IMS AccessPoint - November 2011 by IMS Health RWE Solutions & HEOR publications library

ACCESSPOINT IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

Volume 2, Issue 3 NOVEMBER 2011

News, views and insights from leading experts in HEOR

The era of ‘prove it works’ Real-world evidence drives agenda

Validating the IMS CORE Diabetes Model

US senior drug costs defy expectations

Xavier Badia and Núria Lara Surinach consider challenges PageOUTCOMES 1 - Issue 1 of studies in Asia Page 16

Dana Morlet-Vigier Chris Blanchette and Arnaud Troubat presents a novel on impact of drug linkage Page 1 IMS HEALTH ECONOMICS AND OUTCOMESdata RESEARCH reform in France technique for CER Page 8 Page 30

ACCESSPOINT IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

News, views and insights from leading experts in HEOR

‘Prove it works’ The growing need for real-world evidence heralds a new era for pharma page 12

Planning for observational research in Asia Emerging markets offer challenges and benefits for primary data collection page 16

Capturing the real world in real time Technological advancements extend capabilities of IMS LifeLink™ EMR database in Europe page 20

Validating the model Major updates to IMS CORE Diabetes Model are undergoing rigorous validation page 34

Extending the outreach of HEOR In the age of the empowered consumer, we consider the implications of DTC engagement in Europe page 38

“We are moving from a year of impetus and innovation to a new era of transformation”

WELCOME Welcome to the third issue of ACCESSPOINT, a twice-yearly review of news and insights from our international HEOR experts at the IMS Consulting Group – sharing the programs that are expanding our contribution to global health and the real-world research that is enabling more informed, evidence-based decision making. As we approach the end of 2011, we can reflect on a year of impetus and innovation in pharmaceutical markets around the world: in France, the culmination of a drug safety scandal has triggered a radical reassessment of pharmaceutical regulation with major implications long-term (page 8); in the U.S. and Europe, concentrated pressure on the demands of information is driving new initiatives in healthcare datasets from both the public and private sector, enabling more and better evidence generation (page 25); in the dynamic emerging Asian markets, converging trends are creating a need for different approaches to observational research (page 16); and globally, the imperative for real-world evidence is signaling the start of a new “prove it works” era for pharma (page 12). Already, the call for more rigorous outcomes research and evidence of comparative effectiveness is fuelling novel techniques and technology refinements that will transform our ability to evaluate and analyze the value of medicines: sophisticated data linkage approaches promise more holistic patient-level research (page 30); technical enhancements are extending the potential of IMS LifeLink™ EMR datasets in Europe (page 20); and advanced methodologies are proving the feasibility of extrapolating data across multiple markets (page 48). Underpinning it all is the growing need to ensure that our value messages reach out and resonate with a broader audience (page 38). Leveraging the potential of these new developments will be key to meeting the changing demands of the market. IMS is committed to accelerating understanding based on sharper, more effective use of information and continued innovation. Our global team of highly-qualified, multi-disciplinary HEOR researchers and consultants works with government agencies, academic leaders (pages 2, 5) and our unparalleled global data assets to advance evidence-based healthcare in critical and pioneering areas. Major enhancements to the IMS CORE Diabetes Model (page 4), which are now undergoing extensive validation (page 34) underscore our resolve to capture the very latest scientific and technical advances. And findings from our analyses continue to provide important insights into policy impact (page 43) and the key dynamics that are shaping the future landscape (page 7).

CONTENTS NEWS SECTION 2 McGowan collaboration for HEOR in regenerative medicine 3 Budget impact model for pharmacy setting 4 New IMS CORE Diabetes Model goes live! 5 Towards best practice modeling in COPD 6 IMS Pharma Policy Analyzer to launch in Spain 7 IMS Institute explores latest dynamics INSIGHTS 8 DRUG REFORM IN FRANCE Safety scandal triggers major review 12 REAL-WORLD EVIDENCE The era of ‘prove it works’ 16 OBSERVATIONAL RESEARCH IN ASIA Challenges in emerging markets 20 EUROPEAN EMR DATA Capturing the real world in real time 25 IMS ISPOR SYMPOSIUM New horizons for patient-level data 30 PROBABILISTIC DATA LINKAGE Novel technique for comparative research 34 IMS CORE DIABETES MODEL Robust validation after major enhancements 38 COMMUNICATION AND OUTREACH Implications of DTC advertising 43 MEDICARE PART D Why seniors’ drugs costs are going down PROJECT FOCUS 48 CHEMOTHERAPY-INDUCED ANEMIA Adapting country-specific data 50 BREAST CANCER Understanding real-world persistence IMS CONSULTING GROUP OVERVIEW 52 Locations, expertise, LifeLink™ TM

I hope you find this issue of ACCESSPOINT informative and timely as we look forward to the opportunities and challenges ahead in 2012. AccessPoint is published twice yearly by the Health Economics & Outcomes Research team of the IMS Consulting Group. VOLUME 2 ISSUE 3. PUBLISHED NOVEMBER 2011.

Jon Resnick VICE PRESIDENT AND GLOBAL LEADER, HEOR IMS CONSULTING GROUP Jresnick@imscg.com

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NEWS | REGENERATIVE MEDICINE Regenerative medicine offers tremendous potential for tissue and organ repair. A new collaboration taps IMS HEOR expertise for pioneering research.

IMS partners with McGowan Institute to advance HEOR analysis in regenerative medicine IMS HEOR is to design and conduct independent cost analyses for the development, administration, treatment and follow-up of regenerative interventions in two studies being conducted under the Limb Salvage and Regenerative Medicine Initiative. These have been instigated by the McGowan Institute for Regenerative Medicine, a University of Pittsburgh Medical Center program and world-renowned leader in the emerging field of regenerative tissue research. The studies will investigate the use of biologic scaffolds for muscle tissue regeneration in patients suffering from massive loss of skeletal muscle tissue, and allogenic human dermal fibroblasts for remodeling scar contractures. IMS will provide independent health economic (HE) analyses of these efficacy studies. The key sub-tasks to be performed by IMS are the calculation of cost per subject and comparison of costs for the new interventions versus standard of care.

Discussions are underway to cooperate on further initiatives that will underscore the importance of health economics in regenerative medicine and advance its application in this pioneering field

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NEW COLLABORATION The input from IMS HEOR forms part of a new collaboration between IMS Government Solutions and the McGowan Institute for Regenerative Medicine to bring the promise of groundbreaking medical advances to U.S. Service members who have been severely wounded in combat. This centers on an initiative funded by the Office of the Secretary of Defenseâ&#x20AC;&#x201C;Office of Technology Transition (OSD-OTT) to test and implement new approaches to skeleto-muscle regeneration, cranio-facial reconstruction and scar contracture remodeling for wounded soldiers. McGowan medical staff will apply their expertise in tissue engineering and cellular therapies for a group of 100 veterans returning from Iraq and Afghanistan. IMS HEOR will work with the IMS Government Solutions team to provide data analysis, outcomes research and benchmarking services, including establishing a baseline for monitoring patient responses, tracking recovery patterns and advancing new approaches in clinical translation. Among other uses, information from these analyses will provide historical data for similar future efforts of this kind. PROMOTING IMPORTANCE OF HEOR Discussions are also underway between IMS HEOR, the IMS Institute, IMS Government Solutions and the PTEI Center for Regenerative Medicine Economics at the University of Pittsburgh, to cooperate on further initiatives that will underscore the importance of health economics in regenerative medicine and advance its application in this pioneering field. â&#x20AC;˘ For further information on this initiative, please contact Richard Chapman, Principal HEOR, IMS Consulting Group, U.S., Rchapman@imscg.com

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

IMS PHARMACY BUDGET IMPACT MODEL | NEWS Understanding budget impact is key for rational decision making. A new modeling initiative from IMS supports analyses in the pharmacy setting.

IMS pharmacy budget impact model enables new insights for a wide range of stakeholders IMS HEOR and the Payer Solutions unit of IMS Health are collaborating to develop a standardized model framework to estimate the pharmacy budget impact (BI) of adopting or diffusing a new therapeutic intervention. This will initially cover the U.S. with plans for global expansion.

FLEXIBLE, MULTI-USE STANDARDIZED SOLUTION The turnkey modeling solution developed by the collaborative IMS team is a flexible, multi-use and standardized framework to enable multiple analyses across therapeutic areas. It is pre-populated with proprietary data on prescription drug use and drug prices to establish national (or regional) benchmarks for comparison.

Budget impact analyses (BIA) are an essential component of a comprehensive economic assessment of a healthcare technology. They are increasingly required by national regulatory agencies and managed care organizations to estimate the economic consequences of introducing a new drug or technology within a specific setting of care.

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

The IMS initiative reflects growing recognition that despite national and local guidelines for developing BIAs there are still opportunities to address hurdles to their optimal use, such as:

Members of the development team, which includes experts from the IMS Center of Excellence for Health Economic Modeling, believe the BI model’s standardized platform and analytic scope will facilitate BIAs by companies and payers alike.

• Payer skepticism of BIAs developed by manufacturers

Users will include those who manage and plan for healthcare budgets such as administrators of insurance plans, healthcare delivery organizations or employers, as well as manufacturers of new pharmaceutical or healthcare interventions. •

• Opaque (or lack of) benchmarks to evaluate budget impact • Inefficient practice of developing models de novo to support new products/analyses

For further information on the IMS Pharmacy Budget Impact Model, please contact Julie Munakata, Principal HEOR, IMS Consulting Group, U.S., Jmunakata@imscg.com

ERRATUM Putting the P into Outcomes Research. Badia X, Donatti C, Makin C. AccessPoint, 2011; 1(2):31-35. Figure 2 on page 34 of this article, depicting a PRO Framework, should contain the following acknowledgement: Source: Doward L, Gnanasakthy A, Baker, M. Patient-reported outcomes: Looking beyond the label claim. Health and Quality of Life Outcomes, 2010; 8:89. We apologize for this unintentional omission.

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NEWS | IMS CORE DIABETES MODEL Significant enhancements strengthen robustness of IMS CORE Diabetes Model, bringing new analytic possibilities for diabetes decision support.

New version of IMS CORE Diabetes Model goes live! The IMS CORE Diabetes Model (CDM) is widely 2. New patient-level analysis The CDM performs patient-level simulations on the basis recognized as the leading economic model of of mean cohort properties such as age, duration of diabetes. With the prevalence of diabetes diabetes, physiological parameter levels and baseline continuing to grow at alarming rates around the complication rates. A subset of those parameters might world, its critical insights into the long-term be subjected to random sampling in order to incorporate clinical and economic outcomes of new therapeutic cohort heterogeneity, but also the uncertainty relating to interventions are key to identifying optimal the parameter assumptions. In Version 8.0, real-world approaches to managing this disease. In a move that reflects our ongoing commitment to innovation in the field of diabetes and ensuring that the CDM remains the best economic evaluation tool available, we are delighted to announce the recent launch of Version 8.0. With significant scientific and technical updates, together with enhancements to the model interface, the new version offers both augmented capabilities and an improved end-user experience. The updates include new clinical information and/or modifications to reflect alternative or fresh assumptions in the modeling process, such as new relationships of risk factors, the integration of more recent clinical data in diabetes, and structural changes that broaden the model’s scientific scope. KEY STRUCTURAL CHANGES Among the principal structural modifications to the model are: a new treatment-to-target approach, the ability to leverage real-world patient-level data in the model, and the extension of probabilistic sensitivity analysis. 1. New treatment-to-target approach This newly added feature captures HbA1c efficacy data from clinical trials where titration algorithms were applied to treat patients to target levels. In such trials, HbA1c efficacy data is normally expressed in terms of the percentage of patients who reached a target HbA1c value. The treatment-to-target approach allows the user to specify treatment efficacy in terms of a pre-defined HbA1c target (eg, ADA target of 7%) and a percentage of patients who reach the target. It has been integrated into the model alongside the standard approach to define HbA1c efficacy in the CDM (mean change from baseline). Users have the option to choose either approach in the treatment setting of the model (Figure 1).

patient-level data that might come from clinical trial populations or patient registries can be applied directly in the model. Records of patient-level data can be uploaded into the model and applied as an alternative to the Cohort module settings to describe the patient characteristics of the cohort to be simulated. In addition, data for treatment effects can be likewise included in the patient-level dataset. The option of applying real-world patient-level data to explore the parameter uncertainty is important, since parameters may have an underlying covariance structure that might not be reflected by random assignment of patient characteristics and/or treatment effects. 3. Extension of probabilistic sensitivity analysis The CDM uses Monte Carlo simulations, together with a nonparametric bootstrapping approach, to capture parameter uncertainty, enabling the imprecision of cost-effectiveness results to be assessed. The process involves sampling with replacement from distributions for input parameters for each bootstrap iteration of the analysis. FIGURE 1: TREATMENT SECTION OF THE IMS CORE DIABETES MODEL WITH FOUR NEW VARIABLES AND THE OPTION TO CHOOSE BETWEEN “TREATMENT TO TARGET” AND “CONVENTIONAL (MEAN CHANGE)” APPROACH

...continued opposite

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

COPD MODELING | NEWS COPD burden demands robust health economic support.

Promoting best practice COPD modeling Chronic obstructive pulmonary disease (COPD) is becoming a serious concern for global public health. Reflecting the need for more and better real-world evidence in this disease, on 24 September Yevgeniy Samyshkin and Yumi Asukai from IMS HEOR were invited speakers at an expert conference on COPD modeling. Hosted by Maureen Rutten van Mölken of iMTA (Erasmus University) and featuring guest speaker Andrew Briggs of Glasgow University, the meeting took place in Amsterdam, alongside the 2011 European Respiratory Society Annual Congress. The conference reflects concern about the growing burden of COPD – highlighted at a recent high-level meeting of the UN General Assembly – and the need to better understand the value of different treatments. Affecting millions of people worldwide – many of whom remain undiagnosed – this debilitating lung condition is predicted to be the third leading cause of death by 2030.1 It has long been associated with elderly males, but with new research revealing a significant impact on the working population, its economic toll is considered likely to increase considerably.2 1WHO World

Health Statistics, 2008 Accessed Oct 13, 2011 http://www.who.int/whosis/whostat/EN_WHS08_Part1.pdf 2COPD: The New Workplace Epidemic. Fletcher MJ, van der Molen T, Barnes N, Walsh J. Updated September 2011. Education for Health.

WIDE-RANGING INPUT IMS was invited to present our models alongside other leaders in this field such as Professors Briggs and van Mölken and Sixten Borg from the Institute of Health Economics (IHE). Approximately 30 attendees from industry and academia were invited to observe, with representation from all the major pharma companies active in COPD. Presentations drew on rich and varied expertise, ranging from the clinical experience of a COPD specialist to the technical insights of a financial modeler considering issues around model validation. Speakers discussed key methodological and implementation issues in modeling COPD and the potential value of creating a benchmark or reference case for COPD models. Further discussion focused on: • Approaches to describing disease progression • Relevance of GOLD system in classifying disease severity & progression • Impact of disease exacerbations • Limitations of existing COPD models and datasets • Potential data that would help the modeling to better reflect clinical reality The group offers an exciting opportunity to develop best practice in COPD modeling and set benchmarks that future analyses will need to meet. Further gatherings are planned to address the strengths and weaknesses of existing approaches and develop an agenda for advancing the quality of analyses and data available in this area. •

New CDM goes live ...continued from previous page In the previous version of the model, cohort baseline values (age, duration of diabetes and baseline physiological parameter levels) and the treatment effects on physiological parameter levels were subject to random sampling. In compliance with guidelines from NICE, the list of parameters that are subjected to random sampling has been extended to incorporate transition probabilities for cardiovascular events, health state utilities and event dis-utilities, as well as direct and indirect costs. In addition, the distribution type applied to sample treatment effects has been changed from normal distribution to a beta distribution. The beta distribution requires an upper and lower limit for input parameters. Beta distributions were chosen because they enable the definition of a distribution to prevent inconsistent or illogical values without altering the mean or standard deviation. IMPROVED CAPABILITY AND USER EXPERIENCE In addition to the structural changes, Version 8 of the CDM also brings enhancements to calculation speed and user experience to ensure that diabetes model simulations can AccessPoint - Issue 3

be set up, performed and analyzed in an efficient and seamless way. We are confident that the changes and new features incorporated into the Version 8.0 update will strengthen the robustness of the IMS CORE Diabetes Model and enable a greater range of analyses to be undertaken. Feedback to date has been extremely positive and we encourage and welcome comments from all users as they gain experience with the new update. • For further information on the IMS CORE Diabetes Model update, please contact David Grant, Senior Principal HEOR, IMS Consulting Group, U.K., Dgrant@imscg.com

A full validation of the new model version is now underway (see article on page 34 of this issue) and the results will then be submitted for peer-reviewed publication.

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NEWS | IMS PHARMA POLICY ANALYZER Spainâ&#x20AC;&#x2122;s ever changing regional policies are a major challenge for market access in this country. A new on-line tool from IMS Barcelona enables more informed strategic decision making.

IMS Pharma Policy Analyzer prepares to launch in Spain With 17 autonomous regions, each having their 1. Regional Policies: Covers all regional policies about the own pharmaceutical policies, Spain presents one evaluation, selection, acquisition, purchase, prescription and dispensing by region, prescription and dispensing of the most complex environments for achieving channel, and type of drugs. It also contains stakeholder successful market access. Multiple stakeholders and relationship diagrams per region and the impact of disparate rules in primary and secondary care must policies on market access and the decision making process. be addressed against a background of ongoing changes to the current pharmaceutical policies. 2. Stakeholder Dataview: Provides name, surname, department, position and main activities of the regional Understanding the direction of new developments stakeholders, by region. and leveraging them to best effect requires the very latest intelligence â&#x20AC;&#x201C; at both a national and 3. National Healthcare System: Organization and Legislation: Describes official national pricing and regional level. reimbursement policies for pharmaceuticals, all national IN-DEPTH, UP-TO-DATE INFORMATION IMS Pharma Policy Analyzer is a new, web-based tool which charts, captures and clarifies the current policies governing market access in the different regions of Spain (Figure 1). Updated every four months, it brings together into a single source, critical, current information on four key panel areas: 1. Regional Policies 2. Regional Stakeholders 3. National Healthcare System: Organization and Legislation 4. Benchmarks FIGURE 1: HOME PAGE OF IMS PHARMA POLICY ANALYZER

pharmaceutical legislation in chronological order, and the territorial organization of healthcare provision by region. 4. Benchmarks: Enables comparisons of economic data across regions on the basis of: socio-demographic indicators, economic indicators, healthcare budgets, healthcare and pharmaceutical expenditure and pharmaceutical market indicators. All data is extracted from multiple, official Spanish sources. Additional sections include a glossary, main links, latest changes and SOPs to further clarify the complexities of the Spanish pharmaceutical market. An example of the detail provided by Pharma Policy Analyzer is shown in Figure 2 (opposite page). SINGLE REFERENCE, MULTIPLE BENEFITS Health economics and outcomes research experts at the IMS Consulting Group in Barcelona, who have spent many months developing and fine-tuning Pharma Policy Analyzer, are confident of its value as a definitive, single reference when preparing for market access on a regional basis in Spain. With detail that would be time-consuming to generate per se, it enables a fast understanding of the policies that impact market access and the implication of changes as new policies are implemented, as well as the ability to develop and improve relationships with key stakeholders. continued opposite

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IMS INSTITUTE INSIGHTS | NEWS IMS Institute for Healthcare Informatics explores key dynamics that are shaping the future of healthcare.

Weekly insights accelerate understanding of latest trends Since its launch early in 2011, the IMS Institute for Healthcare Informatics has confirmed the strength of its research agenda with a series of comprehensive publications and podcasts, and relevant, objective weekly insights into the leading issues that impact healthcare worldwide. Recent topics covered include: IMS Pharma Policy Analyzer, Spain ...continued from previous page The benefits of Pharma Policy Analyzer are expected to extend beyond market access to medical affairs, marketing, health policy and outcomes research, in facilitating optimal decision making and product positioning in the market. IMS Pharma Policy Analyzer is scheduled for launch at the end of 2011. • FIGURE 2: IMPACT OF REGIONAL POLICIES FOR HOSPITAL DRUGS WITH THERAPEUTIC EQUIVALENTS IN ANDALUSIA

• Cost savings from generics in the United States Supporting a study published by the Generic Pharmaceutical Association (GPhA), research from the Institute reveals the cost savings generated by dispensing for generic versions of brand name drugs in the U.S. over the past decade. • Growth of non-communicable diseases As the United Nations discusses prevention and control of four major non-communicable diseases – cancer, diabetes, COPD and cardiovascular disease – the Institute details the dynamics driving growth and spending of medicines in these disease classes globally. • Spending and growth for NCEs Pharmaceutical manufacturers are pursuing more targeted therapies to treat diseases afflicting smaller patient populations. New therapies and their impact on spending on medicines globally over the next five years are discussed. • Impact of antivirals used for the 2009 H1N1 influenza pandemic A paper co-authored by the CDC and IMS on the impact of antiviral medicines used during the 2009 H1N1 influenza pandemic, finds approximately 10,000 influenzarelated hospitalizations were prevented because of the use of these medicines during the pandemic.

For further information on IMS Pharma Policy Analyzer please contact Xavier Badia, Global Leader Observational Outcomes Research and Senior Principal HEOR, IMS Consulting Group, Spain, Xbadia@imscg.com or Ana Vieta, Engagement Manager HEOR, IMS Consulting Group, Spain, Avieta@imscg.com

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• Spending and growth for global therapies While spending on most therapies for chronic conditions will be lower over the next five years, there will be continued growth for specialty medicines targeted toward cancer, autoimmune disease, multiple sclerosis and HIV. This trend is explored, with reference to the top 20 global therapy classes and their spending growth through 2015. Further information on these and other insights from the IMS Institute, presented with commentary from Executive Director, Murray Aitken, can be accessed from the Institute website at www.theimsinstitute.org, along with details of the Institute's range of research activities. •

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INSIGHTS | DRUG REFORM IN FRANCE

A radical review of drug assessment in France, triggered by the high-profile withdrawal of the anti-diabetic MĂŠdiator, paves the way for potentially game-changing pharmaceutical legislation. With every aspect of the evaluation process now under scrutiny, we consider the far-reaching implications for pricing and market access in this country.

The authors: Dana Morlet-Vigier, MD is Principal HEOR, IMS Consulting Group, France. Dmorlet@imscg.com

Arnaud Troubat, PHARMD, MBA, MHEM is Principal HEOR, IMS Consulting Group, France. Atroubat@imscg.com

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DRUG REFORM IN FRANCE | INSIGHTS

Drug reform in France A TOUGHER WORLD FOR PHARMACEUTICALS?

The scandal involving Servier’s diabetes drug Médiator • Sunshine Act: Manufacturers obliged to fully disclose all payments/financial concessions made to (benfluorex hydrochloride) has shaken the very healthcare professionals, including doctors, nurses, foundations of the French healthcare system - quality, medical students, patient associations, etc. efficiency and equal access - and triggered national debate on the healthcare system, pharmaceutical • ANSM: AFSSAPS, the French drug regulatory regulation and market access. The drug has been agency, whose reputation has been severely damaged associated with severe cardio-pulmonary adverse events by the Médiator scandal, will be renamed the and hundreds, if not thousands, of deaths. Added to this National Agency for Drug Safety (ANSM). ANSM are accusations of weakness on the part of the French will assume new powers and play a central coordinating role. ANSM to have the right to regulatory agency, AFSSAPS, for failing to address demand comparative data when licensing NCEs. pharmacovigilance signals over the course of many years. Following a number of official reviews, reforms were put • Off-label prescribing: Prescribers are to inform forward by Health Minister Xavier Bertrand in June, ANSM about off-label drug use (versus the drug’s 2011. Corresponding draft legislation is currently being official marketing authorization or prescribing examined in parliament. guidelines issued by the High Authority for Health [HAS]) and, moreover, to also inform their patients In spite of the media onslaught following the scandal, and before prescribing. calls from official audit bodies for radical and deep reforms for market access and reimbursement, Bertrand’s proposals represent relatively limited changes. This may have come as something of a relief for stakeholders. But, even if the proposed reforms are quite minor, their impact may yet be quite radical and even more so as the Parliament discusses at the same time the PLFSS 2012 (Social Security Finance Bill, voted every year). The changes under discussion in parliament with respect to these two laws will impact four key areas: stakeholder relationships, prescribing, real-world evidence needs and health economics. 1. STAKEHOLDER RELATIONSHIPS The Médiator affair has only served to exacerbate the long-held perception of “abnormally close” links between pharmaceutical manufacturers, regulatory authorities and prescribers in France. The government’s reaction represents a very serious attempt to sever this association. Moving forward these relationships will be much more tightly controlled. The key reforms currently being discussed in Parliament are as follows: • Expert Charter: Key opinion leaders (KOLs), whose credibility was seriously shaken by the fallout from Médiator, obliged to publicly declare all potential “conflicts of interest”, and regulatory agencies to have the ability to control.

The scandal involving Servier’s diabetes drug Médiator has shaken the very foundations of the French healthcare system - quality, efficiency and equal access The impact of these changes is potentially far-reaching: sponsored trials may suffer; KOL advice will become difficult to obtain; patients will have very limited access to off-label drugs (even in the absence of other choices); and pharmaceutical companies will have to constantly monitor the real-life use of their drugs. 2. PRESCRIBER RESPONSIBILITY To date, there have been few restrictions on physician prescribing in France, and few demand-side controls to limit consumption. However, in future, much greater emphasis will be placed on appropriate (ie, medically appropriate and economically sound) prescribing. Proposed changes Along with increased sanctions reinforcing pharmacovigilance obligations, physicians will be required to officially inform their patients when they continued on next page

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INSIGHTS | DRUG REFORM IN FRANCE ...continued from previous page

prescribe off-label and follow enforced legislation on INN prescribing (mostly through the compulsory HAS certification of medical prescribing software). The “payfor-performance” initiative will be extended to all General Practitioners. Hospital budget deficits are to be eliminated by 2012, with draft reform legislation introducing the possibility for prescribing controls to be enforced at the individual physician level in hospitals. Hospital detailing was initially proposed to be confined to groups of physicians only, a proposal that has been fiercely discussed by Pharma and may finally not be adopted – discussions are ongoing. Finally, there will be strict limits on spending growth for drugs prescribed in hospitals and dispensed via retail pharmacies. Potential impact The primary goal of these measures is to rein in expenditures by finally starting to tackle the “demandside” of the market. While the actual changes could be perceived as minor, in practice they have the potential to result in: • Demand-side prescribing drivers in France replicating ‘stricter’ EU countries • Prescribers moving to distance themselves from industry contacts • Increased uptake of ‘cheaper options’ and decreasing uptake of ‘perceived expensive’ drugs due to new prescriber price sensitivity • Reduced off-label prescribing • Collaborative agreements becoming more difficult to establish.

If the proposed reforms are adopted, France will lead the European Union in terms of real-world evidence compulsory requirements Another critical consideration for manufacturers is the proposed ANSM review of the risk-benefit profile of all existing (in-market) drugs. Reviews will be prioritized based on medical benefit rating (SMR) – in other words, beginning with drugs judged to have an insufficient or weak SMR rating. RWE will be a key factor in this process. 4. HEALTH ECONOMICS In keeping with calls from numerous political stakeholders in France, health economics is set to have an increased and more clearly defined role going forward. Indeed, the 2012 Social Security Finance Bill includes provision for greater emphasis on these evaluations. In future, health economic data will be taken into account by CEPS (the Pricing Committee) during the price fixation process.The exact details are as yet unclear – but may be known by as soon as the end of 2011. What is clear is that the Commission for Economic and Public Health Evaluation (CEESP), part of HAS, will be given new authority to conduct health economic-based assessments of individual drugs, and to provide corresponding advice to the CEPS as part of the initial price fixing process. To date, the CEESP has focused on disease area/therapeutic group reviews only, and has had no involvement in pricing or market access decisions.

What this means is that budget impact modeling and cost-minimization from a national health insurance The provision of real-world evidence (RWE), including perspective will become a “must” for all drugs, both at safety and appropriate-use data, will become a launch and for continued market access.The open use of compulsory requirement to ensure continued market cost per quality-adjusted life year (QALY) or similar access (with a natural milestone at the mandatory five- metrics is nevertheless unlikely to happen in the short year reimbursement reviews, but not restricted to this). term as that would mean a significant political change. Non-compliance may lead to loss of reimbursement Nevertheless, it is expected that progressively the French and/or marketing authorization. The timelines for environment (stakeholders and public opinion) will be provision of RWE data will be agreed before more and more exposed to it. reimbursement is granted. Further, cost-effectiveness assessments of therapeutic This marks a significant change from the current strategies as a whole are likely to become more systematic situation. Requirements for post-marketing data have (with implications for prescribing guidelines). Costexisted in France for some time, but demands for RWE effectiveness data will have to be made available for price (from either AFSSAPS or HAS) are not systematic and fixation and price defense (throughout the lifecycle) in are not always met by manufacturers. the case of high-cost drugs such as cancer treatments. 3. REAL-WORLD EVIDENCE

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DRUG REFORM IN FRANCE | INSIGHTS

FIGURE 1: PRICING AND REIMBURSEMENT ACCESS: PAST, PRESENT AND FUTURE

5 years ago

Today

• ASMR the name of the genre • ‘Standard’ price pressure • ‘Basic’ access restrictions

• SMR is now the key to gaining any access at all • Price cuts announced • Post-marketing data compulsory for continued access • Prescription control taking-off

-5

+5 Next 5 years? • Much more selective reimbursement • High price pressure (at access time) • Formal health economics for expensive therapeutic solutions? • Prescription control at individual and hospital level based on restrictive guidelines

PRICE PRESSURE Overall, these proposed reforms translate to gradually increasing pressure on drug prices, both at launch and across the lifecycle, and significantly increasing constraints on reimbursement access (Figure 1). Historically, almost all drugs for which applications have been submitted have been granted reimbursement in France. Listing was almost guaranteed, the only question being at what price. However, the tide is turning. At least 10 new (innovator) drugs have been rejected for reimbursement by the Transparency Commission (CT) since the beginning of 2011 (accounting for almost 25% of all submissions). The question now is one of “any reimbursement at all?” Going forward, much greater emphasis will be placed on demonstrating first medical benefit (SMR) – actually focusing on the benefit-risk ratio, rather than improvement in medical benefit (ASMR) against comparators. On the other hand, ANSM is given the right to request, if needed, comparative data for licensing purposes. This brings some confusion over the future roles of ANSM and HAS in market access.

Those that are looking to get ahead of the changes should focus on: 1. Being proactive: Collect real-world efficacy and safety data rather than waiting for such demands, ideally beginning as soon as Phase III trials are available; bear in mind the increased emphasis on health economics in France and plan accordingly. 2. Knowing the data sources: Be aware of, and have access to, relevant data sources. 3. Prioritizing activities: Examine the product portfolio and identify drugs with a high budget impact, a high likelihood of prescribing outside of reimbursed indications, low incremental effectiveness, or safety issues, and direct efforts towards collating realworld evidence data for these products first and foremost. LEADING THE WAY IN EUROPE

The Médiator affair has undoubtedly cut to the core of the established healthcare system in France.The outcome could have been worse but if the proposed reforms are adopted, France will lead the European Union (EU) in terms of real-world evidence compulsory requirements PHARMA PREPARATION STRATEGIES and will be closing the gap with other EU countries in Despite the lack of finality over many details of the new terms of prescribing restrictions. Otherwise, it is business regulations in France, the future obligations for the as usual, with about €600 million in drug price cuts industry are known and the key is for companies to expected for 2012 – the deepest wave of price cuts ever anticipate these and begin their preparations now. seen in the country. • AccessPoint - Issue 3

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INSIGHTS | REAL-WORLD EVIDENCE

The growing need for real-world evidence (RWE) to support a product throughout its lifecycle has ended the era in which data was assembled purely for market access. As more stakeholders outside the industry generate evidence themselves, manufacturers will increasingly need to manage their own data packages in dynamic and creative ways.

The authors Jon Resnick, MBA is Vice President and Global Leader HEOR, IMS Consulting Group, U.S. Jresnick@imscg.com

Vernon Schabert, PHD is Global Leader Retrospective Outcomes Research and Senior Principal HEOR, IMS Consulting Group, U.S. Vschabert@imscg.com

Rob Kotchie, MCHEM, MSC is Principal HEOR, IMS Consulting Group, U.K. Rkotchie@imscg.com

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

REAL-WORLD EVIDENCE | INSIGHTS

Driving the industry into the ‘prove it works’ era REAL-WORLD EVIDENCE SETS THE PACE Broader than just observational data, real-world evidence (RWE) is data collected in actual practice for many purposes and applied to prove or disprove a hypothesis that may have nothing to do with its original remit. Although the concept of using RWE makes intuitive sense, in practice the quality of the underlying data, appropriateness of the research question for that data, and the robustness of the methodology, affect whether or not to believe the outcome. Furthermore, the lack of trust in data generated by pharmaceutical companies results in a high bar and creates a real threat that healthcare stakeholders will use RWE to inform value decisions without the voice of the manufacturers.

manufacturers to continue lapping around the market access and regulatory track (Figure 1).

MAJOR SHIFT

Over time, regulators will use RWE to revise product labels to highlight safety concerns, and payers may use RWE to revisit price, act upon conditional access, and inform guidelines that influence or drive clinical practice continued on next page

RWE represents a shift in the timing and use of data to inform the value of a product. Historically, pharmaceutical companies focused on pre-launch randomized controlled trial (RCT) data to develop value arguments and negotiate for market access. RWE is enabling continued scrutiny in the market among all key stakeholders – regulators, payers, healthcare providers, academics and patients. Traditional hurdles of efficacy, safety, quality, and value for money are extended as RWE enables conditional reimbursement and product reassessments. In effect, this shift will eventually force

This may sound far-fetched. However, stakeholders have always desired to understand whether the treatments they are using and paying for truly work in the way they had expected. Now, technology and the proliferation of data enable them to do that, although barriers of trust and stakeholder alignment on appropriate use are slowing the pace. Nevertheless, this ‘prove it works’ era is happening, given budget constraints, safety concerns, a perceived slowdown in innovation, and greater value for money scrutiny.

FIGURE 1: RWE WILL EXTEND THE COURSE AND FORCE PRODUCTS TO REVISIT HURDLES POST-LAUNCH

The former sprint to achieve pricing and market access...

RWE assessments extend the traditional hurdles of efficacy, safety, quality, and value for money Source: IMS Consulting Group

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...now requires multiple laps around the track with conditional reimbursement and access

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INSIGHTS | REAL-WORLD EVIDENCE ...continued from previous page

CHANGES REFLECTED IN KEY MARKETS The era is beginning to manifest itself through specific regulator and payer activities in several key markets, facilitated by regulator-mandated pharmacosurveillance programs (eg, Risk Evaluation and Mitigation Strategies [REMS] in the U.S.). Today, RWE primarily affects product label and uptake by informing safety claims and appropriate use, respectively, although a future consensus is emerging and the evidence of broader applicability is building: Effects on access: Evidence generated by registries in Sweden informs product reassessments and has even improved access. Using data from its Rheumatoid Arthritis (RA) registry, the National Board of Health and Welfare determined that early treatment with TNF-inhibitors was cost-effective. As a result, national RA guidelines prioritized early treatment with TNF-inhibitors. Effects on price: AMNOG legislation in Germany specifies that product prices are to be reassessed post-launch, with likely reduction in price and impact on product use. Effects on price and access: Similarly, in the U.K., value-based pricing may enable post-launch outcomes to support revisions of price and access, and ultimately influence uptake.

The market has already reached a tipping point where the â&#x20AC;&#x2DC;prove it worksâ&#x20AC;&#x2122; era will transform the healthcare industry

Page 14

Effects on price, access, and uptake: U.S. payers have signaled their intent to improve quality and reduce costs by leveraging RWE through strategic acquisitions and establishment of research institutes. For instance, CVS Caremark plans to conduct comparative effectiveness research (CER) using its own anonymized claims data to inform guidelines, restrictions, and negotiations with manufacturers. Over time, regulators will use RWE to revise product labels to highlight safety concerns, and payers may use RWE to revisit price, act upon conditional access, and inform guidelines that influence or drive clinical practice. Although the future will play out at different speeds across markets and channels, core elements of lifecycle scrutiny will occur with certainty.

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

REAL-WORLD EVIDENCE | INSIGHTS

KEY ENABLERS Four enablers shape the pace and strength of RWE in a market: 1. Systems infrastructure and technology must be put in place to facilitate logistics, data collection, and to make linkages between different sources. Recent examples include the General Practice Research Database (GPRD) data link between the primary care and hospital setting in the UK, and innovative solutions with hospital administrations systems to harness techniques such as natural language processing and predictive matching. 2. Defined methods (eg, propensity scoring) must be exploited and developed further. 3. Stakeholders must align around ways of ensuring that data and analyses are used appropriately, especially when pharmaceutical companies are involved. 4. A legal and ethical framework creating a clear governance structure for the way in which data can be used and by whom, is integral to facilitating analyses with real-world data. Freedom of information facilitates the growth and integration of RWE into decision making but access to data and privacy laws vary widely. ADDRESSING THE CHALLENGES The market has already reached a tipping point where the ‘prove it works’ era will transform the healthcare industry. Manufacturers are no longer in a sprint to the ‘finish line’ of launch. The industry now has to run on a perpetual track where the end of the race is never really passed (eg, payers will still care about RWE for a product after patent expiry). Manufacturers must begin to address these challenges strategically and proactively; merely being reactive is a worst-case scenario. As one Italian payer recently advised pharmaceutical companies: “Drive, do not follow.” By increasing efforts to play more strategically today, manufacturers have the opportunity to ‘shape the track’ that defines the impact and role of RWE. Collectively, the pharmaceutical industry must articulate its vision for and broaden its role within RWE.

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To win the race, organizations must refocus on enabling lifecycle evidence development: • Secure a slot in the race: Work with stakeholders to address concerns about the objectives of the analysis, disclosing intended RWE studies at an early stage (as for RCTs) and working with third-parties to remove bias concerns. • Prepare with the end goal in mind: Develop Lifecycle Market Access (LMA) plans that focus on evidence generation early in the lifecycle and support a coordinated RCT-RWE strategy. A winning vision may require calculated risks that move beyond conventional paths. • Get off to a good start: Leverage RCTs to gain pricing and market access by understanding payer questions and concerns. Build confidence with payers by incorporating their questions around a product’s efficacy or safety into RWE planning while still protecting manufacturers’ interests. • Maintain the pace: Remain focused post-launch on LMA by demonstrating and communicating value in a real-world setting and leverage RWE to improve the value proposition or further differentiate in a competitive environment. • Adjust to changing conditions: Stay flexible to respond to evolving market and competitive dynamics. • Consider participating in relays: Build off others’ RWE to help create a greater understanding of the effectiveness of treatments and address broader stakeholder questions. • Continuous learning: Maintain support, refine approaches, and transfer learnings to other assets. To support this approach, manufacturers must reshape to build necessary skill sets and define ownership of RWE within their organizations. Too often, responsibility for RWE exists in siloed functions, deep in countries or with individual brand teams, who cannot drive the broader credibility and skill-development priorities. Accelerating RWE is potentially disruptive, leading to new regulatory and pricing & market access structures, increasing product evidence requirements and requiring changes in relative stakeholder power. However, taking an active role in RWE provides potential opportunities to optimize portfolio assets, leverage internal efficiencies, and create a platform to build stronger stakeholder relationships. •

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INSIGHTS | OBSERVATIONAL STUDIES IN ASIA

Converging trends are driving new requirements for real-world studies in the emerging pharmaceutical markets, especially in Asia. As more companies face the need to plan studies for observational research in Asian countries, we consider the challenges – and the advantages – of primary data collection in the region.

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

Núria Lara Surinach, MD, MSC is Principal HEOR, IMS Consulting Group, Spain. Nlara@imscg.com

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

OBSERVATIONAL STUDIES IN ASIA | INSIGHTS

Conducting real-world studies in emerging Asian markets CHALLENGES FOR OBSERVATIONAL RESEARCH The rising demand for real-world data comparing the relative value of medical technologies has opened up new opportunities for outcomes research, with a corresponding increase in the collection of primary data through observational studies. Coming at a time when most of the major pharmaceutical manufacturers report an increasing percentage of sales revenue from emerging markets, this is creating a need for real-world data – and consequently for observational studies – in Asia. Understanding the issues, hurdles and benefits of running observational studies in the emerging Asian markets is fast becoming essential for pharmaceutical organizations. Companies looking to plan an observational study in this region will need to consider a number of fundamental, but critical, issues. PILOT FEASIBILITY OF STUDY DESIGN AND REQUIRED DATA One of the first things to consider when planning an observational study in Asian markets is the feasibility of the chosen study design.Traditionally, observational studies can collect data in a cross-sectional way, retrospectively (based on medical chart review) or prospectively. However, in many Asian countries, medical records are invariably incomplete and often nonexistent. This is especially apparent within primary care, making retrospective chart reviews a particular challenge in this setting. Another important issue is the type of data to be collected. Although a certain amount of clinical data can be found in the medical charts, in some of the Asian countries at least, information on healthcare resource use may be scarce. Thus, a first recommended step for companies is to undertake a small pilot study in each of the participating countries, in order to evaluate the feasibility of the desired study design as well as the availability of data. This important preliminary activity is often overlooked, due either to time pressures or unwillingness to invest further money in the project. Nevertheless, when planning an observational study that includes clinical, economic or quality-of-life data in emerging Asian markets, a pilot study is highly cost-effective, avoiding both potential delays in field work and failure to meet the desired study outcomes.

PHYSICIAN RECRUITMENT Another critical step for study implementation is physician recruitment. Often working in overcrowded conditions, with many patients to see in a day, doctors in emerging Asian markets have limited time to dedicate to research. Securing their agreement to take part in an observational study, especially a long, prospective investigation requiring follow-up over a defined period, can thus be difficult.When inviting study participation, there is thus a need to contact a high number of physicians, making databases with lists of potential participants crucial. It is also important to offer physicians some kind of incentive to partake in the study apart from the economic one. Doctors tend to appreciate the scientific value of the research and the possibility of being part of the publication. HEALTHCARE ORGANIZATION AND ACCESS When considering the feasibility of certain studies, the structure and organization of healthcare must be taken into account, particularly where there is no provision for continuity in the patient-physician relationship. This lack of continuity can make patient follow-up challenging especially outside the hospital setting where several physicians may be consulted for a single disease episode.The same applies to physicians who frequently move from one hospital/clinic to another in a short period of time. Access to healthcare can also be an issue in some countries, such as India, where only 10% of the population is covered through health financing schemes. This is important in epidemiological studies as the prevalence of certain diseases measured at the physician’s office is probably skewed towards more wealthy parts of the population with access to healthcare. OBTAINING IRB APPROVAL Before commencing field work and data collection, it is necessary to obtain Institutional Review Board (IRB) approval (Figure 1). The lack of clear guidance on evaluating observational studies is creating a lot of uncertainty in a number of countries (eg India, South Korea) in terms of the best way to proceed, and requires an experienced local team. continued on next page

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INSIGHTS | OBSERVATIONAL STUDIES IN ASIA ...continued from previous page

FIGURE 1: ILLUSTRATIVE EXAMPLES OF THE IRB PROCESS IN INDIA, SOUTH KOREA AND TAIWAN

PUBLIC

Despite the challenges, there are clear advantages to conducting observational studies in emerging Asian markets

RECRUITMENT

HOSPITAL ETHIC COMMITTEE

Select institutions and recruit doctors

Receive approval from ethic committee

DCGI NOTIFICATION

IRB

PRIVATE

Submit IRB approval Select institutions and recruit doctors (Screeners) Challenges: All documents must be ready and prepared for recruitment

Duration

Notify DCGI

Not required Note: PI is required to participate in necessary meetings for both ethic committee and IRB approval process

30-35 Days

25 Days

20-25 Days

In India, there are 3-4 processes for obtaining IRB approval, taking approximately 3-4 months.

CLINIC

HOSPITAL

HOSPITAL PI, CO-PI LISTING

CLINIC LISTING

HOSPITAL IRB

Develop Hospital PI, co-PI list that will be specified in the hospital IRB form

Challenges: “Skillful” introduction and persuasion process with hospital PI/CoPIs are needed in the system of dual-punishment*

Submit IRBs to multiple centers (target centers) and gain approval

Develop clinic list that should be included in hospital IRB submission form

*Dual punishment system: Providers as well as the recipients of an illegal rebate will be subject to criminal penalities.

Duration

20 Days

Challenges: • Different requirements by each hospital IRB committee are expected and we have to manage them including protcol modification by hospital • Some hospital IRB officials refused to incorporate clinic physicians in their IRB list • Any change in the clinic list should be reported and approved by PI and each IRB committee even though it is incorporated as an attachment.

60-75 Days

20 Days

In South Korea, multiple-center IRB is required.

CLINIC

HOSPITAL

HOSPITAL IRB

JIRB

Receive approval from Hospital IRB

Not required

Receive approval from JIRB

Not required

150 Days

Duration

15-21 Days

Taiwan requires separate IRB approval for hospitals and clinics.

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

OBSERVATIONAL STUDIES IN ASIA | INSIGHTS

In some cases, observational studies are seen and treated as randomized clinical trials (RCTs). Our experience has shown that even pure observational epidemiological studies, which do not measure any drug-related outcome, may be treated as RCTs, in the absence of specific guidelines and knowledge of observational research. India In India, there are no set norms for including a physician in a study. Government hospital physicians may mention the hospital Ethics Committee (EC) but later on agree for the central EC. Much depends on how strictly the code of conduct is followed in a particular hospital. A similar situation arises with the contract for investigators. Every hospital may try to insist on using their contract template which quite often refers to terms more related to RCTs than observational studies. For some study designs, it would be advisable to opt first for a market research approach, thus avoiding some of these pitfalls. This situation clearly underscores the need to have an experienced team in place that is able to manage the submission and maintain regular contact with the IRB bodies.

DATA COLLECTION Methods for data collection must be adapted to the particular idiosyncrasies of each country. In certain Asian markets, the use of computers at physician-level is quite well spread, while in other countries like India or China, for example, the recommendation is to collect the data using pen and paper. In the case of physician surveys, telephone can be an option in some of the more developed Asian markets, whilst in others a face-to-face approach is needed. Real-world data includes patient-reported outcomes, which can be a challenge in Asian markets if PRO questionnaires have not been validated in the local language. In some cases, translation into more than 10 different languages could be required in a single country in order to cover the entire population! Illiteracy can also be a problem, making the use of self-administered questionnaires problematic.

CLEAR BENEFITS Despite the challenges, there are clear advantages to conducting observational studies in emerging Asian South Korea In South Korea, current government regulations are limited markets: lower costs, access to much higher patient to clinical trials or post-marketing surveillance (PMS) to numbers, and in many countries a shifting spectrum of monitor drug information, including adverse events.There disease which increasingly resembles that of developed are no formal regulations in the IRB process for countries, with growing emphasis on cardiovascular and observational, non-interventional (of drug) studies in clinics. metabolic conditions. All the challenges can be overcome with an experienced local team in each of the participant The Korean Ministry of Health & Welfare (MHW) countries that is able to adapt the study needs to the recommends the incorporation of clinics in the IRB prevailing healthcare system. â&#x20AC;˘ approval process of hospitals whose physicians are involved in the study. However, in studies involving many clinic physicians, GH practitioners tend to hold back from taking a product investigator (PI) or co-PI role as it would leave them responsible for the study: the current system of dual punishment means providers as well as the recipients of an illegal rebate will be subject to criminal penalties. Consequently, skillful communication with GH physicians is extremely important. Recently, the MHW has moved to set a regulation for public IRB in the case of small health centers or clinics where it is difficult to run an independent IRB committee. Draft guidelines have been published with a plan to enact the regulation in the next year.

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INSIGHTS | EUROPEAN EMR DATA

Increasing emphasis on real-world data has seen tremendous growth in the use of patient-level databases as their value in capturing clinical practice becomes increasingly apparent. The IMS LifeLinkâ&#x201E;˘ Electronic Medical Records Database is among the most comprehensive of its kind in Europe, with new features and growing applicability across a range of research applications.

The authors: Massoud Toussi, MD, MSC, PHD is Medical Director HEOR, IMS Consulting Group, France. Mtoussi@imscg.com

Nathalie Grandfils, MSC is Engagement Manager HEOR, IMS Consulting Group, France. Ngrandfils@imscg.com

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EUROPEAN EMR DATA | INSIGHTS

Capturing the real world in real time IMS LIFELINK™ ELECTRONIC MEDICAL RECORDS DATABASE IN EUROPE WHY USE REAL-WORLD DATA?

on some potential confounding variables such as lifestyle;2 there are uncertainties around the completion There is a general consensus that randomized clinical of their data because doctors use their software as they trials (RCTs), with their small sample size, controlled like; they typically overlook non-prescription environment and focus on short-term efficacy and safety, medications; and they are unsuited for outcomes which cannot deliver all the requisite information about the safe are poorly defined by standard classifications of disease. and effective use of a medicine at the time of launch.1 Post-marketing evaluations must generally include a IMS LIFELINK ELECTRONIC MEDICAL RECORDS DATABASE sufficient number of exposed persons to detect adverse One of the most comprehensive pharmacoepideevents with a relatively low incidence rate. However, miological databases available in Europe is the IMS studies of this scale are expensive, challenging and timeLifeLink Electronic Medical Records Database. This is a consuming. Ironically, they are often needed quickly, to longitudinal patient database containing the electronic address immediate and serious regulatory, commercial health records of patients followed up by a representative and public health concerns.2 panel of physicians in France, Germany and the UK. Data are collected directly and continually during patient GROWING ROLE OF HEALTHCARE DATABASES visits, via medical office software and stored in a central In recent years, the use of large healthcare databases for database after de-identification. real-world evidence has expanded significantly. Developed from the automatic electronic recording of The database has formed the basis of many studies filled prescriptions, professional services and and peer-reviewed scientific publications spanning hospitalizations,1 these databases enable long-term epidemiology, pharmacoepidemiology, health economics, observation of large study populations, allow for pharmacovigilance, pharmaceutical guidelines, examination of specific sub-populations, and offer a compliance/persistence, prescribing behavior and drug relatively inexpensive approach to addressing time- applications.i It allows longitudinal follow-up of all visits sensitive issues raised by decision makers.3 Moreover, it by a patient consulting the same practitioner in the panel has been proposed that when adequately controlled, and is true to the principle of observational data collection: observational studies produce similar results to RCTs.4,5 there is no intervention in the participating physicians’ workflow. The strength of medical records databases lies in a A number of key strengths bring particular advantages number of important advantages: the potential for for the LifeLink Electronic Medical Records Database: providing a very large sample size at relatively low cost; the absence of interviewer and/or recall bias; the lack of • Longitudinal with large time span: Patients and practices can be analyzed in both a cross-sectional and need to validate data against a source; and, most longitudinal way over a period of more than 20 years importantly, the possibility to study real-world in Germany and the UK, and 14 years in France. effectiveness and utilization patterns.1 However, they are not without their limitations: they can lack information continued on next page

COVERAGE

GERMANY

FRANCE

Total country population (Millions)

82.5

60.6

Patients (Millions)

4.2

630/238

3100/2500

977/1013

Prescriptions (Millions)

168

42.5

Data available since

1991

1989

1997

Physicians/practices

TABLE 1: LIFELINK ELECTRONIC MEDICAL RECORDS DATABASE COVERS AN EXTENSIVE PATIENT POPULATION iA

list of publications covering the use of IMS LifeLink Electronic Medical Records Database is available on request.

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INSIGHTS | EUROPEAN EMR DATA ...continued from previous page

•

Very large sample size: Approximately 22 million patients representing 287 million prescriptions are available at European level for longitudinal analyses. Table 1 (page 21) shows the number of prescriptions, patients and physicians/practices covered in the database, by country.

•

Valid and representative: In a thorough evaluation, Becher, et al (2009)6 found the LifeLink Electronic Medical Records Database to be sufficiently representative and valid in terms of panel of physician characteristics (age, region) and patients (baseline characteristics, major pathologies and major drug prescriptions) compared to the standard data obtained via official institutions in each country.

•

Regularly updated and rapidly available: The database is updated monthly, with updates available 6 weeks after the end of a month in each country.

FROM DATABASE TO PROSPECTIVE STUDY DESIGN Countering one of the principal shortcomings of databases – the absence of data that may be required for a study – a new feature in the LifeLink Electronic Medical Records Database enables supplementary information to be captured through add-on questionnaires. The main value of these is in offering retro/prospective designs to researchers, where part of the data is collected from the patient’s medical history and the rest by prospective follow-up. Integrated into the usual medical software, the add-on screen questionnaire pops up at the end of the consultation, based on certain patient characteristics or whether a particular drug has been prescribed. The physician is thus not influenced by a “study questionnaire” at the moment of prescribing, nor by any prejudice relating to the patient’s willingness to participate in the study, thereby reducing the risk of selection and selfselection bias. Also, it is now possible to add complete forms to the standard patient record, allowing for prospective collection of specific data for all patients. Add-on questionnaires enable a wealth of supplementary data to be collected including:

Ongoing investment in the database is assured, reflecting a continued commitment to ensuring the best available patient-level EMR data Page 22

• • • • • • • •

Disease severity or diagnosis scales Risk factors (eg, exposure to toxic agents in the past) Additional non-pharmacological therapies (eg, homeopathy, psychotherapy) Scales of evaluation of performance, observance, efficacy of drugs, etc Reasons for discontinuing therapy Information regarding hospitalizations, or consultation of other practitioners Direct or indirect costs not usually found in patient records (eg, lost working days) Quality of life or patient satisfaction questionnaires

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

EUROPEAN EMR DATA | INSIGHTS

Currently operational in France, with the possibility of extensions to other countries, the “add-on” feature enhances the value of the database as a technical solution to link to the physicians’ medical software – subject to prior acceptance and the approval of the regulatory authorities for each specific study. RESEARCH APPLICATIONS As enumerated by Schneeweiss and Avorn1, the research applications of patient record databases enable a better understanding of many different aspects of healthcare, such as drug utilization, adverse drug effects or possible unexpected beneficial drug effects and the impact of changes to health policy. They also support the efforts of pharmaceutical manufacturers in demonstrating the benefits of new medical technologies across a range of analyses. Examples of the way in which the LifeLink Electronic Medical Records Database has informed research in each of these areas include: Drug utilization and off-label use Drug utilization research is an essential part of pharmacoepidemiology as it describes the extent, nature and determinants of drug exposure.7 In fact, the study of real daily dose, respect of the summary of product characteristics (SmPCs) and description of associated prescriptions is important and often required by health authorities when assessing a medicine. A drug utilization study using LifeLink Electronic Medical Records Database by Schröder-Bernhardi, et al (2004)8 provided valuable insights into off-label drug use in primary care in Germany, with a focus on proton pump inhibitors and P-blockers. Identifying adverse/beneficial drug effects One of the major domains of pharmacoepidemiology is research on the safety and beneficial effects of drugs.The LifeLink Electronic Medical Records Database is widely used in the context of Risk Management Plans required by the European Medicines Agency. There are many examples of its role in revealing potential safety issues, such as the findings of Star, et al (2010),9 who identified a potential causal link between prescriptions of antipsychotic medications and the occurrence of pneumonia. Understanding and informing health policy decisions Identifying the effects of delisting, withdrawal or change in prescription status is key to understanding the impact of policy changes on health systems, physicians and patients. A study by Devaux, et al (2007)10 using the LifeLink Electronic Medical Records Database found that delisting mucolytic expectorants had no impact on the cost of treatment for cough: many doctors had replaced the conventional expectorant treatments with

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Robust information supporting the benefits of medical innovations is increasingly needed for manufacturers to negotiate optimal conditions for commercialization more expensive reimbursed classes but the overall cost for the health care system remained the same. This study also enabled the patients and physicians affected by the policy change to be characterized. Studies of disease prevalence and incidence are also important for health policy decisions and are more timeand cost-effective when conducted via databases. Hsia, et al (2009)11 used the LifeLink Electronic Medical Records Database to investigate the prevalence of childhood diabetes over an 8-year period in the UK. The authors found a significant increase in the prevalence of both type 1 and type 2 diabetes in children and adolescents in the UK, providing valuable input for the funding and design of future services. Demonstrating the benefits of medical innovations Robust information supporting the benefits of medical innovations is increasingly needed for manufacturers to negotiate optimal conditions for commercialization. These studies include, but are not limited to, the evaluation of cost-effectiveness, budget impact, persistence and observance, target populations by indication, and unmet medical need. Three recent examples illustrate the use of LifeLink Electronic Medical Records Database in this context:

•

Wade & Haring (2010)12 examined the economic and human costs of depression and the potential savings associated with improvement in patient adherence to treatment with antidepressants through the use of enhanced-care programs. They used LifeLink Electronic Medical Records Database data as a reference to compare the results of their study with real life. The results indicated that enhanced-care programs may lower costs associated with depression and improve patient lives, providing a strong case for companies to establish such programs in association with their drug release. continued on next page

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INSIGHTS | EUROPEAN EMR DATA ...continued from previous page

•

Aballéa, et al (2008)13 compared treatment outcomes and cost associated with choice of fixed-dose inhaled corticosteroid/long-acting beta-agonists for asthma maintenance therapy, using LifeLink Electronic Medical Records Database in Germany. The study enabled a better understanding of cost-effectiveness of two different treatment choices in chronic asthma. Rathmann, et al (2007)14 studied the trends of outpatient prescription drug costs in diabetic patients in Germany from 1994 to 2004. Using 46,017 diabetic patients and 46,017 age and sex matched control subjects in 400 nationwide practices they showed that prescription drug costs among diabetic patients increased 60% during the study period, which was twofold higher than the increase in non-diabetic patients. Using the database, they were able to correlate growth in drug expenditure for diabetes treatment to progress in pharmacological therapy.

A VALID, REPRESENTATIVE RESOURCE The validity and representativeness of the IMS LifeLink Electronic Medical Records Database in retrospective studies has been demonstrated across a range of disease areas. The use of add-on questionnaires in conjunction with data collected from patient records is an important technological advancement, enabling combined retrospective and prospective designs – a particular benefit when research questions involve data that are not generally found in patient records. This is often the case with studies requested by health and drug regulation authorities, such as risk management plans, costeffectiveness studies and outcomes research. Ongoing investment in the database is assured, reflecting a continued commitment to ensuring the best available patient-level EMR, hospital and claims databases, not only in Europe but also the Americas and emerging pharmaceutical markets of the world. •

1Schneeweiss

S, Avorn J. A review of uses of healthcare utilization databases for epidemiologic research on therapeutics. J Clin Epidemiol. 2005, Apr; 58(4):323–37. 2Strom BL, Kimmel SE. Textbook of Pharmacoepidemiology. 1st ed. John Wiley & Sons Ltd; 2006. 518 p. 3Motheral B, Brooks J, Clark MA, Crown WH, Davey P, Hutchins D, et al. A checklist for retrospective database studies : Report of the ISPOR Task Force on Retrospective Databases.Value Health. 2003, Apr;6(2):90–7. 4Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N. Engl. J. Med. 2000, Jun 22;342(25):1878–86. 5Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N. Engl. J. Med. 2000, Jun 22;342(25):1887–92. 6Becher H, Kostev K, Schröder-Bernhardi D.Validity and representativeness of the “Disease Analyzer” patient database for use in pharmacoepidemiological and pharmacoeconomic studies. Int J Clin Pharmacol Ther, 2009, Oct;47(10):617–26. 7World Health Organization. Introduction to Drug Utilization Research. WHO. Oslo, Norway: 2003. 8Schröder-Bernhardi D, Roth K, Dietlein G. Off-label use of proton pump inhibitors and P-blockers in general practices: An analysis using the Disease Analyzer--mediplus patient database. Int J Clin Pharmacol Ther. 2004, Nov;42(11):581–8. 9Star K, Bate A, Meyboom RH, Edwards IR. Pneumonia following antipsychotic prescriptions in electronic health records: A patient safety concern? Br J Gen Pract. 2010, Oct;60(579):e385–94 10Devaux M, Grandfils N, Sermet C. Deslisting of Mucolytics and Expectorants: What is the impact of general practioners’ prescribing? Institute for research and information in health economics: Questions d’économie de la Santé. 2007, Dec; (128). 11Hsia Y, Neubert AC, Rani F,Viner RM, Hindmarsh PC, Wong ICK. An increase in the prevalence of type 1 and 2 diabetes in children and adolescents: results from prescription data from a UK general practice database. Br J Clin Pharmacol. 2009, Feb;67(2):242–9 12Wade AG, Häring J. A review of the costs associated with depression and treatment non-compliance: the potential benefits of online support. Int Clin Psychopharmacol. 2010 Sep;25(5):288–96 13Aballéa S, Cure S,Vogelmeier C, Wirén A. A retrospective database study comparing treatment outcomes and cost associated with choice of fixed-dose inhaled corticosteroid/long-acting beta-agonists for asthma maintenance treatment in Germany. Int. J. Clin. Pract. 2008, Dec;62(12):1870–9 14Rathmann W, Haastert B, Icks A, Giani G. Trends in outpatient prescription drug costs in diabetic patients in Germany, 1994-2004. Diabetes Care. 2007 Apr;30(4):848–53.

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IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

IMS ISPOR SYMPOSIUM | INSIGHTS

New horizons for patient-level data Alongside key developments in healthcare, new enhancements to public- and privatesector datasets are transforming the collection and management of patient-level data in the U.S. An IMS Symposium at the 16th Annual International Meeting of ISPOR explored the progress of these initiatives in enabling faster, more transparent outcomes research.

This article summarizes presentations from the IMS Symposium: New Patient-Level Data from Sentinel, ACA and Recent Commercial Endeavors: Implications for Outcomes Research, held during the ISPOR 16th Annual International Meeting in Baltimore, May 2011. Chair: Gregory Hess, MD, MBA, MSC, VP HEOR and Chief Medical Officer, SDI Health. Speakers: Joshua Benner, PharmD, SCD, Fellow at the Brookings Institution and Managing Director, Engelberg Center for Health Care Reform and Vernon Schabert, PHD, Senior Principal HEOR, IMS Consulting Group.

The authors Vernon Schabert, PHD is Global Leader Retrospective Outcomes Research and Senior Principal HEOR, IMS Consulting Group, U.S. Vschabert@imscg.com

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

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INSIGHTS | IMS ISPOR SYMPOSIUM

New horizons for patient-level data IMPLICATIONS FOR OUTCOMES RESEARCH New innovations in patient-level health data from both public- and private-sector initiatives have the potential to significantly extend the perceived utility of health economics and outcomes research (HEOR) in the U.S. Along with traditional medical claims data, Mini-Sentinel is combining Electronic Health Records (EHRs), detailed hospital data and more, for over 70 million patients; the Affordable Care Act and American Recovery and Reinvestment Act have provided funding to expand and automate routine medical care data capture as well as a means, through the Patient-Centered Outcomes Research Institute (PCORI), for directing these initiatives to improve outcomes research. Commercial datasets are also being enhanced and expanded. CONCENTRATED PRESSURE These advances reflect a number of important developments that are increasing the evidence demands for pharmaceutical market access decisions: greater awareness of the gaps between efficacy and effectiveness in the real world; the move towards conditional pricing & market access; more frequent requirements for risk evaluation & mitigation strategies; the economic consequences to manufacturers of pursuing personalized medicine product strategies; the growing need to address emerging markets in launch strategy; and the increasing threat from biosimilars outside the U.S.This concentrated pressure on the information required from data calls for higher standards of completeness, greater clinical detail, a wider geographic reach, and a broader scope of care than has so far been available. PUBLIC-SECTOR INITIATIVES The Engelberg Center for Health Care Reform at the Brookings Institution is developing and helping to implement various practical, data-driven policy solutions that will enable better evidence on the safety and effectiveness of medicines and the value of the healthcare delivered to patients. Several of these initiatives, involving public and private partners, aggregate and leverage data which is already being collected in the routine delivery of care.

in the U.S. For 10 million of these patients, claims are also linked to electronic medical records (EMRs). The system includes 88 hospitals and a number of device and disease registries. Similar efforts, including the EU-ADR Project and PROTECT, are taking place in Europe. In January 2011, the pilot system was declared open for business with work commencing on the first surveillance project examining a potential association between saxagliptin and acute myocardial infarction (AMI). The Sentinel system is a practical demonstration of a scalable distributed database network which makes respectful use of patient-level data with the help of a common data model that allows one executable query to be implemented across the network. It will not only provide better tools for monitoring medical product safety but also additional resources for others developing evidence from similar data. It offers a model for developing transparent protocols and provides ongoing methods development for quantifying and reducing bias in exposure outcome associations that might also be relevant to comparative effectiveness research (CER) and other inferential analyses. Sentinel also develops standardized definitions of several health outcomes of interest, such as AMI, including the validation of claims-based definition of those health outcomes against medical charts. Perhaps most importantly, the system is helping to build capacity for conducting safety analyses on existing databases at over 100 different participating institutions – capacity that can also be used to conduct other forms of evidence development. 2. Investment in data sources for CER Research from the Engelberg Center in 2010 found that more than half of the US$1.1 billion funding allocated to CER supported new evidence development and synthesis through expanded capacity to conduct observational studies. Initiatives to expand the CER data infrastructure include:

• Multi-Payer Claims Database with the underlying goal of making Medicare, Medicaid and private payer 1. FDA’s Sentinel Initiative claims data more readily available to individual researchers. A further goal is the creation of a The Sentinel Initiative was launched in 2008 to augment sustainable ecosystem where data owners find it in the Agency’s current safety surveillance capabilities. their interest to share their data and partner with Today, the “Mini-Sentinel” pilot system can access the researchers. electronic, integrated claims records of 71 million patients

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IMS ISPOR SYMPOSIUM | INSIGHTS

â&#x20AC;˘ New distributed databases providing access to claims data and EMRs by linking individual primary care practices. â&#x20AC;˘ Product and disease registries enabling the collection of information that is unavailable from claims or EMRs, such as implanted devices or patientreported outcomes. Some of these registries can also be linked to claims databases to further broaden available information. 3. Quality of care: Improving measurement and reporting

Although these initiatives build on the work of many past and ongoing efforts, the exciting progress is that these are no longer disparate activities The results of pilot programs in Colorado and Florida suggest that this approach is reliable, scalable and acceptable to both providers and payers.

The promotion of high-quality, high-value care also requires the ability to measure and report on the performance of individual providers. Efforts in this area focus on facilitating the coordination of care by providing doctors and other healthcare providers with timely, comprehensive information on each patient, and to assist new payment models, such as Accountable Care Organizations (ACOs), by attributing patients and their outcomes to the providers who should be accountable for them.

Although these initiatives build on the work of many past and ongoing efforts, the exciting progress being made today is that these are no longer disparate activities operating in silos. However, further work is needed in a number of areas:

Three notable projects that are helping to addressing barriers to effective performance measurement are the Health and Human Services (HHS) National Strategy for Quality Improvement, the HHS Beacon Community Program, and the Robert Wood Johnson Foundation High-Value Health Care Project. Collectively, these programs are accomplishing three important goals:

2. Policies that protect privacy while supporting learning from the delivery of care.

1. Developing methods for aggregating consistent data from multiple payers in a distributed network that protects patient privacy and the proprietary data of the payers.

1. Consistent use of health IT to transfer paper records to electronic formats and adhere to standards that make systems interoperable so that information can be aggregated and analyzed in a consistent manner.

3. Methodological best practices to reduce bias in exposure outcome associations when conducting observational research. 4. Effective dissemination of the evidence, which is a clear, critical step in improving quality of care. 5. Payment and benefit reforms that can promote quality and value among providers, patients and product manufacturers.

APPLYING THE EVIDENCE The evidence generated from ongoing projects will be used in a number of ways: for safety surveillance, CER 3. Piloting new measures that will help providers and quality measurement reporting. Evidence from benchmark the costs of care they provide to patients Sentinel will be directly considered by the FDA in with specific conditions. regulatory decisions. Sentinel also has a history of A distributed approach to addressing data aggregation impacting formulary decisions by payers and healthcare challenges for quality measurement and reporting has delivery systems. CER will be considered in the context been proposed by Roski and McClellan of Brookingsi. of the overall body of evidence when making coverage The distinguishing feature of this is a feedback loop to decisions and may be requested as a condition of provide the results of quality measurement to consumers, coverage. Finally, for quality measurement, the evidence not just doctors and payers. The goal here is to encourage will be used to reward providers who deliver highgreater engagement in care and the use of high-quality, quality, high-value care, as well as to inform benefit esigns high-value providers by patients and consumers. that can promote the use of such providers. 2. Filling gaps and measures in important areas like cancer care.

Roski J. McClellan M. Health Affairs, 2011; 30 (4):682-9. See also: Higgins A, Zeddies T, Pearson SD. Health Affairs, 2011; 30 (4):673-81

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INSIGHTS | IMS ISPOR SYMPOSIUM ...continued from previous page

PRIVATE-SECTOR INITIATIVES In the private sector, the development of data sources largely reflects anticipated market needs. According to IMS Market Prognosisii, antineoplastics and immunomodulators will be the leading growth market over the next five years. These products include cancer medicines and other biologics, such as monoclonal antibodies, growth factors, disease-modifying antirheumatic drugs (DMARDs) and erythropoietinstimulating agents.

Going forward, data demands will be increasingly driven by market growth concentrated among specialist-managed therapies

Scope of Care

Today, a growing number aim to link data across different sources, for example: 1. Traditional payer data sources are being linked with hospital detail data enabling more specific information This is not the landscape of ten years ago, when HEOR around the consequences of a hospitalization. was primarily focused on CNS diseases and primary care conditions such as diabetes, endocrine and cardiovascular 2. Traditional pharmacy data warehouses are trying to disorders. Going forward, data demands will be link-up this information. The challenge with increasingly driven by market growth concentrated pharmacy data, especially in the U.S., is the absence of among specialist-managed therapies. Although defining diagnostic information and the details of other clinical the target populations for such therapies requires highlytreatments that are provided. There has been an effort specific clinical detail, research questions around these to take that pharmacy data and link it, for example, therapies will still require access to the full scope of care. with claims data that might be available from a medical New data sources must thus be able to address both the switch provider. spectrum of care and specificity of clinical information 3. There have also been attempts to link pharmacy data demanded more frequently in specialty markets. with EMR data and to some extent with lab results to help build a broader clinical history across the full GROWING LINKAGE ACROSS SOURCES scope of care. In cancer therapy, for example, data from Historically, databases have been developed by compiling oncology EMRs â&#x20AC;&#x201C; which have rich detail for multiple instances of a single data type (eg, payer data, identifying biomarkers, stage of disease and clinical pharmacy records, EMRs). This has resulted in most pathways â&#x20AC;&#x201C; has been linked with broader information available sources having either a wide scope of care or from pharmacy data enabling insights beyond the substantial clinical detail, but not both (Figure 1). care itself. These advancements beyond the single-silo focus of data FIGURE 1: MOST COMMERCIAL DATA SOURCES TRADE-OFF are taking place in two ways: Firstly, through the SCOPE OF CARE VERSUS CLINICAL DETAIL technique of probabilistic matching, where independent data sources are used to develop sense of care patterns, High geographic location and other clues to match patients in the hospitals with patients in claims data; and secondly, Payer by creating an uncommon encryption mechanism and Best Utility relying on the strength of a trusted third party to own the encryption keys to match those data together. PC EMR Rx IP Lab

Low Low

Clinical Detail

Source: IMS Symposium, ISPOR Baltimore, May 23, 2011

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High

BEYOND THE US Most of these early efforts have been concentrated in the U.S., but more are now emerging elsewhere. Many of these ex-U.S. initiatives involve public/private partnerships or public academic or government institutions that have more legal and ethical flexibility in joining disparate data sources. Examples include the PHARMO Institute for Drug Outcomes Research in ii

IMS Market Prognosis provides a five-year projection of growth at the country, regional and global level for health technology markets covering 80 percent of the industrialized and emerging markets world.

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IMS ISPOR SYMPOSIUM | INSIGHTS

the Netherlands, the Bremen Institute for Prevention Research and Social Medicine (BIPS) database in Germany, and the Odense University Pharmacoepidemiological Database (OPED) in Denmark. The trade-off is that access may be difficult, particularly access by for-profit companies, who may be treated with suspicion by public-sector collaboratives.

HEOR scientists are sure to play an increasingly important role in improving healthcare

CREATIVE LEVERAGING While there may not yet be a commercially available source for matching every piece of information in every country, there are nevertheless options for leveraging private-sector databases (Figure 2). In the short and medium term, there are two general strategies to leverage not-yet-perfect data:

BETTER DATA, RICHER RESEARCH

1. Creation of custom linkages among one or more identifiable or de-identified data sources. Identifiable sources may come from patient registries or payers and providers with direct access to identifiers. In some cases, those can be linked to commercial data sources through probabilistic matching or common encryption techniques, yielding data that meets demands for both clinical detail and scope of care. 2. Use of a modular approach, where real-world evidence forms the basis of inputs to a decision model, or is used as a portion of a Bayesian adaptive trial, to extend the value of data sources over time or across the scope of care. FIGURE 2: LEVERAGING NOT-YET-PERFECT DATA

Custom Linkages

Source 1

Source 2

Analysis 1 Modular Analyses

Analysis 2

Answer

Analysis 3

Source: IMS Symposium, ISPOR Baltimore, May 23, 2011

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Source 3

Recent advancements in the collection and management of patient-level data from both public- and private-sector initiatives have a number of important implications for health economics and outcomes research: 1. Firstly, they mean more and better data for all, via multi-payer networks that enable the scale of research to be increased. This involves going beyond claims data to EHRs and registries, adding significant richness to our research. 2. Secondly, they will create the opportunity for greater collaboration through distributed database networks. They do, however, imply a need for researchers to collaborate effectively with the owners of the data, whether they are in the government or private sector. 3. Thirdly, they will generate a need for more HEOR investigators with new and different skills, including expertise in health IT, cryptography, patient privacy, ethics, epidemiology, health economics, biostatistics and clinical decision analysis. 4. Finally, above all, growing emphasis on learning from the delivery of care provides a brighter future for, and very high expectations of, HEOR scientists who are sure to play an increasingly important role in improving healthcare by providing the evidence to support higher-quality, lower-cost care for patients and their populations. However, simply having more and better evidence is not enough. Supporting efforts must address the need for consistent use of health IT; policies that protect privacy while supporting learning from delivery of care; methodological best practices; effective dissemination of the evidence; and payment and benefit reforms promoting quality and value among providers, patients and manufacturers. â&#x20AC;˘

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INSIGHTS | DATA LINKAGE FOR CER

The ability to compare the relative effectiveness of different technologies and practices is now imperative to meet the growing demand for more rigorous outcomes research. But, along with the many challenges this brings, there is the need for new, advanced techniques to overcome the limitations of existing data. Here we consider the approach of data linkage in addressing this critical issue.

The author Christopher Blanchette, PHD, MS, MA is Principal HEOR, IMS Consulting Group, U.S. Cblanchette@imscg.com

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Probabilistic data linkage A NOVEL TECHNIQUE FOR COMPARATIVE EFFECTIVENESS RESEARCH DATA LIMITATIONS Today, there are only limited data available to conduct comparative effectiveness research. The two types that exist are survey and secondary databases, both of which have their own particular shortfalls. Survey data have led to landmark studies that have shaped the current practice and treatment of many chronic diseases. However, these data are also traditionally limited in external validity, specificity of measurement on key exposures and outcomes, and historically dated beyond application to current therapies.

MAKING THE LINK Database linkage methods generally employ both deterministic and probabilistic linking algorithms.1,2,3 Deterministic linkage techniques can be applied when both datasets provide patient-identifying information that can be cross-matched between the two datasets. This is the preferred form of data linkage because the focus is on matching the same patient from both datasets.

In the current climate with the regulatory and legal restraints on the use of personal health information (PHI) this approach is limited. In the absence of PHI, a probabilistic Secondary databases, including administrative data method may be applied. However, the focus is not on collected by the infrastructure of the healthcare system for identifying the same patient but rather on two matching the purposes of payment for services, also have limitations. patients with similar behavior and characteristics.4,5,6 The Administrative data are typically restricted to billing claims goal of both of these efforts is to identify the best method and provide limited clinical detail to confirm disease.They for pair-matching between datasets. are also often scarce on patient characteristics, such as race Probabilistic linking methods incorporate varying and ethnicity, and on indigent and self-pay populations, as strengths of identifiers, depending on information well as lacking detail on patients’ perception of disease or provided by the identifier. Stronger weights are given to the impact of disease or treatment on humanistic matches for identifiers upon which matching is less likely. outcomes. Electronic medical record (EMR) systems, For example, matching on sex – male or female – is less newly created to replace paper-based chart systems in likely to produce a matching of equivalent records than tracking clinical symptoms and disease, are still in the early matching a record on the combination of birth-month stages of development. Moreover, they are frequently and year. Assigned weights are related to frequencies of positioned in silos of healthcare practice – traditionally occurrences of values in linked and unlinked pairs and physician practices with limited linkage to inpatient also to the designated level of agreement.7 facilities, other specialists or other physician services, The determination of agreement can be further defined emergency and acute services, and pharmacy services. into subcategories: agreement (yes/no), or varying levels While each of these dataset types provides unique of partial agreement (eg, matching of a date within 2 days information, they lack a significant amount of before/after, matching of data within a week before/after). information about the patient and their treatments as Using probabilistic linking methods generally increases well. There are very few sources offering the complete the sensitivity and specificity of models over a deterministic picture of a patient. Those that do, often have their method in linking records from disparate datasets. own drawbacks, such as geographic homogeneity, small sample sizes or patient selection methods that limit Propensity score methods are increasingly used to match similar individuals in observational studies, along with generalization to real-world populations. other approaches to control for channeling bias.8,9 These LEVERAGING THE BENEFITS methods are similar to the approach used in probabilistic Until the ideal, complete source presents itself, there is data linkage. In propensity score matching, well-matched an alternative: a method whereby researchers can leverage pairs are closely matched on the predicted probability of the benefits of each individual type of data source, experiencing the dependent variable using relevant utilizing data linkage methods to fill in the gaps of one covariates. Matching techniques then employ a variety of database with the strengths of another. This approach was approaches based on the predicted probability score presented at a workshop during the ISPOR 13th Annual (ranging from 0 to 1) including nearest neighbor European Congress in 2010. and preliminary results, matching heuristics, and often employing sampling demonstrating the application linking the two without replacement.10,11 administrative databases, were discussed at a subsequent workshop during the ISPOR 16th Annual International Meeting in 2011. continued on next page AccessPoint - Issue 3

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INSIGHTS | DATA LINKAGE FOR CER ...continued from previous page

In the absence of complete data, the approach offers a good start and paves the way for further examples of this type of linkage method to be explored

CASE IN PRACTICE Comparative effectiveness of an inhaled corticosteroid/ long-acting beta agonist combination versus an anti-cholinergic among commercially insured patients with COPD STUDY DESIGN The study used a historical cohort design. Patients aged 40 and older with a principle or secondary diagnosis of COPD (International Classification of Disease, 9th Revision codes: 491, 492 and 496) and at least three years of continuous enrollment between January 1, 2004 and April 30, 2009 were selected from Database A and Database B. The index date was assigned as the date of the first claim (defined by a twelve month wash-out pre-index period) for the study drug, an inhaledcorticosteroid/long-acting beta agonist combination, or an anti-cholinergic. The effectiveness measure was risk of COPD-related hospitalization observed in the 12-month post-period and baseline characteristics were identified in the 12-month pre-index period. STUDY DESIGN

Time frame of analysis January 1, 2004

January 1, 2005

March 31, 2008

April 30, 2009

Index Period

12-month pre-index

12-month post-index

PROBABILISTIC DATA LINKAGE METHOD Steps taken to define and link the cohorts: 1. Restrict the samples to two cohorts in each database with similar pre-index and post-index time periods. 2. Pool data and develop a logistic regression model predicting the propensity to be in Database A using overlapping pre-index variables. 3. Match patients propensity score.

from

both

databases

the

4. Impute Database A outcomes for matched controls from Database B. 5. Conduct comparative effectiveness study in each cohort (A, B, and A with imputed outcomes).

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CONCLUSIONS

PROBABILISTIC DATA LINKAGE METHOD Pre-Index

Database A

Index

The probabilistic linkage demonstrated that patients from different databases matched on similar pre-index characteristics may demonstrate similar outcomes in the post-index period. The implications of these findings and this approach is significant as it calls into question the case for linkage of simulated cohorts from varying databases – EMR and administrative datasets, administrative datasets and surveys, EMR and surveys, etc. Creation of simulated cohorts could help explain a more complete picture of patient outcomes and allow us to explore all sides of a patient experience – economic, clinical and humanistic through the use of retrospective data analysis.

Post-Index

PS Match

Database B

Imputation by match

Database A with imputed outcomes from Database B

RESULTS The event rate of hospitalizations in each cohort was nearly identical as was the odds ratio and corresponding confidence intervals from the adjusted logistic regression models. This is not entirely surprising since the probability of being in each cohort was determined by the overlapping similarity in characteristics between the two cohorts, just as if the propensity score match was used in a traditional cohort analysis. RESULTS Rate of Exacerbation Data

PAVING THE WAY FOR FURTHER EXAMPLES Several caveats are worthy of note with this method: the divergence of the measures between the databases may also cause a divergence in “like” patients thereby introducing error in the outcomes assessment; care should be taken to ensure that similar measures are used to build the logistic regression model to create the propensity score; and the assumption is that probabilistic matching produces two individuals with similar attributes and not the same individual. However, in the absence of complete data, this method appears to be a good start. Further examples of this type of data linkage should be explored with various databases to determine the limitations. •

Adjusted Results*

Treatment 1

Treatment 2

95%

Database A

39.3%

46.3%

0.72

0.66

0.79

Database B

39.7%

47.1%

0.74

0.67

0.81

Database A with imputed outcomes

40.1%

46.8%

0.72

0.65

0.80

*Adjustment for age, geographic region, comorbidities and pre-index utilization of health services and respiratory medications using logistic regression.

1da

Silveira D, Artmann E. Accuracy of probabilistic record linkage applied to health databases: Systematic review. Revista de Saude Publica, 2009; 43:875-882 2Jaro M. Probabilistic linkage of large public health data files. Statist Med, 1995; 14:491-498 3Lyons R, Jones K, John G. The SAIL databank: Linking multiple health and social care datasets. BMC Med Inform Decis Mak, 2009; 9(3) 4D'Agostino Jr R. Propensity score methhods for bias reduction in the comparison of a treatment to a non-randomized control group. Statist Med, 1998; 17: 2265-2281 5Rose S, van der Laan M. Why match? Investigating matched case-control study designs with causal effect estimation. Int J Biostat, 2009; 5:26 6Van der Laan M. Estimation based on case-control designs with known prevalence probability. Int J Biostat, 2008;4:1-17 7Mason C, Tu S. Data linkage using probabilistic decision rules: A primer. Birth Defects Research, 2008; 82:812-821 8D'Agostino Jr R. Discussion of statistical and regulatory issues with the application of propensity score analysis to non-randomized medical device clinical studies. J Biopharmaceutical Stat, 2007;17:29-33 9Rosenbaum P, Rubin D. Reducing bias in observational studies using sub-classification on the propensity score. J Am Stat Assoc, 1984; 79:516-524 10Gonzalez-Smith M, Storer J. Parallel algorithms for data compression. ACM, 1985; 32(2):344-373 11Parsons L. Reducing bias in a propensity score matched-pair sample using Greedy Matching techniques. In: 26th Annual SAS User Group International Conference, 2001; 214-226

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INSIGHTS | IMS CORE DIABETES MODEL

The IMS CORE Diabetes Model is recognized by healthcare decision makers worldwide for its valuable insights into the long-term clinical and economic outcomes of interventions for diabetes. Recently updated with significant enhancements, it is now undergoing extensive validation to verify its new capabilities.

The authors: Phil McEwan, PHD is an independent researcher with IMS HEOR, IMS Consulting Group, U.K. Phil.mcewan@heor.co.uk

David Grant, MBA is Senior Principal HEOR, IMS Consulting Group, U.K. Dgrant@imscg.com

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Validating the IMS CORE Diabetes Model A RIGOROUS PROCESS FOR CONFIDENT USE

The IMS CORE diabetes model (CDM) is a policy support simulation model that predicts expected longterm clinical events, health outcomes and costs associated with the management of Type 1 or Type 2 diabetes mellitus.1 The model has been used extensively to evaluate the cost-effectiveness of new diabetes therapies, although its capabilities extend well beyond technology assessment. Increasingly, simulation models such as the CDM are being used to evaluate a range of issues from capacity and resource planning and trial design through to optimal patient management strategies.

RECORD OF ROBUST VALIDATION The CDM has a robust validation pedigree. A major validation exercise, published in 2004, demonstrated the operational predictive validity of the model to 66 epidemiological and clinical studies.2 Furthermore, the CDM’s development has been closely linked to the Mount Hood Challenges3,4 – forums for computer modelers of diabetes to compare predicted model output with data from clinical trials.

The fifth and most recent Mount Hood Challenge in 2010 saw the CDM and seven other models simulate trials of a The CDM has recently undergone a major update: its lipid-lowering intervention (ASPEN); blood glucosecapabilities now include the ability to model individual lowering intervention (ADVANCE); and blood pressurepatient-level data and incorporate treat-to-target analysis. and blood glucose-lowering intervention (ACCORD). The probabilistic analysis module has also been updated The results of this meeting are to be published shortly; and improved. Demonstrating that the CDM is an previous challenges have demonstrated that the CDM accurate representation of the system it is designed to performs well, particularly when predicting the relative simulate is of fundamental importance. Individuals who benefit of interventions.3,4 are developing, making and implementing decisions informed by the model’s analyses need to know that the continued on next page CDM and its results are robust; such reassurance is achieved through model validation and verification. FIGURE 1: SCHEMATIC OUTLINING THE GENERALIZED MODEL DEVELOPMENT PROCESS (DASHED LINES) AND THE VALIDATION AND VERIFICATION (CIRCULAR) ACTIVITIES CONDUCTED ALONGSIDE

Diabetes (Real World) Operational Validity

pe Ex

Computerized Model

e rim

An al ys is

n io at t n

Conceptual Model Validity &

DATA VALIDITY

Mo de lin g

Computer Programming & Implementation

Conceptual Model

Computerized Model Verification Source: Sargent RG. Verification and validation of simulation models. In: Proc 1996 Winter Simulation Conf., ed Charnes JM, Morrice DJ, Brunner DT, Swain JJ, 55-64. Piscataway, New Jersey: IEEE

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INSIGHTS | IMS CORE DIABETES MODEL ...continued from previous page

Individuals who are developing, making and implementing decisions need to know that the CDM and its results are robust; such reassurance is achieved through model validation and verification.

CONCEPTUAL VALIDATION AND VERIFICATION Figure 1 (page 35) is a graphical representation of the model development process.5 The rectangular blocks represent the modeling problem and process; the diabetes box, the real-world diabetes phenomena; the Conceptual Model, the particular mathematical and logical representation of the real-world system; and the Computerized Model is the physical (computer) implementation of the model. The current validation of the CDM focuses on assessing conceptual model validity, verification and operational validity. Each of these is discussed in turn, below. 1. Conceptual model validity Conceptual validity documents the model structure, logic and mathematical and causal relationships at the conceptual level and includes the following items:

•

UNDERLYING THEORIES AND ASSUMPTIONS: These are required for each module and sub-module to ensure that the model has face validity. This involves setting-out mechanisms within the model that control how disease progression occurs, what modifiable and nonmodifiable variables contribute to differential profiles of disease progression, and what specifications of treatment effects alter the course of disease progression.

•

DEFINITION OF VARIABLES: All variables are required to be appropriate, justifiable and unambiguously defined. For example, all disease states and clinical endpoints, resource drivers and model and patient attributes must be clearly delineated.

•

MODEL CONTENT AND STRUCTURE: This requires a

demonstration that the CDM is sufficiently complete to adequately undertake a diabetes economic evaluation, including documentation of areas where model structure is weak due to limited data availability.

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•

PARAMETER VALIDITY: The CDM contains approximately 600 parameters. Of primary concern is an understanding of possible bias in the choice of parameters selected and the degree of uncertainty associated with each. This is viewed against the importance of each parameter in driving the results of the model – which may differ across model applications.

•

PARAMETER SOURCE: While the source of parameter values is often limited by data availability, it is important to document the source and quality of parameter values used in the model (eg expert opinion, literature, data analysis, calibration).

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IMS CORE DIABETES MODEL | INSIGHTS

2. Model Verification Model verification ensures that the programming and physical implementation of the conceptual model have been completed correctly.

•

IMPLEMENTATION: The choice of model design must be justified, together with the software platform used to interface with the user (web interface) and perform the underlying calculations (compiled C++ libraries). For the CDM, this requires justification of a cohort-based micro-simulation with a compiled C++ run-time library and web-based interface.

•

VERIFICATION: Ensuring that the CDM operates as intended is of fundamental importance to ensure its validity and credibility.The following process has been undertaken to verify the model:

•

The major sub-programs within the core model have been built as stand-alone routines within Microsoft Excel to achieve two objectives:

3. Operational validity Operational validity asks whether the model’s behavior possesses the necessary accuracy required for its intended purpose across the domain of its intended use. It is an idealistic goal of validation to determine whether the simulation model is good enough to make a decision about the system (eg, cost-effectiveness of new diabetes therapies) similar to that which would have been made had it been feasible to experiment with real diabetes patients. This extends beyond the usual approach to validation where model output is compared to real-world studies – whether clinical trial, epidemiological study or observational. The Mount Hood Challenges have provided an excellent platform for assessing the operational validity of the CDM – pitching the model against other diabetes models with respect to reproducing the effects observed in long-term outcomes studies, cost-effectiveness analysis and model convergence.

1. Verify that the source codes used in the compiled model are correct.

•

CONCLUSION It is important to appreciate that simulation models are 2. Facilitate the testing of each sub-routine, eg, not universally valid; they are designed for a specific assessing the effect that relevant input parameters purpose and their validity requires assessment set (singularly and in combination) have on the against their intended use. Furthermore, the ultimate goal of credibility is achieved only when users have results predicted by each sub-routine. enough confidence in the model to utilize it and rely The CDM has been run under a variety of on its output. Arguably, the IMS CORE Diabetes scenarios and under simplified assumptions to Model has already achieved this standard.The primary ensure that the model output is reasonable and objective of the current validation process is to verify internally consistent with the output obtained from the extent to which the most recent update has the analysis of individual sub-routines. improved the model. Once this is completed, the key The simulated trajectory of a patient over time is elements of the validation will be submitted for peerfollowed to facilitate the testing of model logic, reviewed publication. • timing of clinical events and the correct application of costs and dis-utilities.

1Palmer, et

al. The IMS Core Diabetes Model: Projecting long-term clinical outcomes, costs and cost-effectiveness of interventions in diabetes mellitus (Types 1 and 2) to support clinical and reimbursement decision making. CMRO, 2004;20 (8 Suppl): 5-26 2Palmer, et al.Validation of the CORE Diabetes Model against epidemiological and clinical studies. CMRO, 2004; 20 (Suppl 1): S27-40 3Brown, et al. The Mount Hood challenge: Cross-testing two diabetes simulation models. Diabetes Res Clin Pract. 2000; 50 (Suppl 3):S57-64 4Computer modeling of diabetes and its complications. A report on the Fourth Mount Hood Challenge Meeting. The Mount Hood 4 Modeling Group. Diabetes Care, 2007; 30:1638-1646 5Sargent, R. G.Verification and validation of simulation models. In: Proc. 1996 Winter Simulation Conf., ed. Charnes JM, Morrice, DJ, Brunner DT and Swain JJ, 55-64. Piscataway, New Jersey: IEEE

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INSIGHTS | COMMUNICATION AND OUTREACH

Health economics and outcomes research is a pivotal tool for decision makers but there is work to be done in reaching out to a broader audience. In the age of the empowered consumer, we consider the costs, benefits and policy implications of DTC engagement in Europe.

The author Jacco Keja, PHD is Regional Leader EMEA HEOR, IMS Consulting Group. Jkeja@imscg.com

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COMMUNICATION AND OUTREACH | INSIGHTS

Extending the outreach of HEOR HEALTHCARE VALUE AND POLICY IMPLICATIONS OF DTC IN EUROPE “There are a number of benefits that would likely come from expanding our communications activities. The first is that it would help us translate our research into concrete policies - and help move health systems forward so that decisions better reflect evidence of value. Our work in pharmacoeconomics and outcomes research should resonate with varied audiences, including payers, physicians, patients, and the media.The second likely benefit is an improvement in our own work.The practice of communicating well – to scientific audiences and to audiences unschooled in our methods - will help us shape and focus our analyses.”

UNDERSTANDING THE ISSUES

As noted by PhRMA in 2008, efforts that form part of pharmaceutical marketing and promotion have an important role to play in educating and informing consumers, helping to create awareness of diseases and treatment options and empowering patients with information.2 This is particularly valid amid growing awareness of the need to “bring the patient back into the center of the conversation”.3 Although currently permissible only in the U.S. and New Zealand, directto-consumer advertising (DTCA) is reported to be the fastest growing form of pharmaceutical marketing.4 It is These words were delivered by Peter Neumann as also one of the most contentious, fuelling major concerns President of ISPOR in 20061 but they remain as valid and policy discussions around the world. At the heart of today within the broader context of health economics this debate is the fundamental health economic question and outcomes research (HEOR). Typically, HEOR raised by Block in 20075: What are the costs and benefits specialists excel in science; where we can improve attributable to DTCA for society as a whole? More is in translating our work into practical policies. specifically in this context, what is its value for healthcare To this end, there is a need for deeper engagement with in Europe - and what are the implications of proceeding our stakeholders. in this direction? We are already making progress towards this goal: ten COSTS AND BENEFITS years ago, the endpoint for most of our work was solid, scientific papers; five years ago, we had moved beyond One of the main challenges in determining the costs and that, with value dossiers becoming the new pinnacle – benefits of DTCA in a European context is the dearth albeit a rather static one, focused on launch. In recent of studies in the academic literature evaluating how it years, we have seen these documents become far more may directly impact healthcare in the region. The most dynamic, constructed early in development and vocalized arguments against DTCA in the EU focus on maintained over the lifecycle, enabling gap analyses and concerns that it may lead to increased drug expenditure, informing R&D on appropriate endpoints, study over-utilization of brands, the provision of misleading or 4 populations and relevant comparators, and those involved false information, or patient safety issues. Advocates, on the other hand, propose that DTCA can improve public in RWE generation, on requirements for data. health by increasing awareness about particular disease Alongside these developments, we have seen fledging states and motivating patients to talk to their physicians.6 efforts by pharma to embed the value messages in multichannel communications – and it is here where At the heart of these polarized views is the role of DTCA HEOR embarks upon a higher level of communication as a vehicle for information – something that has been to healthcare providers and payers. But, as Peter stressed long recognized by economists for its potential to impact in his address, we cannot underestimate the importance not only the immediate consumer, but also at a of educating “patients and the media” as well. This issue broader level, pharmaceutical prices, principal-agent of outreach to a wider public audience is an interesting relationships and the overall functioning of 7 one as solutions can only be implemented and healthcare markets. valued if the scope and dimensions of the problem are continued on next page well understood.

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INSIGHTS | COMMUNICATION AND OUTREACH ...continued from previous page

As a conduit for information As noted by Reinhardt, from a societal perspective the benefits of pharmaceutical marketing activities such as DTCA lie in the utility of the information that can be communicated to physicians and patients.8 Debatably, the argument in its favor hinges on the role of DTCA as a tool for health promotion. Matear and Dacin recognize three areas where DTCA can serve as a vehicle for information: clinical, economic and consumer. However, their findings from a comprehensive review indicate little or no consensus on its ultimate effects in this capacity.9

There appears to be a growing body of evidence disputing the assertion that DTCA has a price-rising impact on pharmaceuticals Impact on physician-patient relationship

There is a view that DTCA may compromise or challenge the traditional physician-patient relationship by creating demand for an advertised drug,15 which in turn Opponents of DTCA have inferred that consumers are leaves physicians pressured to prescribe the product not in a sufficiently knowledgeable position to assess its requested.16 Physicians themselves have reported feeling complexity and often place unjustified trust in adverts.10 less able to control the direction of treatment because However, a comprehensive review of evidence from U.S. patients have already decided on a medication17 or surveys looking at the educational potential of DTCA receiving patient requests for advertised pharmaceuticals would appear to contradict this: more than 50% of that in and of themselves may do very little to improve physicians surveyed agreed that DTCA educates patients their overall health.18 about health conditions and available treatments; and However, these arguments only serve to underscore the patients felt that it improved their understanding of recent paradigm shift in patient attitudes and the way diseases and treatments and helped play a role in their they gather information in today’s high-tech world.With decision making process.11 This is clearly an area a far greater thirst for knowledge on matters of health requiring further research. and wellness than previous generations, and the Impact on pharmaceutical prices One criticism levied at DTCA is that it may inadvertently increase drug prices by driving up requests for the advertised product – with potentially serious implications for universal access to healthcare. Countries banning this form of promotion argue that it would reduce price sensitivity of demand for prescription drugs and consequently lead to negative welfare effects.12

technology to seek it out, a growing number of patients and consumers today consider mass media the most important source of information, second only to their healthcare providers.19

Thus, DTCA may actually encourage patients to educate themselves and become more active in managing their own healthcare.18 As Harvard University economist Meredith Rosenthal has postulated: “It does not seem unrealistic that, however accidentally, DTCA could have It is interesting to note that the U.S. – where DTCA a salutary effect, even if advertisements are misleading and proliferates – pays, on average, one-third to a half more factually incorrect, simply by creating an opportunity for for the same pharmaceutical drugs than other developed discussion with a physician”.20 It would also be countries with national healthcare systems.13 However, interesting to see if DTCA-educated patients are more there is no substantial evidence in the current literature motivated and show an increased level of therapy that shows a direct correlation or positive association of adherence. Non-adherence is major healthcare issue. high prices resulting directly from DTCA.13 Indeed, the Even clinical trials report average adherence rates of only findings of a recent methodological study conducted by 43 to 78 percent among patients receiving treatment for Capella, et al, utilizing data on brand medications in five chronic conditions and of all medication-related hospital major therapy classes in the U.S., suggest that DTCA admissions in the U.S, 33 to 69 percent are due to poor does not decrease price elasticity and thus does not lead medication adherence, with a resultant cost of to increases in the price of pharmaceutical prescription approximately $100 billion a year.21,22 drugs.14 While more research is needed to verify these results, there appears to be a growing body of evidence disputing the assertion that DTCA has a price-rising impact on pharmaceuticals.

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COMMUNICATION AND OUTREACH | INSIGHTS

POLICY IMPLICATIONS IN EUROPE DTCA, if used as a mediator of information, clearly has the potential to improve healthcare by increasing a patient’s right to take a proactive and informed role in their health and treatment decisions. It may also have a positive welfare effect. Its ability to achieve this goal in Europe would depend, to a large extent, on the type of structure that could be established to oversee and police the advertisement of pharmaceuticals to the public. In the U.S., the FDA has been severely criticized for shortcomings in this regard. Currently, EU law does not clearly distinguish between what is considered advertising and the provision of non-promotional information on medicines.23 However, ongoing discussions concerning the potential revision of the absolute ban on DTCA within the EU Health policy framework may present an opportunity to do so. Can objectivity be assured? Some of the skepticism regarding DTCA in Europe concerns the industry’s ability to offer objective and nonpromotional information on its products without promoting them.24 The EU framework banning DTCA for prescription-only medicines is laid out in Article 88(1) of Directive 2001/83/EC of 1992, the application of which resides with each member state.

DTCA has the potential to improve healthcare by increasing a patient’s right to take a proactive and informed role in their health and treatment decisions In 2007, recognizing disparate interpretations of this Directive across Europe, changes in public attitudes towards health and medical information, and the availability of new channels such as the internet, the EC launched a public consultation proposing a revised framework for the provision of information on prescription drugs (not advertising) directly to consumers and patients. This was followed by a second consultation in 2008, maintaining the ban on DTCA, but opening up the possibility for the pharmaceutical industry to provide certain information about prescription-only drugs through various multi-media channels. Most interestingly real-world evidence (RWE) was given a special position AccessPoint - Issue 3

in the original proposal, meaning that pharmaceutical companies would be allowed to disseminate to the public information on non-interventional studies (subject to control by competent authorities prior to dissemination). Recent developments More recently, on 11 October, 2011, the EC adopted revised proposals amending those of 2008 and clarifying the information that pharmaceutical manufacturers can provide to the public on prescription medicines. This makes provision for only certain information on prescription medicines (eg, from the label and package inserts as well as trial information) to be provided through limited channels of communication (eg official websites or printed information when specifically requested by the public) fulfilling recognized quality criteria (ie unbiased, evidence-based, factually correct, not misleading, and understandable) and verified by competent authorities prior to dissemination if it has not been approved before. It gives companies not only the right but also the obligation to make certain information available. The proposals also address pharmacovigilance issues.25 In general, the newer revised proposal seems to move away from a more patient- and reality-oriented framework, and regress back to a regulatory focus, eg, by reorienting the text from the right of marketing authorization holders to make available some information, to the right of the patients to have information. Another fundamental change is replacing the original Article 100b text (“medicinal product-related information about non-interventional scientific studies, or accompanying measures to prevention and medical treatment, or information which presents the medicinal product in the context of the condition to be prevented or treated”) by text which is much more package insertoriented where perhaps only the following text paves the way for RWE dissemination: Article 100g.: “other types of information approved by competent authorities that are relevant to support the proper use of the medicinal product.” CONCLUSIONS AND IMPLICATIONS The value of DTCA remains hotly debated, and as evidenced by the recent step back in the amended Directive 2001/83/EC (as regards information to the general public on medicinal products subject to medical prescription and as regards pharmacovigilance) it seems that the old prejudice and political notions on the potential negative impacts of DTCA are still dominant. continued on next page

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INSIGHTS | COMMUNICATION AND OUTREACH ...continued from previous page

For the industry and HEOR community, the imperatives are threefold: 1. We must step up our presence and become more visible and audible in the relevant arenas and with the relevant audiences in order to balance the RCTdominant views, taking care that RWE is appropriately positioned and valued.

serious financial implications of poor or nonadherence to therapy as well as evidence that DTCA has limited impacted on price elasticity. It is here, for example, that a typical health economist view is needed. One final thought on this is that perhaps DTCA may push the public to higher acceptance of medicine co-payment, thereby transferring part of the anticipated burden arising from the feared increased use of drugs, to the patients themselves.

2. More research is needed to determine the ROI and societal value of direct-to-patient communications. 3. Article 100g: Other types of information approved by Current policies seem to draw heavily on political competent authorities that are relevant to support the views, undervaluing its positive potential. They also proper use of the medicinal product need further close seem to over emphasize the fear of DTCAs from a scrutiny in order to understand their impact on the budgetary impact perspective. There is a high way we can communicate the findings of our work to likelihood that these views are shortsighted given the the wider community. • This article partially draws on a recent MSc Thesis by Rina Mae Acosta, "When Customer Relationship Matters: The Return on Investment of Direct-to-Consumer Advertising and Direct-to-Physician Marketing", working under Dr Keja’s supervision to explore new models for calculating ROI of DTCA and DTPM. 1. Presidential Fireside Chat: ISPOR Initiatives in Communication and Outreach. http://www.ispor.org/news/articles/feb06/president.asp Accessed October 22, 2011 2. The Facts about Pharmaceutical Marketing and Promotion, PhRMA, 2008. Accessed October 22, 2011 at http://www.phrma.org/sites/default/files/159/marketing_and_promotion_facts_071108_final.pdf 3. Landro L. The Informed Patient: Many Pills, Many Not Taken. Wall Street Journal, 10 October, 2011. Accessed October 22, 2011 at http://online.wsj.com/article/SB10001424052970203388804576616882856318782.html 4. Liang BA, Mackey T. Reforming Direct-to-Consumer Advertising. Nature Biotechnology, 2011, 6 May; 29(5): 397-400 5. Block AE. Costs and Benefits of Direct-to-Consumer Advertising: The Case of Depression. Pharmacoeconomics, 2007; 25(6):511-521. 6. Hughes-Morgan M, Kendrick JL, et al. Strategic Change within the Pharmaceutical Industry: The Impact of Direct-To-Consumer Advertising for Prescription Medicines. International Journal of Information Systems and Change Movement, 2010; 4(3): 246-257. 7. Avery R, Kenkel D, et al. Health Disparities and Direct-to-Consumer Advertising of Pharmaceutical Products. Advances in Health Economics and Health Services Research, 2008; 19: 71-94. 8. Reinhardt, U E. An Information Infrastructure for the Pharmaceutical Market. Health Affairs, 2004; 23(1): 107-112 9. Matear, M, Dacin PA. Marketing and Societal Welfare: A Multiple Stakeholder Approach." Journal of Business Research, 2010; 63: 1173-1178 10. Conners, A. Big Bad Pharma: An Ethical Analysis of Physician-Directed and Consumer-Directed Marketing Tactics." Albany Law Review, 2009;73(1): 243-248. 11. Frosch D L, Grande D, et al. A Decade of Controversy: Balancing Policy With Evidence in the Regulation of Prescription Drug Advertising." American Journal of Public Health, 2010; 100 (1): 24-32. 12. Leeflang, PSH, Wieringa JE. Modeling the Effects of Pharmaceutical Marketing. Marketing Letters, 2010; 21: 121-133. 13. Harter, T.D. In Sickness and in Health: Analyzing the Ethical Limits of the Marriage between Health Care and the Market in the United States. Philosphy. Tennessee, University of Tennessee, 2010; PhD: 237. 14. Capella ML, Taylor CR, et al. Do Pharmaceutical Marketing Activities Raise Prices? Evidence from Five Major Therapeutic Classes. Journal of Public Policy & Marketing, 2009; 28(2): 146-161. 15. Gellad, ZF, Lyles KW. Direct-to-Consumer Advertising of Pharmaceuticals. Am J Med, 2007;120: 475-480. 16. Martinez, LS, Lewis N. The Role of Direct-to-Consumer Advertising in Shaping Public Opinion Surrounding Prescription Drug Use to Treat Depression or Anxiety in Youth. J Health Communication,2009; 14(3): 246-261. 17. Geyer, R. The Politics of EU Health Policy and the Case of Direct-to-Consumer Advertising for Prescription Drugs. Br J Politics & International Relations, 2011; 13(4):586-602. Published online 23 May 2011. 18. Matear, M, Dacin PA. Marketing and Societal Welfare: A Multiple Stakeholder Approach." Journal of Business Research, 2010; 63: 1173-1178. 19. Austovoll-Dhalgren, A. Bottom-up Approach to Successful Implementation of Pharmaceutical Policy. Expert Review of Pharacoeconomics Outcomes Research, 2009; 9(3): 193-195. 20. Rosenthal, M B."Comment: The Economics of Direct-To-Consumer Advertising of Prescription-Only Drugs: Prescribed to Improve Consumer Welfare." Journal of Health Services Research & Policy, 2004; 9(1): 39-42. 21. Osterberg L, Blaschke T. Adherence to Medication. N Engl J Med, 2005;353:487-497 22. Sabaté E. Adherence to Long-Term Therapies: Evidence for Action, WHO, 2003 23. Hancher L, Foldes ME. Push or Pull? Information to Patients and European Law. Tilec Discussion Paper No 2011-032, 16 June, 2011 24. Velo G, Moretti U. Direct-to-Consumer Information in Europe: The Blurred Margin Between Promotion and Information. Br J Clin Pharmacol, 2008; 66(5): 626-28 25. Empowering the Patient: EC Wants Clearer Rules for Information on Prescription Medicines. EC Press Release. Accessed October 23, 2011 at http://ec.europa.eu/health/files/patients/ip_10-2011/i11_1171_en.pdf

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Medicare Part D: Not such a high price to pay? When the Medicare Part D benefit became effective in 2006, critics predicted a significant increase in the price of seniors’ prescription drugs, and a consequent dramatic rise in Medicare expenditure. With figures released in 2010 showing a substantial reduction in anticipated costs, researchers ask “What happened to senior drug Rx prices - and why?” Summarized from: “Medicare Part D At Age Five: What Has Happened To Seniors’ Prescription Drug Prices?” by Murray L Aitken, IMS Institute for Healthcare Informatics and Ernst R Berndt, MIT Sloan School of Management and National Bureau of Economic Research.

The author Murray Aitken, MBA is Executive Director, IMS Institute for Healthcare Informatics. Maitken@theimsinstitute.org

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INSIGHTS | MEDICARE PART D

Medicare Part D: Not such a high price to pay?

There are undoubtedly many reasons underlying this development. In this analysis we have focused on one: the declining daily cost of therapy as patents expired and generics entered the market, and competitive prescription drug plans relayed the cost savings to Part D beneficiaries. Specifically, we have examined trends in the average daily costs (ADCs) of therapy over the five years since Medicare Part D came into effect, focusing on the ten therapeutic classes which had the largest volume of Medicare Part D prescriptions in 2006. The analysis was enabled by access to IMS Medicare Part D prescription data from the IMS PlanTrak database; IMS Health represents 100% of Part D plans, and combined with IMS’ National Prescription Audit (NPA), measures the prescription volume associated with those plans. The NPA is projected to national levels, based on a sample of retail and mail order outlets. Using data on the total number of prescriptions dispensed, we identified the ten therapeutic classes in 2006 having the greatest Medicare Part D prescription volumes: lipid regulators, ACE inhibitors, calcium channel blockers, beta blockers, proton pump inhibitors (PPIs), thyroid hormone, angiotensin II receptor antagonists, codeine and combination products, antidepressants, and seizure disorders. For each of the molecules in these ten classes, we used data from IMS National Sales Perspective which tracks invoices from wholesalers/manufacturers to retail and mail order pharmacies. ADCs were computed using dispensing data from the NPA. Based on annual Part D prescription quantity data from IMS PlanTrak, we constructed a weighted average aggregate ADC of therapy over the entire ten therapeutic classes, both monthly (Jan 2006– Dec 2010) and annually (2006-2010). The daily cost of therapy calculations are thus interpreted as based on acquisition prices paid by pharmacies; they include

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prompt payment discounts, but not discounts extended directly to Part D beneficiaries, pharmacy margins and manufacturer rebates paid to third-party payers such as Medicaid, private health benefit insurers and Part D private prescription drug plans. TRACK RECORD IN THE FIRST FIVE YEARS Our analysis shows that from the time of the Medicare Part D launch in 2006, through the end of 2010, on average over the ten largest volume Medicare Part D therapeutic classes, there has been a cumulative 30% decline in the annual ADC of therapy (Figure 1).

FIGURE 1: AN AVERAGE 30% REDUCTION IN THE DAILY COST OF THERAPY OCCURRED WITHIN THE TOP 10 PART D CLASSES BETWEEN 2006 AND 2010 60%

% CHANGE IN COST PER DAY (2010 VS. 2006) (WHOLESALE)

Former Congressional Budget Office Director Peter Orszag has identified the “primary cause” of the cost reduction reflected in the 2010 Medicare Trustees report,1 as lower than expected bids submitted by prescription drug plans offering coverage, stating “The bids are coming in and the pricing is coming in better than anticipated, and that is likely a reflection of the competition that’s occurring in the private market”.2 But what has enabled competitive prescription drug plans to offer unexpected lower bids?

40% 20% 0% -20% -40% -60% -80%

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Source: IMS Institute for Healthcare Informatics; National Sales Perspectives; National Prescription Audit, Dec 2010

Cost declines occurred in four of the five cardiovascularrelated classes, with the largest decline seen in calcium channel blockers, and successively smaller declines in ACE inhibitors, lipid regulators and beta blockers. Substantial daily cost declines also occurred in the CNS classes of antidepressants and seizure disorders, and smaller declines within the PPIs (some of which are now available in less costly OTC versions frequently not covered by Medicare Part D, therefore understating price declines experienced by seniors) and for the thyroid

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

MEDICARE PART D | INSIGHTS

hormone medicines, where there have been no patent expirations for quite some time. Negative compound annual growth rates were greater than 20% for the calcium channel blockers and ACE inhibitors (both of which experienced generic entry in 2007); between 10% and 20% for seizure disorder, antidepressants, and lipid regulators (with significant patent expirations in 2009, 2006 and 2006, respectively); and less than 10% among the PPIs, beta blockers and thyroid hormone products.

The dynamics of medicine costs are affected substantially by the impact of patent expiration

In contrast, daily cost of therapy increases occurred annually among the angiotensen II receptor antagonists where only Cozaar/Hyzaar lost patent protection in 2010 and physicians/consumers migrated towards the remaining Diovan, Avapro and Benicar brands.The only other class experiencing a daily cost increase is codeine and combination products, which similarly experienced no patent expiries during 2006-2010. One way of summarizing these various trends is to plot the average daily cost of therapy aggregated over the top ten Medicare Part D prescription volume classes, on a monthly basis from January 2006 through December 2010. This shows that coincidentally, between Jan 2006 and Dec 2010 the average daily cost of therapy in these classes declined by a third, from $1.50 to $1.00 (Figure 2, left half). Overall, in the first 60 months of Medicare Part D, cumulative ADCs of therapy declined by greater than 50% within four classes (calcium channel blockers, ACE inhibitors, seizure disorders, and antidepressants), between 30% and 50% among the lipid regulators and PPIs, and less than 20% for beta blockers and thyroid hormone products. In contrast, over the same time period, the cumulative ADC of therapy increased by 11.9% for codeine and combination products, and by 22.3% for the angiotensin II receptor antagonists, implying annualized average cost increases of 2.9% and 5.2%, respectively.

The cost declines observed in the first five years of Medicare Part D can be expected to continue. In aggregate, over these ten classes, the 2006-2015 decade is one of steadily decreasing ADCs of therapy continued on next page AccessPoint - Issue 3

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INSIGHTS | MEDICARE PART D ...continued from previous page

HISTORICAL QUIRK OR CONTINUING TREND? A natural question that arises is whether this general decline in ADC of therapy in the studied period is an historical oddity which is unlikely to recur or a cost phenomenon that is likely to continue for years to come.

FIGURE 2: SUSTAINED DECLINES IN AVERAGE DAILY COST OF THERAPY BETWEEN JAN 2006 AND DEC 2015 1.60

$1.50/day

1.40

COST PER DAY ($)

1.20 To begin to address this issue, we have projected annual 1.00 2011-2015 and monthly Jan 2011–Dec 2015 ADCs of $1.00/day therapy for the same ten classes. This analysis is based on: 0.80 IMS Institute current expectations for the timing of patent 0.60 $0.65/day expirations in each of the ten therapeutic classes; no new 0.40 “blockbuster” drug launches from 2011-2015 in these 0.20 classes; class-specific standard generic erosion curves 0.00 benchmarked to 2006-2010 data; constant brand price and 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 volume growth equal to mean pre- and post-patent protection expiration historical growth rates from 2006 to Source: IMS Institute for Healthcare Informatics; National Sales Perspectives; National Prescription Audit, Dec 2010 2010; constant form-strength distributions within these 3 classes at 2010 values for the respective molecules ; and a fall in generic prices consistent with standard historic BIG PICTURE: SUSTAINED DECLINES generic erosion curves. Over the entire ten therapeutic classes, the projected ADC The “big picture” pattern of sustained decline in ADC of therapy falls from $1.00 per day in Dec 2010 by an of therapy in the ten largest volume Medicare Part D additional 35% to $0.65 (Figure 2, right half), resulting in a classes over the entire period from Jan 2006 through Dec cumulative -57% change between Jan 2006 and Dec 2015. 2015 can be seen visually by observing the steadily downward sloping line in Figure 2. Despite some Between Dec 2010 and Dec 2015, the ADC of therapy “bumps” triggered by patent expirations and substantial drops by more than 40% in five of the ten classes: lipid generic entry, the cost declines observed in the first five regulators -50.8% (Lipitor patent expiry expected Nov years of Medicare Part D can be expected to continue. 2011); beta blockers -45.2% (Bystolic patent expiry In aggregate, over these ten classes, the 2006-2015 decade expected Dec 2012); PPIs -42.0% (Aciphex patent expiry is one of steadily decreasing ADCs of therapy. expected May 2013; Nexium Nov 2014); angiotensin II receptor antagonists -48.8% (Avapro patent expiry expected PATENT EXPIRATIONS, GENERIC SUBSTITUTION KEY DRIVERS March 2012, Diovan Sept 2012); and antidepressants - Our analysis suggests that patent expiries and the 52.0% (Lexapro patent expiry expected March 2012; substitution of generics for brands played a major role in Cymbalta July 2014). eight of the ten classes experiencing declines in ADC of therapy between 2006 and 2010. In aggregate, ADCs Average daily therapy costs are projected to increase declined from $1.50 to $1.00 per day during this period. modestly between Dec 2010 and Dec 2015 for ACE inhibitors (18.2%), calcium channel blockers (13.9%), Given the anticipated expiry of patent protection between thyroid hormone products (3.8%) and seizure disorders 2011 and 2015, along with other continued market (3.7%) classes, already heavily genericized with little, if any, development assumptions, and in the absence of new expected patent expiry between 2011-2015, and to decline product surprises, we expect daily cost declines in aggregate modestly for codeine and combination products (-10.0%). over these ten therapeutic areas to continue over the 2011Despite the modest expected price increases in these four 2015 time period, with Part D prescriptions in Dec 2015 classes, since 2006 all but codeine and combination costing on average $0.65 per day of therapy - a number products will have experienced declines in ADC of therapy. coincidentally equal to the beneficiary age at which ADC of therapy for the latter will have increased a penny. Medicare Part D benefits currently become available.

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New approaches to the aggregate cost analyses of medicines merit further scrutiny and consideration to avoid substantial errors in estimating future program costs

FURTHER REARCH WARRANTED Useful future research suggested by this analysis involves a more detailed examination of changes since 2006 in the quantity of Medicare Part D prescription drugs dispensed (which according to the IMS Institute have increased 61% in volume from 541 million prescriptions in 2006 to 871 million in 2010) and the relationship between this increased access to therapies and the decline in the ADC of therapy over time.

This analysis shows that the dynamics of medicine costs are affected substantially by the impact of patent Hence, when generic drug savings are taken into expiration, which can generally be predicted several years account, ADCs of therapy for the top therapeutic classes in advance. Unlike medical devices, physician services and in Part D will have fallen on a sustained basis between hospitalizations, the costs of medicines regularly decline 2006 and 2015. This reflects the Schumpeterian lifecycle by up to 90% following expiration of patent protection. process of “creative destruction” in biopharmaceutical The extent to which the price dynamics of these markets in which, over time, R&D investments produce medicines are understood and incorporated into aggregate medical advances with finite market exclusivity. These cost projections associated with new private or public generate further funding for R&D, then make way for healthcare programs or policy initiatives is currently generic copies to be available at low costs for many years, unclear to us, but the unique Medicare Part D experience enabling the savings and benefits of biopharmaceuticals suggests that new approaches to the aggregate cost to flow to the next generation of medical advances. analyses of medicines merit further scrutiny and The cost calculations in our analysis are based on consideration to avoid substantial errors in estimating acquisition prices paid by retail and mail order future program costs. • pharmacies. Given the exclusions already noted, our daily cost of therapy trends might therefore differ from those actually experienced by Medicare Part D beneficiaries. Moreover, we focus on Part D prescriptions dispensed in the retail and mail order environment; prices of specialty and other drugs dispensed in the hospital and outpatient setting may have differing trends. Our 2011-2015 projections are based on IMS Institute estimates of patent expiration for those brands still patentprotected in 2010, and on historic patterns in brandgeneric erosion. To the extent that actual dates of expiration for patent protection and generic entry differ from those expected by the IMS Institute, future brandgeneric erosion curves differ from that observed historically, and new “blockbuster” products are launched in these ten therapeutic classes, actual future daily cost of therapy trends may differ from those projected in this study.

1. Medicare Trustees [2010], 2010, p189. Annual Report of the Boards of Trustees of the Federal Hospital Insurance and Federal Supplementary Medical Insurance Trust Funds, 2010. Available online at https://www.cms.gov/ReportsTrustFunds/downloads/tr2010.pdf 2. As quoted in “CBO Lowers 10-Year Cost Estimate Of Medicare Prescription Drug Benefit”, 30 January 2007, available online at http://www.medicalnewstoday.com/releases/ 61768.php, last accessed 9 June 2011 3. Hence, while new branded products in these therapeutic classes launched between 2006 and 2010 are included in the sample, potential new branded products are not included in the 2011-2015 projections. A review of molecules in late-stage development in these therapeutic classes suggests that there will be few if any blockbuster products launched in the 2011-2015 period.

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PROJECT FOCUS | CHEMOTHERAPY-INDUCED ANEMIA Advanced, innovative methodological techniques that adjust for specific characteristics can enable rigorous adaptations of data across a range of geographic settings. The Author: Mark Lamotte, MD is Principal HEOR, IMS Consulting Group, Belgium. Mlamotte@imscg.com

Demonstrating cost savings in chemotherapy-induced anemia by extrapolating country-specific data to multiple markets Access to new therapeutic innovations is increasingly contingent on their economic value in relation to alternative interventions. The ability to demonstrate cost and health benefits based on usage in the real-world setting is thus essential for supporting rational decision making â&#x20AC;&#x201C; and successful product differentiation. This is especially valid in complex and costly disease areas such as oncology, where new interventions that are perceived to be expensive can add considerably to overall expenditures. Analyzing longitudinal healthcare data, drawn from large medical, patient and health claims databases, affords unique opportunities to understand the clinical and economic outcomes associated with a particular intervention and the impact of events that may occur more often with one drug compared to another. Today, increasingly sophisticated methodologies are extending the applications of these databases further. For one leading manufacturer of innovative therapeutics, the retrospective analysis of anonymized patient-level data, combined with advanced techniques for its extensive adaptation, proved pivotal in demonstrating superior product efficiency in chemotherapy-induced anemia (CIA) in multiple country settings. BACKGROUND CIA is a common complication of cancer treatment and its associated fatigue can significantly impact the quality of daily living. The use of erythropoiesis-stimulating agents (ESAs) to increase inadequate hemoglobin (Hb) levels has been shown to improve quality of life (QoL) and reduce the need for red blood count transfusions â&#x20AC;&#x201C; a widely used intervention.1 Further, by improving QoL, secondary to improving Hb, these agents may enable patients to receive the correct doses of chemotherapy in a more timely way than cancer patients who remain anemic.2 In 2006, having recently launched a new ESA, and given the cost-intensive nature of treatment for cancer, the company wanted to reach a better understanding of the costs associated with CIA. In particular it was keen to identify the potential for savings through the use of its drug compared to competing agents. The initial focus was on Belgium, but an expansion to additional European markets was envisaged in a 3-4 year period. In IMS they found a partner with an expert global team that had extensive experience in the design and analysis of retrospective research, access to unparalleled patient-level assets and the ability to collaborate seamlessly across multiple markets.

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CHEMOTHERAPY-INDUCED ANEMIA | PROJECT FOCUS KEY INSIGHTS INTO COST AND OUTCOMES The study was conducted using the IMS Hospital Disease Database (HDD), a longitudinal database containing individual patient/admission-level data on diagnoses, procedures, and pharmaceutical products. Unique to Belgium, this includes information on 46 hospitals, representing 34% of day clinic visits and hospital beds in the country. Although focused on a different setting, in terms of completeness and level of detail, HDD is comparable to the GP Research Database (GPRD) in the UK. Applying propensity score matching using epidemiology and treatment pattern-related variables to adjust for selection bias, the IMS team was able to demonstrate the greater efficiency of the company’s ESA due to shorter treatment duration compared to competitor products. The study was the first real-life matched retrospective analysis comparing ESAs in terms of costs and outcomes.3 EXPLORING BROAD APPLICABILITY In the follow-on analysis, IMS was asked to determine the applicability of the Belgian findings to different settings across Europe, estimating differences in costs between ESAs by similarly adjusting for baseline characteristics using propensity score matching. However, when a literature search revealed that no comparable databases to HDD existed in the relevant countries, it was clear that a different approach would be needed. Applying their extensive analytic expertise, the IMS team focused on adapting the Belgian dataset, developing a rigorous methodology that involved: 1. Replacing Belgian unit costs with local unit costs for drugs, daycare visits, hospitalization and blood transfusions for each country. 2. Validating epidemiology and treatment patterns by country, including gender/age distribution of the general population, use of ESAs and blood transfusions, incidence/distribution of cancer types, and use of chemotherapy. Differences between countries were adjusted using data from Eurostat, national cancer registries, IMS sales data, and reimbursement and treatment guidelines. 3. Weighting Belgian data to reflect treatment patterns in the local setting based on calculations of total chemotherapy sales in hospital (mg) for all countries. Finally, adjusting for country-specific drug use and cancer incidence, the costs of the drugs were analyzed from the healthcare payer perspective, using a mixed-effects model stratifying for propensity score quintiles (Figure 1). 1Rizzo

JD, Seidenfeld J, Piper M et al. Erythropoietin: A paradigm for the development of practice guidelines. Hematology Am Soc Hematol Educ Program 2001; 10-30. 2Khan FA, Shukla AN, Joshi SC. Anaemia and cancer treatment: A conceptual change. Singapore Med J 2008; 49:759-764. 3Spaepen E, Demarteau N,Van Belle S, Annemans L. Health economic evaluation of treating anemia in cancer patients receiving chemotherapy: A study in Belgian hospitals. The Oncologist, 2008; 13: 596-607 4Duran A, Spaepen E, Lamotte M, Walter E, Lucioni C, Pinheiro B, Brosa M, Kutikova L, Pujol B, Annemans L. Cost analysis of anemia treatment with erythropoiesis-stimulating agents (ESAs) in cancer patients receiving chemotherapy: A multi-country approach. ISPOR 16th Annual International Meeting, Baltimore, MD, 21-25 May, 2011

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FIGURE 1: ANALYSIS OVERVIEW 1. INITIAL PATIENT SAMPLE IMS Hospital Disease Database, January 2003 - June 2005 Cancer patients, receiving chemotherapy and ESA darbepoetin alfa (n = 539) - epoetin-α (n = 1,594) - epoetin-β (N = 380) 2. PROPENSITY SCORE MATCHING Darbepoetin alfa (n = 429) - epoetin-α (n = 1,584) - epoetin-β (N = 380) COUNTRY-SPECIFIC COSTS 3. On propensity scores matched patients, replace Belgian costs with: • Drug costs (replace unit cost) • Procedures cost (replace on DRG level) • Hospitalization cost (calculate DRG country-specific day-cost and multiply with length of stay) 4. POPULATION WEIGHTS Adjust on country-specific drug and cancer incidence using sample weighting: Drugs: • On molecule level, assess the national ratio of Belgium sales. • Average of molecule ratios per patient is ‘chemotherapy weight’. • The higher the ratio, the higher the patient uses country-specific chemotherapy, the more weight the patient receives.

Cancer incidence: • For 4 major cancer types (breast, lung, female genital, hematological), assess the ratio of the incidence of Country vs Belgium. • The higher the ratio, the higher the patient has a country-specific cancer, the more weight the patient receives.

5. FINAL WEIGHTING 1. Final weight: Drug weight x Cancer weight 2. Final normalized weight: Final weight adjusted for sample size per group (sum of weights has to equal sample size per treatment arm)

PROVEN FEASIBILITY OF DATA ADAPTATION The demographic country profiles revealed broad similarities between all countries and Belgium in average age and gender distribution. There were differences in cancer incidence but no major differences in the use of ESAs or the administration of blood transfusions for chemotherapy patients. To reflect country-specific epidemiology, the relative weight of four tumor types in the focus countries compared to Belgium was used to adjust the original dataset. In all countries, total costs and anemia-related costs were lowest in patients receiving the company’s ESA compared with its competitors – findings that were fully in line with those of the Belgian analysis. The results of the IMS analysis clearly demonstrate the feasibility of adapting real-world, country-specific data to other clinical settings by adjusting for differences in patient characteristics, treatment strategies and costs. By partnering with the IMS team on this work, the company was able to demonstrate the greater efficiency of its ESA in the hospital setting in multiple markets, with clear differentiation from competitor products based on compelling, real-world evidence. The results have been presented at major international conferences including ISPOR4, form the basis of scientific global and country manuscripts and will enable the distillation of key messages regarding the real-life costs and effects associated with treatment of CIA. •

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PROJECT FOCUS | BREAST CANCER Retrospective cohort analyses leveraging large healthcare databases can yield important insights for optimal drug use within emerging preferences for care. The Authors: Vernon Schabert, PHD is Global Leader Retrospective Outcomes Research and Senior Principal HEOR, IMS Consulting Group, U.S. Vschabert@imscg.com Elise Pelletier, MS is Engagement Manager HEOR, IMS Consulting Group, U.S. Epelletier@imscg.com

Understanding real-world persistence in adjuvant breast cancer patients Ensuring that patients derive the maximum benefit from the use of a medical intervention is key to supporting the achievement of optimal outcomes. However, a product’s use may be influenced by prescribed co-medications, particularly within the context of complex regimens such as oncology treatment protocols. This can become a particular challenge for manufacturers, as evolving treatment options can influence real-world practice patterns, often with unintended consequences for established products. Companies looking to gain a clearer perspective of the way their products are being used by physicians and the impact of changing preferences for protocols of care, have come to appreciate the important role of anonymized healthcare databases. With their large patient cohorts, direct relevance to the general population, and the ability to track the real-world use of medicines over time, these powerful datasets bring unique insights into prescribing behavior, emerging trends, and the issues that are driving – or potentially undermining – the optimal use of a drug. FINDING THE EVIDENCE A top U.S. biopharmaceutical company with a leading breast cancer treatment (trastuzumab) wanted to reach a better understanding of the drug’s real-world use within the context of two different regimens – anthracycline-based (AB) and non-anthracycline-based (NAB). Breast cancer is the fifth leading cause of death worldwide1 making efforts to inform its optimal treatment critical. Trastuzumab is indicated for a sub-group of women with HER2-positive tumors, suggesting more aggressive disease and significantly shortened survival. Its addition to adjuvant therapy has been found to reduce the risk of death in these patients. When anecdotal reports suggested a change in physician preferences for adjuvant breast cancer protocols, the company commissioned IMS HEOR to both confirm this apparent finding and determine the implications for the use of trastuzumab in this setting. In particular, it was keen to explore issues around patient persistence as these would clearly influence potential outcomes. Having partnered with IMS on a number of previous economic evaluations in oncology using the IMS LifeLink™ Health Plan Claims Database (HPC), the company trusted both the rigor of the analyses and strength of the underlying data. LifeLink HPC is one of the most comprehensive datasets of longitudinal patient-level medical and pharmaceutical claims available. Incorporating claims from 80 health plans across the U.S., it enables granular analyses across multiple dimensions, including patterns of care, resource use, and

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BREAST CANCER | PROJECT FOCUS

UNDERSTANDING THE TRENDS The goal of the IMS team was to identify annual trends in the use of trastuzumab in the U.S. over the previous four-year period and to compare levels of persistence in AB versus NAB protocols. They began by screening claims recorded in LifeLink HPC to identify the study cohort: women aged 18 years and over with an early stage primary diagnosis of breast cancer, evidence of surgery for their disease, and evidence of trastuzumab used in one of the two treatment regimens. Nearly 600 patients were found to fulfill the studyâ&#x20AC;&#x2122;s detailed selection criteria, 550 of whom were included in the final analysis. These patients were then followed to determine duration of use, defined from the time of first claim for the drug (index) to the earliest of: discontinuation, metastasis, end of health plan enrollment or 360 days after the index claim. Persistence was compared across regimens using KaplanMeier survival curves and the Cox proportional hazards model. The primary independent variable was the protocol in which the drug was used, with additional variables including patient characteristics. REVEALING THE BENEFITS

FIGURE 1: KAPLAN-MEIER ANALYSIS OF THE PROPORTION OF PATIENTS PERSISTENT WITH TRASTUZUMAB THERAPY: AB vs NAB

100% 90%

SURVIVAL DISTRIBUTION FUNCTION

medical costs, and comparisons across a range of demographic variables such as age, gender, in-patient and out-patient diagnoses and procedures, concomitant therapy and co-morbidities.

80% 70% 60% 50% 40%

AB Group (N=291)

30% NAB Group (N=259) 20% 10% 0% 30

120

150

180

210

240

270

300

330

360

Days

Source: Lalla D, Pelletier EM, Goodman S, Brammer M, Schabert VF. Trastuzumab treatment patterns among patients diagnosed with adjuvant breast cancer: Results from a U.S. claims data analysis.

Given that patients derive maximum benefit from their medications when they are persistent over the long term, these findings have important clinical and economic implications. They have been presented at several keynote oncology conferences and a manuscript is being prepared for publication to support their wider dissemination and advance the understanding of optimal treatment for this important disease. â&#x20AC;˘

The results of the IMS analysis2 provided important real-world confirmation of a shift towards greater use of the NAB protocol in the U.S. over the study period, thus confirming the anecdotal reports. A further revelation was that patients persisted longer on therapy within the NAB regimen, providing support for its preferential use over the AB regimen (Figure 1). In a therapy area where precise patient subgroup definitions often yield very small cohorts, the large LifeLink HPC database cohort gave the client increased confidence in the findings compared to databases available elsewhere.

1WHO

Factsheet 297, February 2011. Accessed at http://www.who.int/mediacentre/factsheets/fs297/en/index.html, October, 2011 D, Pelletier EM, Goodman S, Brammer M, Schabert VF. Trastuzumab treatment patterns among patients diagnosed with adjuvant breast cancer: Results from a U.S. claims data analysis. European Multidisciplinary Cancer Congress, Stockholm, Sweden, 23-27 September, 2011.

2Lalla

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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.

Revealing true product value The IMS Consulting Group HEOR unit is a multi-disciplinary, global team with proven success and publication experience in virtually all therapy areas and more than 40 countries worldwide, including emerging economies in Central and Eastern Europe, Latin America and Asia. Our bibliography extends to more than 2000 references. Our leading experts combine rigorous scientific research with a customer-focused consulting model to help you: •

Address growing HTA requirements nationally, regionally and locally

•

Build powerful health economic support through disease modeling and outcomes evaluations

•

Create enduring value propositions across the product lifecycle supported by scientific evidence

•

Develop innovative solutions to real-world market needs that leverage both bespoke observational research and access to our unparalleled medical, hospital and patient-centered pharmaceutical databases.

Strategy

Evidence Development

Communication

HEOR STRATEGY & DETERMINING VALUE

DEMONSTRATING VALUE

COMMUNICATING VALUE

Our integrated approach – spanning world-leading skills in strategy, evidence development and value communications – is reflected in all of our work.

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

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 online catalog of more than 2000 references at www.imsheorbibliography.com

IMS HEALTH ECONOMICS & OUTCOMES RESEARCH

LOCATIONS | IMS IMS HEOR experts are located in 17 countries worldwide and they have published on projects completed in more than 40 countries on all continents.

Global scope, local expertise YOUR PRIMARY CONTACTS: Dr. Michael Nelson Regional Leader Americas Health Economics & Outcomes Research IMS Consulting Group 1725 Duke Street, Suite 510 Alexandria, VA 22314 USA Tel: +1 703.837.5150 Email: Mnelson@imscg.com

Dr. Jacco Keja Regional Leader EMEA Health Economics & Outcomes Research IMS Consulting Group 7 Harewood Avenue London NW1 6JB, UK Telephone: +31 (0) 631 693 939 Email: Jkeja@imscg.com

IMS HEOR office locations 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 LATIN AMERICA REGIONAL HEADQUARTERS Insurgentes Sur # 2375 5th Floor, Col. Tizapan Mexico City D.F. - C.P. 01090 Mexico Tel: + 52 (55) 50.62.52.00 ext 5269

FRANCE 91 rue Jean Jaurès 92807 Puteaux cedex France Tel: +33 1 41 35 1000 GERMANY 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 Certosa 2 20155 Milano Italy Tel: +39 02 69 78 6721

SPAIN Dr Ferran, 25-27 08034 Barcelona Spain Tel: +34 93 749 63 00 SWEDEN Sveavägen 155/Plan9 11346 Stockholm Sweden Tel: +46 8 508 842 00 SWITZERLAND Theaterstr. 4 4051 Basle Switzerland Tel: +41 61 204 5071 UNITED KINGDOM 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@imscg.com or visit www.imsconsultinggroup.com/heor AccessPoint - Issue 3

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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 and market access of any organization in the world. Our highly-qualified consultants and researchers have multi-disciplinary experience and proven skills covering all key therapy areas.

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

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.

OUR SENIOR TEAM

Renée J. G. Arnold, PHARM D • Dr. Renée Arnold is Principal at the IMS Consulting Group in the U.S., with particular expertise in the use of technology to collect and/or model real-world data to facilitate rational decision making by healthcare practitioners and policy makers. • Renée was previously President and CEO, Arnold Consultancy & Technology where she developed and oversaw outcomes research for the pharmaceutical, biotech and device industries as well as federal government programs. Her distinguished career in health economics and outcomes research includes roles as President and co-founder of Pharmacon International, Center for Health Outcomes Excellence and Senior VP and Medical Director at William J Bologna International. • Founding member and former Chair of the Education Committee of ISPOR, Renée has several adjunct appointments and is the author of numerous articles on pharmacoeconomics and cost-containment strategies. She holds a Doctor of Pharmacy degree from the University of Southern California in Los Angeles.

Xavier Badia, MD, MPH, PHD • Dr. Xavier Badia is 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 Master’s in Public Health and Health Economics from the University of Barcelona.

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

EXPERTISE | IMS Karin Berger, MBA • Karin Berger is 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. Christopher M. Blanchette, PHD, MS, MA • Dr. Chris Blanchette is Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the U.S., bringing extensive experience in retrospective database research and observational studies with particular emphasis on respiratory diseases. • Chris was previously Director of Clinical & Outcomes Research at the Lovelace Respiratory Research Institute, where he led a team of 50 people conducting clinical research, biostatistics, and outcomes research programs. He also spent time in market access and R&D health economics at GlaxoSmithKline, most recently as Director for Health Data Analytics, and was formerly a researcher at the Premier Hospital Alliance and Agency for Healthcare Research and Quality. • In addition to serving in leadership positions for ISPOR and several respiratory disease associations, Christopher is on the editorial board of the Journal of Medical Economics and advisory board of Current Medical Research and Opinion. He holds a PhD in Pharmaceutical Health Services Research and an MS in Epidemiology from the University of Maryland, and an MA in Medical Sociology from the University of North Carolina. Nevzeta Bosnic, BA • Nevzeta Bosnic is Principal at IMS Brogan 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 Bachelor’s degree in Business Economics from the School of Economics and Business at the University of Sarajevo, Bosnia-Herzegovina. Joe Caputo, BSC • Joe Caputo is 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 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.

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IMS | EXPERTISE 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. Frank-Ulrich Fricke, PHD, MSC • Dr. Frank-Ulrich Fricke is 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 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. Rob Kotchie, MCHEM, MSC • Rob Kotchie is Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the UK, with particular expertise in health economics, outcomes research, evidence-based medicine and real-world evidence. • Previously with ZS Associates, Rob specializes in the design and roll-out of global pharmacoeconomic models, the production of health technology assessment dossiers and the use of retrospective database analytics. He has a strong focus on the areas of cardiovascular medicine, oncology, respiratory and mental health, in addition to organizational design and market access capability assessments. • Rob holds a first class honors degree in Chemistry from the University of Oxford and an MSc in International Health Policy & Health Economics from the London School of Economics.

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EXPERTISE | IMS Mark Lamotte, MD • Dr. Mark Lamotte is 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 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 Master’s in Economics from the University of Grenoble II, and a PhD in Economics from the Graduate Center of the City University of New York.

Claude Le Pen, PHD • Dr. Claude Le Pen is a member of the strategic committee of IMS 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, MS, MBA, MM, BS • Charles Makin is Principal, Health Economics & Outcomes Research at the IMS Consulting Group in the U.S. focusing on naturalistic trials, adherence interventions, chart abstractions, patientreported outcomes and other studies involving primary data collection. • During a career that includes senior roles at the UnitedHealth Group and Wellpoint, Charles has led numerous studies involving database analyses, economic modeling, multi-country patient registries, systematic literature reviews and survey-based research. • Charles holds a BS in Pharmacy from the University of Pune, India, an MS in Pharmacy Administration from Purdue University, Indiana, U.S. and an MBA in Marketing Management and a Master’s in Management, both from Goldey Beacom College, Delaware, U.S.

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IMS | EXPERTISE Eva Marchese, PHD • Dr. Eva Marchese is 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 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).

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

Dana Morlet-Vigier, MD • Dana Morlet-Vigier is 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. Julie Munakata, MS • Julie Munakata is 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, Julie has extensive experience in managing clinical trials, health economic studies and decision analytic modeling work, gained in senior roles at ValueMedics Research LLC, the VA Health Economics Resource Center and Stanford Center for Primary Care & Outcomes Research, and Wyeth Pharmaceuticals. • Julie holds an MS in Health Policy and Management from the Harvard School of Public Health and a BS in Psychobiology from the University of California, Los Angeles.

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EXPERTISE | IMS Karl-Johan Myrén, MSC • Karl-Johan (Kalle) Myrén is 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. Olaf Pirk, MD, PHD • Dr. Olaf Pirk is Senior Scientific Consultant to IMS and previously Principal, Health Economics & Outcomes Research 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. Vernon Schabert, PHD • Dr. Vernon Schabert is Global Leader Retrospective Outcomes Research and Senior Principal at the IMS Consulting Group in the U.S., leading the assessment and validation of patient-reported outcomes (PRO) instruments, retrospective analyses of claims and survey databases, and primary data collection surveys. • A founder and former President of Integral Health Decisions, Inc, Vernon has extensive experience in conducting claims analyses, creating custom administrative databases, developing business intelligence software, and leading national quality research projects, gained in roles with Thomson Reuters, Strategic Healthcare Programs LLC, and CIGNA HealthCare. His expertise spans numerous disease areas and diverse topics including medication adherence, in-patient safety and outcomes in post-acute care. • Vernon holds a PhD in Personality and Social Psychology from Stanford University and a BA in Psychology from Princeton University.

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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 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 Master’s in Public Health from the London School of Hygiene and Tropical Medicine and London School of Economics.

Massoud Toussi, MD, MSC, PHD • Dr Massoud Toussi is Medical Director, Health Economics & Outcomes Research at the IMS Consulting Group in France, where he brings in-depth knowledge of methodological and operational aspects of clinical research to assure the quality of interventional, observational and database studies. • A medical practitioner, Massoud was previously Head of Global Clinical Research Operations at Cegedim. His background includes roles at the French High Authority for Health (HAS) and various CROs as Project Lead, Scientific Manager and Operations Director. He has also used his extensive knowledge of IT tools and pharmacovigilance to define a new service process in drug safety signal detection and transmission. • Massoud holds an MD from Mashad University in Iran, an MSc in Medical Informatics and Communication Technology from Paris IV, and a PhD in Medical Informatics from Paris XIII University. He also holds a diploma in Transcultural Psychiatry from Paris Nord University.

Arnaud Troubat, PHARM D, MBA, MHEM • Arnaud Troubat is Principal, Health Economics & Outcomes Research at the IMS Consulting Group in France. He has extensive consulting experience and special expertise in the development of registration dossiers and market access strategies across a large number of therapeutic areas. • A pharmacist by training, Arnaud began his career at the French pharmaceutical industry association (LEEM), supporting members in understanding and interpreting the changing economical environment in France. He then spent a number of years in pharmaceutical affairs at ICI, leading regulatory work on registration submissions and reimbursement strategies, before subsequently moving into consulting. Most recently, he was Director at Carré-Castan Consultants, managing a team working for a wide range of pharmaceutical companies. • Arnaud holds a Doctor of Pharmacy degree and an MBA from IAE Paris and a Master’s in Health Economics and Management from Paris-Dauphine University.

Meng Zhang, MBA • Meng Zhang is 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 Master’s 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 | 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)

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Reveal True Product Value Developing products that are fit to succeed in the ‘real world’ requires a sharp scientific focus. The IMS Consulting Group Health Economics & Outcomes Research unit is a multi-disciplinary, global team — with proven success in more than 40 countries worldwide. Our team of leading experts combines rigorous scientific research with a customer-focused consulting model to help you: Address growing HTA requirements Build powerful health economic support Create enduring value propositions Develop innovative solutions for real-world market needs Next time you need HEOR support, consider the IMS perspective.

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HEORinfo@imscg.com UK + 44 (0)20 3075 4800, US +1 (703) 837-5150, AsiaPac +86 10 8567 4255, Latin America + 52 (55) 50.62.52.00 www.imsconsultinggroup.com/heor