurdles to generating lack of safety data. Thus, it is very much weighted real-world evidence (RWE) and the practical challenges towards late and post-launch development. facing health economists in this environment.

• Internal hurdles: Among the main hurdles encountered with OS are the lack of regulatory CHALLENGES FROM AN ORGANIZATIONAL PERSPECTIVE guidance and, more particularly, the lack of dedicated Pharmaceutical manufacturers in today’s healthcare SOPs for this type of research. Even more of an issue, sector face a new and increasingly important imperative reflecting some uncertainty in pharma around the in the development of medical technologies – the need ROI from observational studies, is the ability to sell to provide evidence of product value in the real-world, this type of work internally and the consequent clinical setting. This key shift in focus to external validity constraints on budgets. This is quite a surprising not only adds to the existing complexities of bringing a finding given that most of these studies are for postdrug to market, but also has significant implications for launch commitments and failing to complete them internal organizational processes. will likely impact P&R status. They are a given, yet Generating RWE is a growing core competence for apparently difficult to justify. pharma but determining who owns which part of the • Low awareness: Lack of internal recognition around process is no easy task. A typical transactional study, for the value of RWE and OS appears to be creating example, will often be undertaken by market researchers; frustration and sometimes skepticism among those safety assessments and long-term follow-up studies, working in this area. on the other hand, are usually conducted by AccessPoint - Issue 2

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INSIGHTS | IMS SYMPOSIUM ...continued from previous page

RESEARCH • Describe epidemiology of disease • Quantify unmet medical need • Assist in assessment of new indications • Genetic research

DEVELOPMENT • Refine understanding of disease epidemiology • Supply data for economic modeling • Assess co-morbidities and potential safety issues • Inform clinical trial protocol design • Contribute to risk management planning

POST-REGISTRATION • Provide input to reimbursement/formulary submissions • Evaluate compliance • Support pharmacovigilance • Conduct pharmacoepidemiology studies • Supply real-world data on cost and resource utilization

Source: Adapted, ABPI

FIGURE 1: OBSERVATIONAL DATA HAS RECOGNIZED POTENTIAL ACROSS THE ENTIRE PRODUCT LIFECYCLE

• Poor knowledge of guidelines: Awareness of existing guidelines on conducting OS, such as those published by the AHRQ (Registries for Evaluating Patient Outcomes: A User’s Guide, 2007), STROBE (Strengthening the Reporting of Observational Studies in Epidemiology; Explanation and Elaboration, 2007) and IEGES (International Ethical Guidelines for Epidemiological Studies, 2008) appears to be low – even for individuals involved in this work.

• Need for guideline consistency: Perceived inconsistency in the use of guidelines by stakeholders further underscores the importance of harmonization at the international level and the need for education around these guidelines and their role in facilitating the generation of RWE. Content improvements would be welcomed, with particular emphasis on the need for more detail in pricing guidelines – in terms of statistics, analysis, and more particularly, design. In some ways, this is analogous to the situation with PROs about 10 years ago: despite a good deal of scientific effort, many pharmaceutical companies struggled with implementing PROs in the clinical trial setting and following through with approval from regulatory bodies.

What is clear from these findings that some companies are more advanced than others in generating RWE, but in all cases there is a shortfall in recognizing the need to start early. OS have a key role to play in this area and companies should be looking to invest more in their use.

Knowledge of current guidelines is limited and in the absence of an established gold standard, there remains a strong need for harmonized guidelines with particular emphasis on standardizing statistical confounders, analysis and methodology.

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CHALLENGES FROM THE HEALTH ECONOMIST PERSPECTIVE In the past, a very few OS were conducted within the context of pharmaceutical R&D. Those that were undertaken focused primarily on disease epidemiology, generally during drug development or occasionally, early post-registration. More recently, however, with new hurdles, new challenges and more intense competition, companies have come to recognize the potential of observational data across the entire product lifecycle (Figure 1).

Today, OS have increasing validity across a range of scientific issues associated with product use in nonexperimental circumstances. Most of the new applications relate to health economics, such as quantifying unmet medical need, providing input for economic models, and evaluating compliance - not only with medication, but also with the growing number of treatment guidelines that are now being developed in many therapy areas.

The result is something of an explosion in the topics, objectives and applications of OS in recent years. A topline literature search provides some indication of just how extensive this growth has been since the 1990s, particularly in the wake of key events such as the

In many cases, people are simply used to doing things a certain way within the context of clinical trials and the confines of their own role and personal experience IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

IMS SYMPOSIUM | INSIGHTS

establishment of NICE in England and Wales and IQWiG in Germany, for example.The ISPOR task force has also confirmed that payers and decision-makers alike are requesting more and more observational data.

For every post-authorization product entering the pricing and market access process, it is the task of the health economist to generate evidence of its value in the real-world, clinical setting. Not in isolation, but by working closely with the research group, medical team, biostatistics, data management, study management, possibly an epidemiologist, and other operational units – all of whom have a great deal of expertise but, in most cases, minimal-to-no experience of observational research. For the health economist, this can often mean that efforts to bridge the scientific/real-world divide trigger questions and challenges across a number of areas.

Among the most typically encountered are: 1. Questions regarding the need for RWE • Why do we need to replicate what we saw in better designed RCTs? • What is the validity and credibility of these studies?

• Who requested this data? By when?

• Which countries need this type of evidence?

Will it impact our P&MA? 2. Questions regarding how to generate RWE • Prospective versus retrospective • All comers (comparative?) versus single-arm • Sample size • What to collect? PROs - is this an intervention?

We did it in our RCTs! • Recruitment of patients: feasibility & confounding by indication • Informed consent & selection bias 3. Practical challenges • How to follow patients between different levels of care?

• Standard dataset structures are designed for RCTs 4. Challenges for the analysis • Analysis too flexible for the analyst liking • Methods are unusual • Dissatisfaction & distancing by some functions /individuals

The key is to help every function appreciate that the need for RWE is now a given for every product ADDRESSING THE ISSUES Some of these challenges are extreme examples, and not all of them will apply in every situation, but they do underscore the need for a lot of internal work. In many cases, people are simply used to doing things a certain way within the context of clinical trials and the confines of their own role and personal experience. The key to addressing and forestalling their concerns over the use of real-world data is inclusion: helping every function to fully appreciate that in the current environment, with so many payers, HTAs, and new decision makers at the national and regional level, the need for RWE is now a given for every product and they must be a part of the process.

Internally, communication is key.This implies an element of training and motivating, explaining to the different functions about what can be done and why it is needed, and sharing respected medical publications on observational research, so that rather than feeling led down a strange route, they understand the need for RWE, realize it is here to stay and even accept it as a potential opportunity for their careers. Crucially, the health economist should not be seen internally as a second-class citizen: RWE needs solid investment and clear ownership in every organization.

Externally, there is a need for more standards, more clarity and a structural framework for establishing appropriate practice in RWE generation, to set the benchmark for good OS design and good analysis. There needs to be more effort in establishing standards in collaboration with the industry, with a means of making sure they are enforced. Fundamentally, this is about attitudinal change and working together with well-developed, scientific guidelines. ISPOR members and health economics and outcomes researchers have a key role to play in helping to achieve this goal. •

5. Challenges for the findings • What if unexpected safety signals are found?

• Asymmetries in reporting AEs of new versus existing therapies due to familiarity • Are the results “representative” of each country?

• What can actually be said?

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PROJECT FOCUS | ACUTE RESPIRATORY FAILURE Rigorous, complementary modeling techniques support new innovations with informed insights into multiple dimensions of their real-world clinical, cost and economic implications The Authors: Karl–Johan Myrén, MSC is a Principal HEOR, IMS Consulting Group, Sweden.

KMyren@se.imshealth.com Jonas Hjelmgren, MSC is a Senior Consultant HEOR, IMS Consulting Group, Sweden.

JHjelmgren@se.imshealth.com

Demonstrating cost-effectiveness and budget impact in acute respiratory failure Innovative treatments and breakthrough technologies continue to open up new possibilities for advancing patient care, but often at a cost that has challenging implications for health policies, budgets and payers.

Facilitating the ability of healthcare stakeholders to understand the true value of a new intervention from a clinical, patient and financial perspective is increasingly relevant to ensuring its optimal utilization. Rigorous cost-effectiveness and budget impact analyses can play a key role in informing this process, with their powerful and complementary insights into the cost, outcomes and potential system savings arising from new innovations. This is particularly true in areas that are resource-intensive, such as critical care, where the introduction of a new technology can significantly increase an already high economic burden.

COUNTERING PAYER RESISTANCE Facing just this situation, a leading provider of medical products for use in intensive care units (ICUs) needed to understand the health economics evidence for its new device in acute respiratory failure (ARF) – a condition typically requiring mechanical ventilation in patients admitted to ICUs. The technology’s unique approach, based on monitoring diaphragm activity, resulted in an improved patient breathing pattern compared to alternative techniques. This paved the way for IMS Consulting to demonstrate a reduction in the required length of stay in intensive care.

Despite its acknowledged benefits, the device had met with some resistance from hospital payers and reimbursement bodies in the U.S. and several European countries. By engaging with the Nordic HEOR team in the IMS Consulting Group, the company found a partner with the skills and experience in developing evidencebased health economic models, combined with powerful analytics and the local market knowledge to understand and place the results in context.

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

ACUTE RESPIRATORY FAILURE | PROJECT FOCUS

SYSTEMATIC PROCESS DELIVERS COMPREHENSIVE EVIDENCE

NEW PRICE POTENTIAL – AND COST SAVINGS

The IMS HEOR experts began by conducting an extensive and systematic review of available clinical data on the device.

Studies deemed to be of sufficiently high-evidence value – primarily RCTs and meta-analyses – were identified for inclusion. They next reviewed and summarized the health economic evidence for mechanical ventilation, together with relevant cost information for the ICU setting.

The findings of the analysis provided the company with key insights into the price potential of their new device, and robust economic evidence of the cost savings that could be achieved for ICUs through its use. As a result of working with the IMS team, they now have the ways and means of discussing not only the clinical but also the economic implications of introducing the new device into clinical practice.

The results of this analysis were then incorporated into a validated, interactive model built in Excel. As the model was designed to combine patient-level data of clinical effectiveness with unique resource intensity data at the ICU level, it addressed both cost-effectiveness per patient as well as budgetary impact per ICU department. Ease of use and flexibility were key features, with an interface that facilitated communication with payers.

The model has been rolled out to a number of markets and serves as an important payer tool in the company’s active market access strategy, supporting key discussions with hospital payers and ICU Heads of Department. •

This first phase was followed by extensive internal and external evaluation of the model, with simulations to test and determine price sensitivity (Figure 1).

1. Model development phase

2. Model application Internal evaluation

Inventory of available data

Processing of available data

Model design

Model development phase • Systematic literature review to collect clinical evidence • Selection and processing of data in order to define model outcomes • Development and validation of model

Determination of price

External evaluaion

Publication of results

Justification of price

Model application phase • Internal use of model to test and evaluate price sensitivity of product • Publication of model and findings from model simulations • Using the model to justify the price for payers (TLV, county councils)

FIGURE 1: THE TWO-PHASE APPROACH TO MODEL DEVELOPMENT

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PROJECT FOCUS | HTA STRATEGY Understanding the diverse international HTA environment can be key to an optimal value development strategy

Leveraging historical HTA decisions to optimize future submissions Greater emphasis on maximizing health service efficiency and cost containment has seen healthcare payers increasingly challenged by issues around comparative value, affordability and healthcare priorities. The result has been the use of more sophisticated approaches by decision makers to restrict access to products, including greater reliance on Health Technology Assessments (HTAs).

CHALLENGING VARIATION IN HTAs

The Authors: Joe Caputo, BSC is a Principal HEOR, IMS Consulting Group, U.K. JCaputo@uk.imshealth.com David Bertwistle, BSC, MSC, PhD is a Consultant HEOR, IMS Consulting Group, U.K. DBertwistle@uk.imshealth.com

In addition to meeting traditional regulatory hurdles that have historically served to support use of a new product in clinical practice, the pharmaceutical industry is becoming well versed in the need to demonstrate the product’s clinical and economic value via HTA submissions. However, the process of HTA varies widely between countries; HTA bodies differ in their approach to clinical and economic evaluation, utilizing a variety of assessment criteria and methodologies. For example, in France, the Commission de la Transparence (CT) places greater emphasis on the level of clinical improvement offered relative to competitors, whilst in the UK, the National Institute for Health and Clinical Excellence (NICE) and the Scottish Medicines Consortium (SMC) quantitatively convert level of benefit offered into Quality Adjusted Life Years (QALYs) to allow direct comparisons of costs between therapy areas.

Furthermore, HTA opinions and recommendations are not static. The HTA bodies themselves are evolving over time, resulting in altered perceptions of value and constantly changing evidence requirements. The heterogeneity and variability of the international HTA landscape presents a considerable challenge for pharmaceutical companies, with disparate assessment outcomes and guidance across different markets (Figure 1).

This lack of consistency and uniformity among HTAs means that drug development programs must be tailored carefully and in a timely fashion to allow for product value to be developed and demonstrated across multiple markets, thereby maximizing the likelihood of its success.

PLANNING FOR FUTURE REQUIREMENTS In order to help plan for future HEOR and market access strategy across several therapeutic areas, a leading global pharmaceutical company was keen to understand historical HTA evaluations and decisions and determine the key drivers behind them.

Recognizing the complexity of searching, identifying and capturing data from HTA decisions in 8 countries, the company approached HEOR experts in the IMS Consulting Group for help. In IMS it found a partner with the global reach, HEOR presence and a network of

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

HTA STRATEGY | PROJECT FOCUS

In this example for one drug, its value was considered to differ between 4 different cost-effectiveness-focused agencies SMC (Scotland)

NICE (UK)

CVZ (Netherlands)

TLV (Sweden)

Key drivers

Insufficient information on primary endpoint, and lack of robust economic argument

Benefit only for patients who have not been treated with other products

HTA decision

Not recommended

Should only be used in patient population where effectiveness is demonstrated

Should be restricted for use when other treatments have failed

Recommended for inclusion for conditional reimbursement

Impact on market access

Access denied by Scottish NHS

Restricted to first line use only by PCTs

Restricted to patients who have failed on previous therapy

Fully reimbursed as label indication (conditional – to be reassessed when more data is available)

High unmet need, Benefit unclear due to even though costlack of experience.

Concerns over unknown effectiveness has a high level of uncertainty long term side effects

FIGURE 1: PERCEPTION OF A DRUG’S VALUE VARIES WIDELY BETWEEN MARKETS, RESULTING IN DIFFERENCES IN ASSESSMENT OUTCOMES AND GUIDANCE

local contacts in the majority of markets where formal HTA processes existed, as well as the ability to complement the company’s own skill set by providing in-depth therapeutic knowledge and HTA expertise.

GATHERING THE EVIDENCE The analysis was focused on a core list of products – either in current practice or considered to be key competitors – within each therapeutic area of interest. In a coordinated program of data collection and supplementary research, the IMS experts set about identifying the data and information sources to be used in collecting relevant information on market access and HTA decisions for each country. Where information was available only in the local language, IMS locally-based experts were able to translate the findings into English.

Additionally, for selected markets where the drivers behind the HTA decision were less transparent, the on-the-ground IMS teams were able to conduct primary research in order to confirm and understand the rationale for key findings from the desk-based research.

HTA and market access information was supplemented by extracting data on the uptake of marketed products using IMS MIDAS data, a unique integration, viewing and analysis platform for IMS Health audits. This enabled the IMS experts to track sales versus competitor products as well as assess the impact of HTA decisions – both positive and negative – on sales over time.

AccessPoint - Issue 2

DRIVERS, PITFALLS AND A DEEPER UNDERSTANDING The result of the analysis was a sizeable body of evidence which provided an understanding of current trends in HTA decisions and market access within and across markets. The key drivers behind them were drawn out in each market with respect to clinical and economic data, and countries highlighted where HTA bodies posed a greater or lesser challenge to new products in each therapeutic area.

By understanding previous decisions and drivers, the client was able to identify potential pitfalls to be avoided in future submissions and better understand the data requirements in each market (eg, the need to present indirect cost data in Sweden). Critically, this project was undertaken sufficiently early in the drug development cycle for the client to benefit from the insights provided by addressing potential data gaps within the clinical trial program and other targeted HEOR projects.

A CLEAR ADVANTAGE The collection and synthesis of HTA information on an international scale can be a great advantage to pharmaceutical companies during their drug development programs, providing both a better understanding of the HTA environment and the opportunity to learn from competitor failures and successes. •

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IMS HEOR | OVERVIEW The IMS Consulting Group offers a spectrum of world-class expertise in HEOR to deliver the local excellence you need.

Realizing product value •

Insights and experience of more than 300 highlyqualified, multi-disciplinary experts in Health Economics, Outcomes Research and Pricing & Market Access

•

Strategy

Evidence Development

Communication

HEOR STRATEGY & DETERMINING VALUE

DEMONSTRATING VALUE

COMMUNICATING VALUE

Market expertise combined with local presence and a relationship network of key healthcare decision makers and opinion leaders worldwide

•

Scientifically-sound, commercially-relevant solutions for the entire product lifecycle

•

Highly respected, world-leading skills in strategic strategy, evidence development and value communications –

Our integrated approach – spanning world-leading skills in

planning, evidence development and market access •

is reflected in all of our work.

Experience in virtually all therapy areas with a bibliography of over 2000 references

•

Outstanding results with the world’s most comprehensive pharmaceutical and medical information, analytics and consulting resources

•

Relied on and consulted by policy makers and regulatory

IMS HEOR ONLINE Visit us online at www.imshealth.com/heor

authorities globally

REALIZE

COMMUNICATE DEMONSTRATE DETERMINE

IMS HEOR brings unrivalled experience and specialist expertise to help you determine, demonstrate, communicate and realize product value.

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IMS HEOR BIBLIOGRAPHY Please ask us for a copy of our current bibliography covering publications from 2008-2011 or access the full online catalog of more than 2000 references at www.imsheorbibliography.com

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

LOCATIONS | IMS IMS HEOR is located in 14 countries worldwide and has published on projects completed in 40 countries on all continents.

Global scope, local expertise IMS HEOR experts are located in key markets around the world.

YOUR PRIMARY CONTACTS: Dr. Michael Nelson Regional Leader Americas Health Economics and Outcomes Research IMS Health 1725 Duke Street, Suite 510 Alexandria, VA 22314 USA Tel: +1 703.837.5150 Email: MNelson@us.imshealth.com

Dr. Jacco Keja Regional Leader EMEA Health Economics and Outcomes Research IMS Health 7 Harewood Avenue London NW1 6JB, UK Telephone: +31 (0) 631 693 939 Email: JKeja@nl.imshealth.com

IMS HEOR office locations worldwide NORTH AMERICA REGIONAL HEADQUARTERS 200 Campus Drive Collegeville, PA 19426 USA Tel: +1 610.244.2000

EUROPE REGIONAL HEADQUARTERS 7 Harewood Avenue London NW1 6JB 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

FRANCE 91 rue Jean Jaurès 92807 Puteaux cedex France Tel: +33 1 41 35 1000 GERMANY Hefnersplatz 10 90402 Nürnberg Germany Tel: +49 911 24270 6300 Max-Lebsche-Platz 32 81377 München Germany Tel: +49 (0)89 45 79 126411 ITALY Viale F. Restelli 1/A 20124 Milan Italy Tel: +39 02 69 786 1

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 7 Harewood Avenue London NW1 6JB 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 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@uk.imshealth.com or visit www.imshealth.com/HEOR

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harmaceutical companies worldwide rely on LifeLink to drive patient-centered decisions – from the first explorator

IMS | EXPERTISE

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

IMS has one of the largest global teams of experts in health economics, outcomes research, pricing and market access of any organization in the world. We have more than 300 highly-qualified consultants and researchers with multi-disciplinary experience and proven skills covering all key therapy areas.

Our experts have extensive capabilities in a wide range of health economic & outcomes research disciplines in industry, consulting, government and academia, with a global grasp, local experience, and a unique, inside perspective of key market access issues.

The strength of our ability to support clients in healthcare decision making for HEOR, pricing & market access is built on the quality of our global team.

OUR SENIOR TEAM

Franck Amalric, PHD • Dr. Franck Amalric is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in France.

• Formerly Deputy Director of Human Sciences and Economics at the French National Cancer Institute, Franck has extensive experience in the management and development of economic projects, gained in roles as a Program Director at the Society for International Development (SID) in Rome, a Senior Economist at UBS in Switzerland, and as Head of Research at the Center for Corporate Responsibility and Sustainability.

• A graduate of the Ecole Polytechnique in France, Franck completed his training at the Ensaé (National School of Statistics and Economic Administration) and holds a PhD in Economics from Harvard University.

Xavier Badia, MD, MPH, PHD • Dr. Xavier Badia is Global Leader Observational Outcomes Research, and Senior Principal HEOR at the IMS Consulting Group in Spain.

• 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 Masters in Public Health and Health Economics from the University of Barcelona.

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

ry questions that drive clinical development to tactical sales planning for mature brands.

EXPERTISE | IMS Karin Berger, MBA • Karin Berger is a Senior Scientific Consultant to IMS and previously Principal, Health Economics & Outcomes Research, at IMS in Germany 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.

Nevzeta Bosnic, BA • Nevzeta Bosnic is a Principal at IMS Brogan in Canada, 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 Bachelors degree in Business Economics from the School of Economics and Business at the University of Sarajevo, Bosnia-Herzegovina.

Joe Caputo, BSC • Joe Caputo is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the U.K., leveraging more than 15 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. Richard H. Chapman, PHD • Dr. Rick Chapman is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the U.S., directing the design and analysis of economic evaluations and health outcomes studies addressing a range of client issues.

• Formerly a Senior Director at ValueMedics Research, and Research Associate at the Center for Risk Analysis, Rick has considerable experience in designing and conducting cost-effectiveness analyses, and particular expertise in the methodological quality of health economic analyses, medication adherence and patient-reported outcomes, including quality of life and patient preferences.

• Rick holds a PhD in Health Policy (Decision Sciences) from Harvard University and an MS in Health Policy and Management from the Harvard School of Public Health.

Mandy Chui, MBA • Mandy Chui is Regional Practice Leader, Pricing & Market Access at IMS in the Asia Pacific, helping clients formulate growth strategies, optimize price and reimbursement, and address issues in business model, sales force and marketing optimization.

• In a career spanning more than 15 years at IMS Health, including roles as Country Principal for China and Director of Area Sales & Marketing in Singapore, Mandy has developed an exceptional understanding of Asian market dynamics and an extensive network of major stakeholder contacts in this rapidly evolving region. She has also authored various publications on China and emerging markets.

• Mandy holds an honors degree in Biology from the University of Hong Kong and an MBA from McGill University, Montreal.

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IMS | EXPERTISE Frank-Ulrich Fricke, PHD, MSC • Dr. Frank-Ulrich Fricke is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group and Professor for Health Economics, Georg-Simon-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.

David Grant, MBA • David Grant is a Senior Principal and Global Leader, Strategic & Applied Health Economics & Outcomes Research, at the IMS Consulting Group in the U.K., 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 Regional Leader, EMEA, Health Economics & Outcomes Research, at the IMS Consulting Group, 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 a Principal and Group Manager, Health Economics & Outcomes Research at the IMS Consulting Group in Belgium 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 a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the U.S., 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 Masters in Economics from the University of Grenoble II, and a PhD in Economics from the Graduate Center of the City University of New York.

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

EXPERTISE | IMS Claude Le Pen, PHD • Dr. Claude Le Pen is a member of the strategic committee of IMS France 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.

Adam Lloyd, MPHIL, BA • Adam Lloyd is Global Leader Health Economic Modeling and Senior Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the U.K., where he leads the economic modeling practice with a particular focus on economic analysis 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 pre-launched 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, BSPharm, MS, MBA, MM • Charles Makin is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the U.S. 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 in Management, both from Goldey Beacom College, Delaware, U.S.

Eva Marchese, PHD • Dr. Eva Marchese is a Principal, Pricing & Market Access at the IMS Consulting Group in Italy, with a particular focus on market access, regulatory, pharmacovigilance, pricing and reimbursement, and health economics and outcomes research.

• An experienced consultant and founding partner of S&M Consulting, Eva has been involved in several ministerial committees at the Italian Ministry of Health, looking at cost evaluation and analysis of day surgery procedures. She was previously Professor of Public Management and Policy at Bocconi-SDA, the foremost Italian Business School, and a contracted Research Fellow at the Centre for Research on Healthcare and Social Management at Bocconi University.

• Eva holds a PhD in Public Management from the Parma State University, and a degree in Business Administration from Bocconi University in Milan.

Frédérique Maurel, MS, MPH • Frédérique Maurel is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in France, 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).

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IMS | EXPERTISE Joan McCormick, MBA • Joan McCormick is a Principal at IMS Brogan in Canada, 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 Bachelors degree in Life Sciences from Queen’s University in Kingston, Canada, and an MBA from the University of Ottawa, Canada.

Dana Morlet-Vigier, MD • Dana Morlet-Vigier is a Principal and Team Leader, Health Economics & Outcomes Research at the IMS Consulting Group in France, 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.

Juliet Munakata, MS • Juliet Munakata is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the U.S., 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, Juliet 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.

• Juliet 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.

Karl-Johan Myrén, MSC • Karl-Johan (Kalle) Myrén is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group, with responsibility for the Nordic region. He has extensive expertise in global and affiliate pricing, market access, reimbursement and health economics and a deep understanding of many different national healthcare systems.

• Karl-Johan’s career spans more than 13 years experience in global health economics gained in roles at the Swedish Institute of Health Services Development, Astra Zeneca and Eli Lilly, latterly as Senior Area Health Economist coordinating and managing health economic activities for the European middle-sized (EMS) countries, including the Nordic markets, Belgium, Switzerland, the Netherlands and Portugal.

• Karl-Johan holds an MSc in Economics and a BSc in Mathematics from the University of Stockholm.

Michael Nelson, PHARM D • Dr. Michael Nelson is Regional Leader, Americas, Health Economics & Outcomes Research at the IMS Consulting Group in the U.S., with particular expertise in retrospective database research, prospective observational research, health program evaluation, and cost-effectiveness 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.

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

EXPERTISE | IMS Tini Nguyen, PHARM D • Dr. Tini Nguyen is Regional Principal, Health Economics & Outcomes Research at the IMS Consulting Group in France.

• Previously European Market Access Director at Sanofi-Aventis in Paris, Tini has more than 15 years experience in the global pharmaceutical industry, including 7 years in senior roles focusing on health economics, health outcomes, pharmacoeconomics and market access in the Asia Pacific, Russia, Latin America, Middle East and Africa.

• Tini holds a diploma in Health Economics for Healthcare Professionals from the University of York, and a diploma in Marketing and a doctorate in Pharmaceutical Sciences from the Université René Descartes in Paris.

Olaf Pirk, MD, PHD • Dr. Olaf Pirk is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in Germany, 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 and Global Leader Health Economics & Outcomes Research at the IMS Consulting Group, advising pharmaceutical and biotech companies on a wide range of strategic, pricing and reimbursement issues.

• A former Legislative Research Assistant in Washington DC and member of the Professional Health and Social Security staff for the U.S. Senate Committee on Finance, Jon combines public policy and industry expertise to provide a unique grasp of the healthcare market place. He has co-authored several major U.S. healthcare initiatives, including proposals to reform managed care.

• Jon holds an MBA from the Kellogg School of Management, Northwestern University, where he majored in Management and Strategy, Finance, Health Industry Management, and Biotechnology.

Javier Sabater, MPHARM, MHE • Javier Sabater is a Principal, Health Economics & Outcomes Research at the IMS Consulting Group in Spain, where he leads a wide range of projects across many therapy areas for major international pharmaceutical companies, healthcare providers and national policy institutions.

• A pharmacist by training, Javier has considerable industry experience in clinical research, medical information, health economics, market access and outcomes research gained in roles at GlaxoSmithKline, Roche and Schering-Plough. He has co-authored a number of publications and abstracts in HEOR. • Javier holds a Bachelors degree in Pharmacy, a Masters in Health Economics and has completed a post-graduate course in Pharmaceutical Marketing.

Vernon Schabert, PHD • Dr. Vernon Schabert is a Senior Principal and Global Leader Retrospective Outcomes Research at the IMS Consulting Group in the U.S., leading the assessment and validation of patientreported 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.

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he best results were seen from adherence programs involving medical professional to patient contact on a egular basis.

IMS | EXPERTISE Núria Lara Surinach, MD, MSC • Dr. Núria Lara is a Principal, Health Economics and Outcomes Research at the IMS Consulting Group in Spain, where she leads the Outcomes Research group in 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 Masters in Public Health from the London School of Hygiene and Tropical Medicine and London School of Economics.

Jonothan Tierce, CPHIL • Jonothan Tierce is a Senior Scientific Consultant to IMS in the U.S., and former global leader of the IMS HEOR practice, supporting the industry’s growing need for real-world evidence of the clinical and economic value of new technologies in advancing health.

• A pioneer in applied pharmacoeconomics and value strategy development, and co-founder of ValueMedics Research LLC, Jonothan has nearly 25 years experience in health economics, working with clients to identify customized strategies and tactics for product access, value propositions and evidence-based demonstrations of value.

• Jonothan holds a C Phil, MA, and BA in Political Science from the University of California in Los Angeles. He also received two years of post-graduate training in econometrics and experimental design.

Meng Zhang, MBA • Meng Zhang is a Principal, Pricing & Market Access at IMS in China, applying evidence-based analytics to help clients address key business issues in global pricing, product launch readiness, market opportunity assessment and product portfolio optimization.

• During the course of his career in the U.S. and China, Meng has developed extensive expertise in pricing and reimbursement, new market entry, competitive analysis and corporate strategic planning, in consulting roles at SDI Health and Accenture, business development at J&J, and as a professional representative at Xian-Janssen Pharmaceutical Ltd in China.

• Meng holds a degree in Biology from Nanjing University, a Masters in Biochemistry from the University of New Brunswick, Montreal and an MBA from the Wharton School of the University of Pennsylvania, with a major in Healthcare Management.

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

IMS | LIFELINK Pharmaceutical companies worldwide rely on IMS LifeLinkTM to drive patient-centered decisions – from clinical development to mature brands.

Powering a patient perspective Your business models have changed. So have the metrics that keep the healthcare industry moving forward. Today, a patient perspective is a must.

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 simple – by integrating patient-level intelligence into our industryleading offerings and giving you expert consultants who apply it to your key issues.

IMS LifeLink provides insights of primary research with the benefits of secondary – lower cost, repeatable, faster and a larger sample size.

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

POWERING A PATIENT PERSPECTIVE We make a patient perspective easy, with familiar tools, integration into our industry-leading offerings and expert consultants who apply patient insights to your business issues.

A PARTNER YOU CAN TRUST Pharmaceutical companies worldwide rely on LifeLink to drive 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 with 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

AN UNPARALLELED ARRAY OF ANONYMIZED PATIENT-LEVEL DATA WORLDWIDE CANADA • Longitudinal Rx • Health Plan Claims Database • Longitudinal drug utilization data

EUROPE • Longitudinal Rx (Belgium, Germany, Netherlands, UK)

• Anonymized Patient-Level Data from Electronic Medical Records (France, Germany, Italy, UK)

(Oncology, hospital)

• Oncology Analyzer UNITED STATES • Longitudinal Rx

(France, Germany, Italy, Netherlands, Spain, Turkey, UK)

• Health Plan Claims Database

• Hospital Disease Database (Belgium)

• Oncology Analyzer

• Longitudinal Patient Database

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

• Longitudinal Rx (Japan, South Korea)

AUSTRALIA • Longitudinal Rx

(Sweden)

IMS has made extensive investments in anonymized patient-level data in markets around the world.

Today, we capture information for more than 260 million patient lives – for unparalleled treatment insights.

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IMS helps you realize the potential of your products

Maximizing market access demands the best scientific evidence and the right commercial awareness to deliver the insights you need.

The IMS Consulting Group has built a global team of more than 300 experts in Health Economics & Outcomes Research and Pricing & Market Access – with publication and project experience in more than 40 countries across all continents.

We combine rigorous scientific research – evidenced by nearly 200 publications each year – with commercially-focused consulting to help you determine, demonstrate, communicate and realize product value.

Our HEOR experts leverage unparalleled claims, medical, hospital and patient-centered pharmaceutical databases to create an Evidence-Based ConsultingSM powerhouse.

So the next time you think about product value, think about us.

MORE INFORMATION For additional information on the IMS Consulting Group and our HEOR expertise and offerings, please email HEORinfo@uk.imshealth.com or visit: www.imshealth.com/HEOR IMS HEOR EXPERTS ARE LOCATED IN MANY COUNTRIES AROUND THE WORLD WITH PRINCIPAL OFFICES IN: UNITED STATES 1725 Duke Street, Suite 510, Alexandria, VA 22314, USA • Tel: +1 (703) 837-5150 UNITED KINGDOM 7 Harewood Avenue, London NW1 6JB, United Kingdom • Tel: +44 20 3075 4800 ASIA PACIFIC 7/F Central Tower, China Overseas Plaza, Jianguomenwai Avenue, Chaoyang District, Beijing 100001, China • Tel: +86 10 8567 4255

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