RWE Market Impact on Medicines: A Lens for Pharma

Transcription

1 RWE MARKET IMPACT ON MEDICINES May 2013 RWE Market Impact on Medicines: A Lens for Pharma International comparisons of the impact of Real World Evidence on creating value from medicines

2 2 The pharmaceutical industry s increasing focus on RWE reflects the greater supply of electronic patient-level data and higher stakeholder demand for RWE-based decisions. So why have manufacturers struggled to act? They have been constrained by a limited fact base and isolated case examples, prompting this research. Here, we detail data supply dynamics and over 100 cases studies of actual RWE influence on product decisions. These quantifiable insights debunk a number of common beliefs: RWE s influence on decisions about medicines has increased in magnitude and scale in western markets: more than 100 observed case studies illustrate its evolution beyond pharmacovigilance (PV) Payers have applied RWE in assessing value in a variety of ways, including expanding medicines use where warranted: cost containment is not the sole objective Although payers are a powerful stakeholder in setting the RWE agenda, proactive pharma engagement matters: manufacturer-generated RWE influenced over 25% of observed decisions RWE strategies need a local context but four fundamental market archetypes can focus pharma efforts: pharma does not need a unique approach in every country This study provides a detailed understanding of market dynamics, consolidating them into four dominant archetypes. It enables manufactures to focus RWE investments via improved internal alignment and gain greater value from stakeholder engagement. The insights it provides are also relevant to policy makers and payers seeking value from RWE. RWE MARKET IMPACT RANKING 1 United Kingdom 2 Sweden 3 Netherlands 4 United States 5 France 6 Italy 7 Denmark 8 Canada 9 Germany 10 Spain AUTHORS Ben Hughes Senior Principal Real World Evidence Solutions [email protected] Marla Kessler Vice President and Region Europe Leader IMS Consulting Group [email protected]

3 3 Contents The struggle for decisive action 4 Fact-based insight 4 Relative market comparison 6 Market clusters and strategies 8 Pioneers 8 Explorers 9 Traders 10 Laggards 10 From insight to action 10 Appendix Country deep-dives 11 United Kingdom: 11/20 11 Sweden: 10/20 12 Netherlands: 8/20 13 United States: 8/20 14 France: 6/20 15 Italy: 6/20 16 Denmark: 5/20 17 Canada: 4/20 18 Germany: 3/20 19 Spain: 2/20 20 Case library of RWE application 22 Methodology and summary comparison tables 31 Key contributors 38 Further reading 39

4 4 THE STRUGGLE FOR DECISIVE ACTION The increasing need to obtain better value for healthcare spend has elevated RWE s importance as a decision-making tool. This is particularly true for medicines. In separate research, IMS estimated that improved medicines use could avoid USD billion of cost worldwide. Even stakeholders who see the RWE opportunity and its increased use struggle to act on it. Limited, isolated public case studies create a narrow picture of how RWE has affected decisions and misjudge the complexities in the underlying drivers of RWE across markets. The debate is muddied further by different stakeholder perspectives industry versus payers, health economics versus pricing and market access (PMA). The result is confusion, misalignment, and even organizational paralysis over what to do about RWE in pharmaceutical companies. Some see RWE narrowly supporting safety or mandatory submissions while others see a broad lever to engage stakeholders. While RWE evangelists clash with skeptics wanting proof that RWE matters, they themselves are split between those who see many positive opportunities and those focused on using it to mitigate risks. FACT-BASED INSIGHT To forward the debate, we sought an objective demand and supply lens on RWE. This focused on licensed medicines use rather than innovation, PV, or broader payer and provider use such as patient pathway evaluation. Payers, health technology assessment (HTA) experts and clients provided insights in over 50 interviews. FIGURE 1: RWE APPLICATION CASE STUDIES ACROSS COUNTRIES Sources of impact Label Launch Access Ongoing Access 2 Price Use Italy USA UK Sweden Canada Spain Netherlands France Germany Denmark 11. Launch Ongoing Access: access: Agreement RWE used for to RWE support generation access post-launch for market access at launch 22. Ongoing Launch access: Access: Agreement RWE used to for support RWE generation access post-launch for market access at launch

5 5 Approximately 25% of these decisions reflect industry-generated RWE, demonstrating that pharmaceutical companies influence this evolving landscape. To characterize demand, more than 100 non-safety examples were identified in which RWE impacted medicines (Figure 1). Mainly driven by payers, RWE has influenced license (label), access, pricing, and use across countries and therapeutic areas (TAs). Approximately 25% of these decisions reflect industrygenerated RWE, demonstrating that pharmaceutical companies influence this evolving landscape. In addition to demand, we examined real-world data (RWD) supply, focusing on database use rather than (costly) prospective data generation. A proxy for supply, RWE output through peer-reviewed research varied from the thousands of publications in the US and UK to only a few hundred in Germany and France. This difference reflects varying usefulness of electronic data and different stakeholders ability to access it. Useful data would have extensive coverage, illustrate the full patient journey, and have high clinical depth and quality. While only selected actors might need this level of data to create value, in practice widespread appropriate access generates more research output (Figure 2). FIGURE 2: RWE SUPPLY FROM DATABASES SOURCES USA Total supply potential UK Bubble size indicates total journal publication output Access CA NL SE IT DE FR DK ES Usefulness Overall, no country has an ideal data supply, with usefulness of or access to data constraining supply to different extents. In access-led countries (above the arrow), improving supply focuses on usefulness, such as the UK s national CPRD 1 linkage program. Companies play a role too, such as IMS US strategy of developing sophisticated HIPAA-compliant 2 linkage technology. In usefulness-led countries (below the arrow), debates are ongoing to improve access, such as to payer data in France. Meanwhile individual companies are engaging directly with physicians and patients for consent to lever data for research. 1 Clinical practice research database 2 Health insurance portability and accountability act

6 6 This new fact base is not complete without market-making mechanisms or frameworks. Enabling demand, these detail how decision making could include RWE. Examples include evaluation mechanisms (e.g., HTA, reimbursement processes, clinical guideline development), dissemination, and measurement (e.g., prescriber incentives, payment for performance, quality indicators). This complete framing can help pharmaceutical companies, payers, and policy makers alike derive the fuller potential of RWE. RELATIVE MARKET COMPARISON To highlight markets individual characteristics, we created an RWE assessment scale based on supply and demand. Data supply and demand frameworks were each scored out of five, and application was scored out of ten to reflect the importance of observing RWE demand in practice. This reveals major differences in RWE impact, with countries scoring between 2 and 11 of a potential 20 (Figure 3). The maximum score of 11 reflects that no country has the ideal conditions for RWE use in a scalable manner and highlights RWE s infancy. er scores indicate that RWE is relatively less available or more costly to generate with less consistent or transparent use in decision making. But even in markets with lower scores, RWE is still relevant. In terms of data supply, the US scored highest, with a commercial market ensuring data availability for research needs, enabling research output greatly surpassing other countries. The US did not score a maximum five as ongoing linkage efforts are yet to achieve their potential, and underlying Electronic Medical Record (EMR) data capture is lower relative to other countries. Conversely, countries such as Spain score low given limited pockets of usable data. FIGURE 3: RWE MARKET IMPACT SCORES (OUT OF 20) Ranking 1 UK Sweden Netherlands USA France Italy Denmark Canada Supply 9 Germany 10 Spain Frameworks Application Demand

7 7 On demand frameworks, the UK is closest to the ideal because RWE is used in systematic review for most evaluation processes (HTA, reimbursement, clinical guidelines). Stakeholders can disseminate RWE directly to prescribers, and RWE-enabled payment-for-performance contracts encourage appropriate prescribing. Even the UK can go further: for example, RWE-enabled prescribing indicators are still limited. Conversely, countries like Denmark and Spain lack clearly defined roles for RWE in decision frameworks. In terms of application where RWE has informed decisions all countries are distant from the ideal. Consistent, transparent use of RWE in decision making is lacking across therapeutic areas and patient populations. Case studies from the UK suggest the most extensive application, given the number, variety, and breadth of resulting decisions relative to the entire health system. Conversely, in countries such as Germany, public case studies of RWE application are rare. Combining the strengths in frameworks and application with strong patient-level databases, the UK becomes the highest scoring market. In the UK primary care datasets are long-standing and high quality, supporting over 1,000 peer-reviewed research papers. These are being transformed into a wider linked dataset, the Clinical Practice Research Database (CPRD) under government leadership. Sweden ranked second, has even richer and more integrated datasets than the UK but the insights derived are applied less consistently to medicines decision making. Sweden boasts extensive primary and secondary-care EMR coverage and rich quality registries, though access to them can be arduous. With centralized HTA, the Dental and Pharmaceutical Benefits Agency (Tandvårds- och läkemedelsförmånsverket, TLV) has made visible use of RWE, including its decision to use anti-tnfs earlier in the treatment paradigm after looking at their holistic impact on RA patients. But since Sweden has both fewer examples of RWE application and lower expected impact of TLV RWE-informed decisions given the influence of regional payers, it ranked second to the UK. The Netherlands scored third because of its high quality data and explicit guidance on the use of RWE for cost modeling, outcomes research, and cost-effectiveness. It has a long history of RWE use and specific programs to apply it. The Netherlands is behind Sweden, however, because RWE is not used as extensively to inform the management of medicines. The US ranked fourth with a score reflecting its world-leading and commercially-oriented data sets, but inconsistent interpretation and narrow application of RWE. Payers are fragmented and only selected payers make RWE related decisions. So while the ability to conduct RWE analyses is high, the consistency and spillover of any study across multiple stakeholders is low. In fifth place, France s score indicates a market yet to realize the full potential of its extensive patient-level data, even as it pushes for further RWE use in the evaluation of medicines. One issue is that access to data is limited, though a traditional focus on RCTs for launch decisions and reliance on market share information for price and access decisions are also contributory factors. A clear framework for using RWE to inform cost-effectiveness analysis has been implemented with the result that France could advance quickly if HAS 3 implements it consistently. Italy at sixth place has some reasonable patient-level databases and consistent application of RWE in selected areas but lacks true depth in RWE generation in use. Commercial and public administrative databases offer opportunities for research but are limited by either population coverage or access issues. Despite having the highest number of applications of RWE, examples are mainly from AIFA (the Italian Medicines Agency s) risk share schemes focused on product-specific questions at launch and limited to high cost products. Use to inform post-launch decisions is in reality quite low.

8 8 Denmark s seventh place represents untapped potential given its extensive data sets in terms of population and care settings coverage. This results from difficult data access and lack of frameworks to incorporate RWE insights into decisions on medicines, including in HTA which itself is voluntary. Although the analysis found two RWE case studies that aimed to use RWE to ensure payers only paid for positive outcomes, the unusual choice of TAs (erectile dysfunction and blood pressure) provide little insight into how this will evolve in the future. Canada has a long history of using private and public claims data to provide insight on medicines utilization and cost but still only ranked eighth. The claims data used for this purpose has limited clinical depth relative to other countries and has not been linked across settings of care. Although the national HTA agency creates a framework for using RWE for medicines evaluation, the independence of the regions lowers the influence of the framework. Instead, Ontario is leading the application of RWE with other regions yet to follow. Despite high electronic data capture and explicit mention in AMNOG 4, RWE for medicines in Germany is almost nonexistent and ranked second lowest in the study. Selected stakeholders such as payers do use RWE to inform decisions in areas such as disease management programs. Overall, however, conservatism related to privacy and use of data, and skepticism about the quality of data leads stakeholders to base their decisions on medicines more on RCTs. Spain ranked last based on lack of patient-level data and RWE use outside of a few specific regions. Spain has regional pockets of extensive electronic data capture but the lack of translation into research datasets limits its ability to generate RWE. National HTA approaches are under development but have yet to explicitly address RWE use in evaluation. Different case studies of RWE use could be identified at the regional level particularly in relation to access, though the extent to which medicine use was really impacted was limited. MARKET CLUSTERS AND STRATEGIES The analysis explains markets through RWD supply and RWE demand (clear frameworks and application to decisions). These dimensions and scores segment markets into four groups: Pioneers, Traders, Explorers, and Laggards (Figure 4). Pioneers Stakeholders in Pioneer markets use their relatively notable RWD supply to inform drug decisions. Countries in this group the Netherlands, Sweden, and the UK all have strong national HTAs, suggesting an impact from concentrated decision making. In these markets, pharmaceutical companies should set high ambitions for RWE plans, demonstrating value and engaging stakeholders based on a variety of real-life views (e.g., disease, product, class, cross care settings, long-term outcomes, payer-relevant quality of care indicators). They must fully exploit RWE beyond traditional evaluations to enable commercial strategy, leverage outcomes-based marketing, and use innovative evidence tools with local health systems. For example, one ground-breaking manufacturer developed a mobile (ipad) evidence platform to support its diabetes drug launch in the UK. It used RCTs and various RWD sources to build models of prescribing patterns, cost and outcomes for general practices. Trained sales representatives engaged prescribers by adjusting the pre-loaded parameters of the model (e.g., patient numbers, prescribing profile, cardiovascular risk factors) to discuss prescribing from the clinician s perspective. As RWE becomes an accepted dialogue with payers and clinicians in Pioneer markets, companies without these capabilities will be disadvantaged against or unable to respond to more innovative competitors. 3 French National Authority for Health 4 The Act on the Reform of the Market for Medicinal Products

9 9 FIGURE 4: MARKET SEGMENTATION FOR PHARMACEUTICAL INDUSTRY STRATEGIES Explorers Pioneers UK NL SE Demand Laggards IT FR Traders CA US ES DE DK Supply Explorers Explorers, such as France and Italy, have a significant demand-side vision but limited RWD supply. France s bold vision includes using RWE for cost-effectiveness assessments and regular class reviews without detailing how extensive data in the health system can be accessed or levered. In Italy, there is widespread use of pay-for-outcomes or Coverage with Evidence Development (CED), but how these schemes inform coverage or pricing decisions based on the captured data remains unclear. While manufacturers can react to these limited demands for RWE, the more innovative ones might place a bet that the markets will expand RWE use over time. There is no crystal ball, but this RWE demand could signal an evolution to pioneer style markets. Either way, pharmaceutical companies must develop some RWE capabilities for payer s current focus areas. While manufacturers can react to these limited demands for RWE, the more innovative ones might place a bet that the markets will expand RWE use over time. There is no crystal ball, but this RWE demand could signal an evolution to pioneer style markets. For example, one inventive company has gambled on developing a high quality evidence platform in France. With no access to payer data, it has partnered with commercial vendors to use innovative and cost-effective approaches to maximize the value of existing EMR and Ministry of Health datasets. Using these as an initial platform, the company is gathering supplementary data to develop a high quality reference cohort in a chronic disease. In addition to classic RWE, this generates process-of-care indicators, setting a benchmark for understanding patient outcomes.

10 10 Traders The US is the only country representing the Traders, though other countries not in scope could have a similar model. Owners of RWD share it without stipulating how it should be used beyond ensuring individual privacy. Most US insurance companies and providers sell data and only use it to support specific analyses about their own populations. Thus, pharmaceutical companies have broad data access to drive performance, from trial design through commercial support. Successful US strategies involve evidence platforms and tools that support multiple internal stakeholders. However, without clear frameworks, the channels for external engagement are more nuanced. Only selected payers engage readily on RWE, and FDA regulations on RWE dissemination are more restrictive than in Pioneer countries. A differentiated engagement approach is needed, requiring creative thought and investment. One leading company, for example, developed a rich platform in one priority therapeutic area rather than a ubiquitous platform across TAs. Over several years it linked all relevant datasets (Rx, Claims, EMR, registries, RCTs, observational studies, biobanks) and developed different internal customer tools to exploit it. This asset supports traditional RWE and multiple peer-reviewed publications. More impressively, it generates hundreds of internal standard reports even improving sales forecasting accuracy. This capability enhances external engagement too, as the manufacturer is now a reference for local prevalence estimates or characterizing local unmet patient needs. Laggards Finally, there are the Laggards who may use RWE more in future but face significant hurdles today. The Laggards in this study are Canada, Denmark, Germany, and Spain, all of which illustrate different challenges (e.g., strong data privacy, fragmented healthcare landscapes). In these markets, pharmaceutical companies benefit from engaging directly with selected stakeholders willing to lead on RWE. Markets with strong regional payers may see that leadership from those regions, such as Cataluña in Spain or Ontario in Canada. In Germany, some sick funds have expressed willingness to partner on RWE. Given the limited resources of these stakeholders and the large number of manufacturers, developing a clear value proposition and local RWE capabilities are essential to becoming a preferred partner. Innovative companies have long been in dialogue with regional stakeholders, quietly making co-investments in research capabilities to further all parties goals. FROM INSIGHT TO ACTION How can senior executives lever these insights for actionable RWE strategies? The emphasis and insights can be used to engage their teams to determine Where will additional investments in RWE create most value for our portfolio (e.g., market types, therapy areas, stakeholders, phases of the lifecycle)? What changes to brand evidence plans or stakeholder engagement approaches on evidence can capture the RWE potential in each of the four market types? How should our RWE generation capabilities be reinforced, such as scalable platforms, targeted stakeholder engagement, or deployment of innovative channel tools? While franchise and brand teams naturally drive questions on the where, increasing leadership from PMA is required on the what, as is leadership from HEOR, epidemiology, and other evidence functions on the how. Senior executives may need to personally champion cross-functional RWE discussions given the strategic issues involved and given organizational hesitancy around perceived RWE risks even at the expense of potential gains.

11 11 Appendix Country deep-dives 1: UNITED KINGDOM SCORE 11/20 Combining the strengths in frameworks and application with strong patient-level databases, the UK distinguished itself in this research. In the UK primary care datasets are long-standing and high quality, supporting over 1,000 peer-reviewed research papers. These are being transformed into a wider linked dataset, the Clinical Practice Research Database (CPRD) under government leadership. Supply: 3/5 Underlying UK electronic data capture is among the highest worldwide, thanks to partly to the NHS program for IT, and physician s financial incentives for high quality data recording (QOF 5 pay for performance or HRG 6 based payments). This has partly enabled world-leading observation research datasets, such as the CPRD (previously GPRD), HES (Hospital Episode Statistics), THIN, Disease Analyzer or HTI to name a few. Moreover, specific data collections such as National Audits or SACT 7 are nationally relevant datasets in specific disease areas of interest. Across this infrastructure, information and governance mechanisms protect patient confidentially but promote use. This includes government-led subscription services, rapid protocol approval for CPRD or HTI use, clear patient confidentiality risk approaches (e.g., the small numbers rule), or innovative promotion of datasets such as the UK s Open Data initiative. This results high research output, with over a thousand peer-reviewed publications from CPRD alone. Despite these strengths, the UK has fundamental limitations in terms of coverage and linkage. Primary care EMR databases covering no more than 10% of the population, and data is generally still in separate silos despite the ambitions CPRD linkage program. Finally, genuine UK coverage is a challenge, with different approaches in the four nations (England, Scotland, Wales, and Northern Ireland). Demand frameworks: 4/5 Frameworks use RWE in UK. This is partly driven by high familiarity with RWE across UK stakeholders, a historical use of research databases such as the GPRD, and a long history of HTA, NICE uses systematic review processes that lend themselves to RWE use: comparators, resource use, reference populations, effectiveness, natural history, and clear value metrics such as the QALY (Quality-adjusted life-year). Although subject to criticism, this cost-effectiveness measure helps establish a clear decision framework within the UK. Outside evaluation processes, reporting is a RWE strength including via QOF 5 or QIPP 8 indicators relying partly on RWE infrastructure or methods. Suggested evolutions in payment for performance schemes imply this will grow over time. The UK also has a flexible framework for RWE dissemination. With individual physicians playing a role in cost-effective care, RWE can be disseminated by various actors to individual prescribers. Application: 4/10 The UK leads RWE application, evidenced by the volume and nature of 16 case examples found. Their impact was often at the national level and in drug classes relevant to a large range of pharmaceutical manufacturers. The variety of application was also significant: at launch and for coverage with evidence development schemes, for ongoing or long-term access and coverage, and on use by physicians in daily practice. NICE 9 also uses RWE to steer drug usage across the product lifecycle by periodically publishing guidelines but it does not have the capacity to conduct such assessments systematically. However, RWE use not systematic across drug classes, and the UK s world leading score of 4 out of 10 reflects the infancy of RWE based decisions globally. 5 Quality and Outcomes Framework 6 Healthcare Resource Group 7 Systemic Anti-Cancer Therapy 8 Quality, Innovation, Productivity and Prevention 9 National Institute for Health and Care Excellence

12 12 2: SWEDEN SCORE 10/20 Sweden ranked second, has even richer and more integrated datasets than the UK but the insights derived are applied less consistently to medicines decision making. Sweden boasts extensive primary and secondary-care EMR coverage and rich quality registries, though access to them can be arduous. With centralized HTA, the Dental and Pharmaceutical Benefits Agency (Tandvårds- och läkemedelsförmånsverket, TLV) has made visible use of RWE, including its decision to use anti-tnfs earlier in the treatment paradigm after looking at their holistic impact on RA patients. But since Sweden has both fewer examples of RWE application and lower expected impact of TLV RWE-informed decisions given the influence of regional payers, it ranked second to the UK. Supply: 4/5 Sweden s deep and comprehensive electronic data capture reaches close to 100% coverage in both primary and secondary care, with varied access for third parties across providers. Established administrative databases contain rich claims data that are used for monitoring physician prescribing and incentivizing adherence to regional guidelines in addition to RWE studies. A series of national registries with high population coverage contain high quality data for different areas of healthcare such as births/deaths, inpatients/outpatients, drug usage and cancer. Yet more registries contain socioeconomic data such as income and education and disease specific registries that have variable population coverage (10% - 95%, depending on the particular disease). Systematic recording of national ID numbers across healthcare settings facilitates a high degree of linkage across different data sets. However peer reviewed research is not as high as other countries due partly to ethics approval taking 3-6 months and the lack of a standing dataset with established linkage. That said, Sweden offers research opportunities not available in other countries and will continue to be a fertile market for RWE generation. Demand frameworks: 3/5 Sweden has a good understanding across different stakeholders of the relative strength and weaknesses of RWE. HTA consistently uses QALYs as a standard value metric and the TLV or the SBU 10 can incorporate RWE into health economic models for cost-effectiveness and budget impact analysis. The TLV has also started using coverage with evidence development approaches and may request this when there is uncertainty around a product s ICER (incremental cost-effectiveness ratio). Beyond HTA and coverage decisions, RWE is not used as extensively as in other countries to monitor or incentivize appropriate prescribing (e.g. compared to QOF in the UK). Results of RWE studies can be directly communicated to physicians by a variety of stakeholders, provided they have been published in a scientific journal. Sweden therefore has a well developed framework in place for the interpretation and dissemination of RWE. Application: 3/10 Sweden although a strong candidate in Europe lags behind the UK for RWE application. Only 11 case studies were identified which is average by international comparison, with the UK also having a slightly wider breadth of impact. Nationally, payers regularly and systematically publish prescribing patterns which affects the real world prescribing behavior of physicians at the regional level, such as with statins and tranquilisers in a geriatric context. On occasion, RWE has been used to affect access (e.g. Atacand remained on formularies based on manufacturer-submitted RWE), but in general the application of RWE is unpredictable and does not affect pricing. 10 The Swedish Council on Health Technology Assessment in Healthcare

13 13 3: NETHERLANDS SCORE 8/20 The Netherlands score reflects its high quality data and explicit guidance on the use of RWE for cost modeling, outcomes research, and cost-effectiveness. It has a long history of RWE use and specific programs to apply it. The Netherlands is behind Sweden, however, because RWE is not used as extensively to inform the management of medicines. Supply: 3/5 The Netherlands is a world leader in both routine electronic healthcare data capture and infrastructure with near 100% EMR coverage in primary care. PHARMO 11, an independent organization for research into drug use and outcomes and the Integrated Primary Care Information (IPCI) collected by GPs underpin the Netherlands national research infrastructure. It covers 2 million residents encompassing data on community pharmacy, clinical laboratory, general practitioner databases, pathology registers, hospital pharmacy, mortality, perinatal registries and cancer registries. Unlike the UK data is not available to third parties under license and information governance agreements, however current governance arrangements for PHARMO have enabled significant research, evidenced by over 300 peer-reviewed publications. Limitations to PHARMO include low levels of patient linkage across data sets (about 200,000 but growing) and limited access to patient level data by third parties, unlike situations in the UK and US. Alternatives are also limited, though databases such as the AgisHealth Database, IMS LifeLink and the LINH Database may be suitable for selected research questions. Overall, the Netherlands offers capabilities for RWE but improvements in coverage and access would be required to be truly distinctive versus other countries. Demand frameworks: 3/5 The Netherlands introduced cost-benefit analysis in the assessment of medicines in Guidance from CVZ 12 (HTA and pricing) is explicit on the use of RWE for research and the type of data sources or databases that can be considered. This approach levers the historic strength of health databases in the Netherlands (e.g. monitor incidence, prevalence, and quality of care). There are specific programs to stimulate the tracking/monitoring of efficient use of expensive and orphan drugs, such as the subsidy programs of ZONMW for measurement of adherence, efficiency, and outcomes. The overall picture is therefore relatively strong historical expertise in RWE use and some consistent application to decision making in many of the areas that RWE can provide benefit. Like all countries, more could be done. Guidance and the use of approaches such as coverage with evidence is not in place, though policy discussions are ongoing in establishing this for outpatient medicines. Moreover, the use and regular reporting of RWE on prescribing to guidelines could be more extensive and payment for performance or quality schemes are not as developed as in countries like the UK. Application: 2/10 The Netherlands is ranked third behind Sweden and the UK for RWE application but mostly because of the lack of impact in other markets. We could only identify four case studies in which payers modified their behavior, including one innovative agreement for Xolair based on effectiveness. Even that may still be a mechanism to reduce net price rather than a statement of intent to increase linkage between price and outcome. This lack of RWE use is striking given that the Netherlands uses a four-year real world evaluation plan to make a national level access decision for high cost hospital drugs. Using RWE to impact drug usage levels is more ad hoc, as illustrated by tightening guidelines around the use of generic statins. 11 Institute for Drug Outcomes Research 12 Healthcare Insurance Board

14 14 4: UNITED STATES SCORE 8/20 The US score reflects its world-leading and commercially-oriented data sets but inconsistent interpretation and narrow application of RWE. Payers are fragmented and only selected payers make RWE related decisions. So while the ability to conduct RWE analyses is high, the consistency and spillover of any study across multiple stakeholders is low. Supply: 4/5 Rapid US EMR uptake is a recent trend linked to Health Information Technology for Economic and Clinical Health (HITECH) Act in 2009, reaching 69% adoption levels in primary care, though significantly lower in secondary care settings. Given the historically low EMR use, RWE in the US has traditionally claims data. Many private vendors and payers make such datasets available. These cover a large proportion of the US population and have increased their value for research by incorporating selected clinical data such as lab values. This has resulted in substantial RWE research output. Regulatory clarification on the use of this data through HIPAA 13, the commercial market for data, rising EMR sources, and the overall importance of the US as a healthcare market combine to make it the most dynamic country for potential use and research using routine data. Ongoing private and national investment will extend these datasets, and are expected to link further non-traditional data types such as purchasing and biobanks, to routine datasets to further extend research opportunities. Demand frameworks: 1/5 Despite its substantial RWE research output, the US has no national or regional HTA bodies, related to the competitive nature of the US healthcare market and wider political and social issues. A framework for comparative effectiveness research has been established by the Patient-Centered Outcomes Research Institute (PCORI) which was created by the Patient Protection and Affordable Care Act in To date, the research carried out by PCORI has been focused on patient-centered outcomes rather than outcomesbased CER 14, cost-effectiveness studies or the use of medicines. The Food and Drug Administration (FDA) has recently started utilizing RWE to understand drug safety post-launch through development of the Sentinel Initiative. Overall national frameworks using RWE are limited. Given this landscape, large payers show the most proactive and consistent use of RWE in decision making. These include WellPoint, Medco and United, who have initiated a large number of RWE analyses and adapted formularies based on results. WellPoint, in particular, has promoted an Outcomes Based Formulary and publicly communicated its activities and decisions. In addition, RWE is being used in quality and prescribing indicators in pay for performance contracts with providers. For example, physicians are measured on their use of major medications in conjunction with appropriate diagnoses or associated interventions, ensuring a level of guideline compliance. However, to highlight the diverse nature of the US healthcare landscape, there are also previous examples of payers such as United choosing not to use RWE for physician drug utilization controls. Outside payers own use, pharmaceutical companies can also disseminate RWE to individual physicians to inform clinical practice. However, options are limited, either having to focus on disease patterns or in scientific exchange when discussed with individual prescribers. The US is been a pioneer for innovation in analyzing patient level data and gaining insights, but its unstructured path and varies perception across stakeholders limits its use. 13 Health Insurance Portability and Accountability Act 14 Cost-effectiveness Research

15 15 Application: 3/10 The private payer model in the US has enabled the frequent but fragmented application of RWE, lowering the overall score. We found 21 case studies in the US, the majority in high budget areas such as primary care and oncology in selected payers. Active payers have mostly used their own RWE to assess drugs on an ongoing basis, rather than at launch, via class and product reviews. Their findings have influenced tiering, restrictions, and even medical versus pharmacy benefit status, with payers willing to punish poor performing products as well as favor products showing clear cost savings on the medical side. However, the spillover across the US health system remains limited since individual insurers have a strong preference for using their own data over competitors. The development and influence of RWE remains ad-hoc rather than systematized. 5: FRANCE SCORE 6/20 France s score indicates a market yet to realize the full potential of its extensive patient-level data, even as it pushes for further RWE use in the evaluation of medicines. One issue is that access to data is limited, though a traditional focus on RCTs for launch decisions and reliance on market share information for price and access decisions are also contributory factors. A clear framework for using RWE to inform cost-effectiveness analysis has been implemented with the result that France could advance quickly if HAS 15 implements it consistently. Supply: 2/5 Electronic data capture is strong in primary care and rapidly increasing in hospital settings based on significant government incentives for EMR adoption. GPs are incentivized by the national insurer based on a pay for performance contract and incentives for the accurate collection of data, which is hoped will promote high quality clinical data recording. France s strong reimbursement data including PMSI, covering 100% of hospital episodes and the national claims dataset (SNIIRAM) covering claims for the entire French population. Data linkage such as PMSI-SNIIRAM in 2007 and links to the cause of death registry in 2011 have recently occurred. Research output is low (estimated at 110 peer reviewed papers in 2009) despite having Europe s largest claims dataset by coverage, which is partly due to restrictive governance and data access models for third parties. However access to PMSI for commercial organizations has recently been relaxed and claims datasets are also supplying data to cohorts that offer possibilities for sponsored research such as PROSPERE or CONSTANCE. There are two major RWE opportunities for pharma: the physician EMR panels run by Cegedim LPD and IMS Disease Analyzer, which cover a small proportion of the French population. Demand frameworks: 3/5 Selected and high profile use of RWE by the national payer is rapidly raising its profile plus a changing approach to HTA and medicines value assessment. Access to the French market is conditional and re-evaluated after three to five years guidelines support the use of RWE including characterizing patient populations, appropriate comparators, investigation of longer-term outcomes, methods for cost estimations, and the potential use of value based metrics like QALYs. Approaches that examine real life practice are emphasized and 25 key databases are identified that fulfill research requirements. A number of challenges remain; firstly the consideration of RWE in this new evaluation approach needs to be understood over time as different treatments are evaluated. Secondly, regular reporting on medicines using RWE approaches appears distant, with current indicators focusing on areas such as generic adoption and prescribing patterns. Finally, restrictions exist on the communication of RWE to individual prescribers in France which is currently focused more on disease or usage understanding with clinical RWE claims only supporting existing claims established through RCTs French National Authority for Health 16 Randomised Controlled Trials

16 16 Application: 1/10 Despite the strong potential to use RWE, application has been limited. French stakeholders could cite few cases in which RWE had been used; this research identified just three examples. Those limited examples do show French payers interest in RWE for both launch and ongoing usage, as demonstrated by the Risperdal arrangement and the national level assessment of the statin class, which led to stricter guidelines. However, such use is ad hoc and commonly focused on the highest budgetary impact items. 6: ITALY SCORE 6/20 Italy at sixth place has some reasonable patient-level databases and consistent application of RWE in selected areas but lacks true depth in RWE generation in use. Commercial and public administrative databases offer opportunities for research but are limited by either population coverage or access issues. Despite having the highest number of applications of RWE, examples are mainly from AIFA (the Italian Medicines Agency s) risk share schemes focused on product-specific questions at launch and limited to high cost products. Use to inform post-launch decisions is in reality quite low. Supply: 2/5 Capture of underlying electronic healthcare data in Italy is mixed. While more than 80% of general practitioners store medical data about patients, the extent of prescribing capture in EMR and the quality of the data is varied. Adoption of EMR in the hospital setting is much lower. Extensive administrative data is captured but there is no national dataset for areas such as hospital discharge. This means research in Italy either relies on limited research datasets in primary care or regional administrative datasets, or registries. Datasets at the regional level offer additional opportunities but access for third party stakeholders is limited. This landscape has significant potential to improve. Regionally, the ongoing roll-out of ecard schemes in Lombardy, Tuscany and Friuli Venezia Giulia are beginning to generate deep medical histories across all healthcare settings. Nationally, there is a major effort to drive adoption of an eprescribing system. In addition, the National Heath Information System (NSIS) is a governance tool currently being implemented that uses data capture to support, monitor, and oversee fundamental levels of healthcare services. A further objective of the NSIS is to provide regions with reporting structures and collection systems that will, among other things, enable accurate collection of outcomes and cost data from healthcare providers. To unlock this potential for RWE, re-examination of the interpretation of stringent data protection and privacy laws might be required, as patient consent is required for the processing of almost all health data. Demand frameworks: 2/5 HTA in Italy is strongly influenced by the National Agency for Regional Health Services (AGENAS) and HTA leadership from 5 of the 21 regions (Emilia Romagna, Venice, Piedmont, Lombardy, and Tuscany. Assessments are passed to AIFA s Pricing and Reimbursement Committee for recommendations on coverage. These decisions consider RWE for disease characterization and costs, as well as evidence from observational studies comparing pharmaceutical therapy with standard care. However, the most significant use of RWE in Italy for CED (Coverage with Evidence Development) and pay for performance schemes. AIFA regularly uses this as an access requirement in certain therapeutic areas such as oncology. Other potential uses of RWE include guideline development, reporting on indicators, adherence to guidelines, and dissemination processes. The National Guideline System (SNLG) also considers RWE through a systematic review process but does not place specific emphasis on its inclusion during the development of guidelines. Reporting, through AIFA s OsMED, generally focuses on prescribing consumption rather than RWE.

17 17 However, selected regions are developing more sophisticated RWE indicators, including for monitoring and addressing adherence (e.g. utilization and adherence, hospital admissions, negative clinical outcomes) with the goal of developing interventions to improve adherence. On dissemination, the gatekeeper role of the general practitioner (similar to that in the UK) creates a degree of flexibility for all actors to disseminate relevant evidence to individual prescribers. Application: 2/10 Actual RWE application to date, however, is limited to patient-specific and product-specific cost-sharing schemes. Almost all of the 27 case studies identified fall into such categories. budget impact drugs in oncology and MS must be entered into an AIFA registry for launch access. However, payer decisions are rarely informed by that data beyond rebating. Payers design the agreements to hedge against the financial risk of non-responders and outlier patients with high consumption levels. Price reviews conducted over the product life cycle at the regional level do not seem to be informed by RWE. With this lack of evidence for using RWE to make decisions outside of expensive specialty products, Italy scores low. 7: DENMARK SCORE 5/20 Denmark s score represents untapped potential given its extensive data sets in terms of population and care settings coverage. This results from difficult data access and lack of frameworks to incorporate RWE insights into decisions on medicines, including in HTA which itself is voluntary. Although the analysis found two RWE case studies that aimed to use RWE to ensure payers only paid for positive outcomes, the unusual choice of TAs (erectile dysfunction and blood pressure) provide little insight into how this will evolve in the future. Supply: 3/5 Denmark has extensive electronic data capture integrated into its healthcare system. As an early adopter of EMRs (early 1990s) in primary care it s had close to 100% coverage for over a decade but with more limited recording of structured or coded data. EMR coverage in secondary care is lower but increasing and expected to mirror primary care in the near future. Administration systems capture hospital inpatient and outpatient data and report to the national diagnosis register. Denmark s research infrastructure is focused around national registries (like other Nordic countries) with disease specific registries covering the vast majority of the population across different healthcare settings, some make unique contributions to health research worldwide (e.g. Twin Registries). Like other Nordic countries, the recording of national ID numbers along with other healthcare data allow linkage of patient data across databases, increasing its value for research. Despite these strengths, access is often limited to academic groups or based on protocol approval via the national statistical bureau. There is limited foundational infrastructure to link datasets on an ongoing basis, though certain university hospitals have standing infrastructure to link assets in their catchment populations (e.g. Aarhus University Hospital covering 1.8m lives). Overall Denmark s strong research potential is limited by a lack of systematic resources and restrictive governance and data access models compared to other countries. Demand frameworks: 1/5 There is low use and acceptance of RWE by stakeholders in Denmark. The DACEHTA 17,the primary Danish HTA body, carries out pharmacoeconomic analysis of new health technologies. However, the addition of pharmacoeconomic evidence into a reimbursement application for the National Board of Health is voluntary, with reimbursement decisions focused on price versus existing treatments and budget impact. In many other countries, the submission of RWE for economic analyses has now become mandatory. 17 The Danish Centre for Health Technology Assessment

18 18 This situation is not improved in pricing (DKMA 18 ) decisions, in identifying standard comparators, or in considering standard measurement (value metrics or reporting). The situation may well evolve, particularly with a policy change to embrace access schemes and five-year reviews of pricing schemes approaches that are both natural conduits for considering RWE in decision making processes. Application: 1/10 Danish stakeholders to date have not used RWE to drive product decisions in any significant way. Only two case studies were identified within the framework of innovative agreements: a blood pressure product and erectile dysfunction drugs. These appear to have been crafted to ensure ongoing access. As with launch access, even these schemes were potentially used to reduce net price rather than actually pay for outcomes. 8: CANADA SCORE 4/20 Canada has a long history of using private and public claims data to provide insight on medicines utilization and cost. The claims data used for this purpose, however, has limited clinical depth relative to other countries and has not been linked across settings of care. Although the national HTA agency creates a framework for using RWE for medicines evaluation, the independence of the regions lowers the influence of the framework. Instead, Ontario is leading the application of RWE with other regions yet to follow. Supply : 2/5 Canadian electronic healthcare data capture is good and improving, with EMR coverage in primary care reaching 52% across different provinces. Adoption of EMRs in secondary care is uneven with varying uptake across the 13 regions. Significant claims datasets exist in many provinces and support extensive epidemiological research despite narrow diagnosis data. We identified over 200-peer reviewed publications from the Saskatchewan and Manitoba datasets alone. But without a link to prescribing data, little of this research has been focused on medicines and observational datasets for pharma epidemiological research are lacking. The recent development of new EMR based and anonymized datasets, such as IMS Brogan RWE, is set to change this landscape. Demand frameworks: 1/5 The national framework for reviewing new medicines from the Canadian Agency for Drugs and Technologies in Health (CADTH) prescribes QALYs 19 as the standard metric for pharmaceutical valuebut is vague on the use of RWE. This may change over time and a recent HTA examining the use anti-tnf drugs for refractory inflammatory bowel disease evaluated non-rct observational data. Nevertheless, the results are not binding on the provinces, who might use RWE differently if they conduct their own analyses. Some regions, including INESSS 20 in Quebec, appear to be actively embracing RWE beyond basic use such as budget impact analyses, but there is generally no systematic use at the provincial level. RWE can be used to inform clinical guidelines and track appropriate use by physicians. It can also be disseminated directly to physicians to inform their clinical practice given a flexible framework for the dissemination of RWE to prescribers and other actors such as pharmaceutical companies. The use of advanced prescribing indicators is limited in comparison to other countries, such as the UK with its payment for performance schemes like QOF Danish Health and Medicines Authority 19 Quality Adjusted Life Years 20 National Institute for Excellence in health and social services 21 Quality and Outcomes Framework

19 19 Application: 1/10 Canada illustrates the challenge of translating intent into actual changes with the nine examples identified in this research showing activity around RWE without widespread impact. Four examples were national-level innovative agreements help provincial payers avoid paying for non-responders, such as the guarantee that finasteride would avoid surgery. But the impact has been somewhat muted because provincial payers can still deny access based on their own criteria. Other examples showed that sub-national payers are open to using RWE to inform post-launch access. For example, Ontario, the most prolific user of RWE in our Canadian analysis, shifted funding from bare metal to drug eluting stents based on RWE. Ontario also employed this type of evidence to inform its diabetes disease management, restricting access to insulin infusion pumps. Overall, however, the application of RWE for product price, access, and use is very low. 9: GERMANY SCORE 3/20 Despite high electronic data capture and explicit mention in AMNOG 22, RWE for medicines in Germany is almost nonexistent. Selected stakeholders such as payers do use RWE to inform decisions in areas such as disease management programs. Overall, however, conservatism related to privacy and use of data, and skepticism about the quality of data leads stakeholders to base their decisions on medicines more on RCTs. Supply: 2/5 Germany s rich electronic data reflects widespread EMR use in primary care and sizable claims datasets held by payers due to legislation requiring electronic processing of all healthcare settlements. However, EMR adoption in hospitals is lower than in some other European countries, and there is no central discharge database across hospitals. Access to payer claims data across stakeholders is also limited. To date, payers have even ignored regulations requiring them to share datasets with IQWiG 23. Not surprisingly, only a few significant databases are available for research. These include IMS Disease Analyzer and Cegedim LPD. Research institutes such as BIPS 24 or Wido provide claims data for payers but they face long wait times for approvals nine months is not unusual. These conditions make the supply of German RWD limited. Demand frameworks: 1/5 Legislative changes (AMNOG) created a role for RWE in medicines decision making with prospective and retrospective RWE data allowed as a supplementary component of the AMNOG benefit assessment for market access and pricing. Theoretically, RWE could provide evidence on standard of care, characterize the patient population through epidemiological data, and inform budget impact with cost and resource use data. But the assessment happens too quickly to use RWE to show the value of a product in market. RWE has helped overcome negative IQWiG assessments, however, such as with sickness funds accepting RWE for price negotiations with short-acting insulin analogues, showing how RWE might play a role in price negotiations outside of AMNOG. Payers and clinicians are working to use RWE more broadly to improve health outcomes and contain costs. Physician-created disease registries, often reflect collaborations with other stakeholders including industry, and provide RWE on safety, usage, adherence, compliance, and health outcomes. Payers RWE capabilities are based on central data warehouses. While use of these datasets is highly regulated, they can potentially help evaluate integrated care programs and physician prescribing relative to guidelines. As in other markets, though, the dissemination of RWE directly to physicians is restricted and no regular reporting of RWE prescribing indicators is in the public domain. 22 The Act on the Reform of the Market for Medicinal Products 23 QInstitute for Quality and Efficiency in Healthcare 24 Leibniz Institute for Prevention Research and Epidemiology

20 20 Application: 0/10 Despite many of the pieces being in place, the application of RWE in Germany remains nominal. Only three case studies were identified, notably few considering the markets size. Although AMNOG defines RWE as a potential support for price definition, there is little evidence that IQWiG has materially used RWE. Inherent time lags make it difficult to provide drug-specific RWE in the year post launch, partly illustrating the challenge. Although several stakeholders note looking at patient-level data in expensive drug classes, they could not cite examples of basing decisions on it. 10: SPAIN SCORE 2/20 Spain s lack of patient-level data and RWE use outside of a few specific regions was notable. Spain has regional pockets of extensive electronic data capture but the lack of translation into research datasets limits its ability to generate RWE. National HTA approaches are under development but have yet to explicitly address RWE use in evaluation. Different case studies of RWE use could be identified at the regional level particularly in relation to access, though the extent to which medicine use was really impacted was limited. Supply: 1/5 Underlying electronic healthcare data capture varies by region, with close to 100% EMR adoption for both primary and secondary care settings in regions such as Catalonia and more moderate levels elsewhere. The Conjunto Mínimo Básico de Datos (CMDB) hospital discharge database is one of the few data assets with national coverage, representing about 75% of hospitals. But since treatment data is not included, the dataset s applications are primarily limited (e.g., descriptive epidemiology of diseases). Catalonia is the leading region for the electronic capture of health records and linkage among data sets but others are making progress as well. The Information System for the Development of Primary Care Research (SIDIAP) is a public primary care database that can be accessed through specific protocols. the Catalan Health Authorities are creating a CPRD-like structure of linked databases across the patient pathway. In Valencia, the ABUCASIS electronic heath recording system captures primary and secondary data for around five million patients and can be linked to other datasets such as mortality databases but is not considered widely accessible. Other regions, including Andalucía and País Vasco, also have advanced data capture but with similar barriers to access. Strong privacy laws, political sensitivity, and a fragmented, autonomous regional system have contributed to a poor environment for the use of patient-level data. Nationally, there is a mandate for eprescribing to be in place in all regions with the supporting infrastructure to capture and store data, but implementation is still uneven by region and locality. Therapy-specific databases, such as for biologic treatments or adverse events, exist but are more difficult to access by for-profit organizations. IASIST is a private organization trying to enable RWE by contracting with many public hospitals for data access and has also gained limited coverage in primary care. Data from IASIST can be used to support certain study questions.

21 21 Demand frameworks: 0/5 Without a clear national framework for medicines evaluation, the role of RWE has been limited to economic models and significant use of prospective methods to develop evidence. So clarity on the use of large scale real world databases in decision making is unclear relative to other countries. Recent legal developments should change this by increasing the use of HTA. A new law has mandated a stronger HTA network and made evaluation mandatory for new treatments. This network is comprised of the national HTA agency (AETS) and regional HTA agencies (OSTEBA 25, AIAQS 26, AETSA 27 ). Following any assessment, the NHS Advisory Committee of Pharmaceutical Benefits (Comité Asesor de la Prestación Farmacéutica del Sistema Nacional de Salud) will advise on coverage and pricing. One immediate consequence of these changes is an increased use of CED, though this has been applied less to medicines and more to procedures and devices (e.g. Sacral root stimulation, aortic valve implantation, MARS albium dialysis). Application: 1/10 While some use of RWE has informed specific risk sharing agreements, the infrequent application of existing RWE is not surprising given Spains limited RWE infrastructure. While nine cases were identified, at least four only affected an individual region. The application of RWE has been greater in some regions, notably Catalonia, than in others, but at the national level it has been almost nonexistent. RWE has been used only for product access and only for products in big primary indications such atrial fibrillation, hyperlipidemia, diabetes, and hypertension. This regional behavior shows a focus on high budget impact areas. 25 Basque Office for Health Technology Assessment 26 Agency for Information, Evaluation, and Quality in Health 27 Agency for Health Technology Assessment of Andalusia

22 22 Case library of RWE application Canada Therapy area Brand Lever Brief Description Oncology Taxotere Launch Access Sanofi-Aventis agreed to reimburse the cost of Taxotere to provincial payers if an agreed responder level had not been reached facilitating formulary listing at launch CV Spironolactone Use A study into the increased use of spironolactone in heart failure patients revealed higher hospitalization rates and associated in-hospital mortality which informed treatment guidelines and use of the product CV Stents Use Prospective pragmatic registry showing that drugeluting stents are only effective in patients at high risk for restenosis; the study informed a funding decision for 30% conversion from bare metal to drug eluding stents for high risk patients Diabetes N/A Ongoing Access Before / after study using micro simulation economic model informing funding for bariatric programs, and suspending funding for insulin infusion pumps Alzheimer s N/A Ongoing Access Data collection on patient characteristics and outcomes for Alzheimer s drugs with the aim of identifying a biomarker that will show which patients will benefit from treatment informing access Schizophrenia Clozapine Launch Access Sandoz Canada would reimburse individuals, hospitals and government drug plans in cases where patients with treatment-resistant schizophrenia must be taken off clozapine within six months CV Various Endovascular abdominal aortic aneurysm repair (EVAR) Extracorporeal photopheresis Launch Access Ongoing Access Prospective observation on safety assessment of endoleak which informed a funding decision for high surgical risk patients only Prospective observational study which resulted in a positive funding decision for graft-versus-host disease (GvH) but an inconclusive funding decision Sézary syndrome BPH Finasteride Launch Access Merck-Frost offered to reimburse provincial governments the full cost if patients prescribed finasteride subsequently required surgery for benign prostatic hyperplasia after one full year of medical therapy

23 23 Denmark Therapy area Brand Lever Brief Description Erectile Dysfunction Erectile dysfunction Ongoing Access No play; no pay schemes for drugs for erectile dysfunction CV Valsartan Ongoing Access A population based no cure, no pay strategy for valsartan to lower BP was initiated to enhance market share France Therapy area Brand Lever Brief Description Diabetes Glitazone Ongoing Access A conditional reimbursement price for Actos was provided on the basis that additional results from clinical or observational studies would be provided. If the results of the studies are negative, the manufacturer would be required to pay back the difference for past overpayments and would apply for future price reductions CV Statins Use Statin class assessment across 1 million patients which informed stricter guidelines depending on LDL level (promoting generic Pravastatine use and more targeted dosing based on patient risk status) Schizophrenia Risperdal Launch Access The full price of Risperdal funds were held in escrow until Janssen provided proof of lower hospitalization costs from 12-month study Germany Therapy area Brand Lever Brief Description Oncology Avastin Ongoing Access Roche agreed to provide full or partial reimbursement for patients in which the Avastin and Taxol combination exceeded a specific total dosage in a study designed to test whether the combination of both medicines could extend patient survival in mbc and mrcc Oncology Remifemin Label A population-based case-control study revealed that Remifemin was associated with a reduction in breast cancer risk which informed the removal of risk warning from the product s label Diabetes Lantus Price Sanofi ran a number of studies confirming Lantus effectiveness and safety, restoring access and premium pricing in Germany

24 24 Italy Therapy area Brand Lever Brief Description Oncology Afinitor Launch Access Novartis pays back 100% of the treatment cost of Afinitor in case of treatment failure after 3 month re-evaluation Oncology Avastin Launch Access Roche offers 50% discount for first 6 weeks of treatment and total dosing of Avastin is capped at 11 g/patient/year Oncology Erbitux Launch Access Merck reimburses 50% of the cost of Erbitux in case of no response Oncology Iressa Launch Access AZ pays back 100% of the treatment cost of Iressa in case of treatment failure after 3 month re-evaluation Oncology Javlor Launch Access Pierre Fabre pays back 100% of the treatment cost of Javlor in case of treatment failure after 3 cycle re-evaluation Oncology Revlimid Launch Access Celgene pays back 100% of the treatment cost in case of Revlimid failure after 3 cycle re-evaluation Oncology Nexavar Launch Access Bayer rebates the cost of Nexavar in full in case of treatment failure after a 3 month treatment Oncology Sprycel Launch Access BMS provides the first month free and rebates 50% of the cost of Sprycel for non-responding patients Oncology Sutent Launch Access Pfizer provides Sutent with a 50% discount on first two cycles of treatment Oncology Tarceva Launch Access Roche provides Tarceva with a 50% discount on first two cycles of treatment Oncology Tasigna Launch Access Novartis provides 100% rebate for Tasigna for non-responding patients, while the first cycle paid in full for all patients Oncology Torisel Launch Access Pfizer provides the first two months of Torisel treatment free while responders are identified Oncology Tyverb Launch Access GSK pays back 100% of the Tyverb treatment cost in case of failure after 3 month re-evaluation Oncology Vectibix Launch Access Amgen and Dompe rebate the full cost of Vectibix therapy for non-responders after a 3-cycle evaluation Oncology Velcade Launch Access JJ pay back 50% of Velcade s treatment cost for all eligible patients during the first cycle Oncology Vidaza Launch Access Celgene provide an 11% of discount for the first three cycles of Vidaza treatment Oncology Xeloda Launch Access Roche reimburses the cost of Xeloda treatment in case of treatment failure in mbc Oncology Yondelis Launch Access PharmaMar / Innovex rebate the full cost of therapy if patients do not respond after a 2 cycles evaluation

25 25 Diabetes Byetta Launch Access Payers agreed to provide provisional market access on that basis that Lilly would monitor Byetta s real life use, collect epidemiological and safety data for P&R reassessment CV Procoralan Launch Access Payers agreed to provide provisional market access on that basis that Servier Italia would monitor Procoralan s real life use, collect epidemiological and safety data for P&R reassessment CV Crestor Price AZ prevented the generic reference pricing of Crestor with a series of real world studies demonstrating that Crestor was able to get more patients to their LDL goal compared to generic simvastatin Diabetes Januvia Launch Access Payers agreed to provide provisional market access on that basis that MSD would monitor Januvia s real life use, collect epidemiological and safety data for P&R reassessment Diabetes Galvus Launch Access Payers agreed to provide provisional market access on that basis that Novartis would monitor Galvus s real life use, collect epidemiological and safety data for P&R reassessment Alzheimer s Acetyl cholinesterase inhibitors Launch Access The IT NHS funded acetyl cholinesterase inhibitors such as donepezil, on the basis of an observational study, which demonstrated health gain in patients with mild to moderate Alzheimer s disease Wet AMD Lucentis Launch Access Novartis was able to achieve reimbursement for Lucentis by agreeing to reimburse the cost of treatment for any patients who do not respond to therapy after an initial 3 month evaluation Wet AMD Macugen Launch Access Pfizer was able to achieve reimbursement for Macugen by agreeing to reimburse the cost of treatment for any patients who do not respond to therapy after an initial evaluation following administration of two doses Alzheimer s Exelon Launch Access Novartis was able to achieve reimbursement for Exelon by agreeing to reimburse the full cost of treatment for any patient that did not achieve remission within 6 months of therapy

26 26 Netherlands Therapy area Brand Lever Brief Description CV Generic statins Use Impact of statin generic substitution was evaluated among specific patient groups which informed stricter guidelines as a result of a lack of cost-effectiveness in certain patient populations Asthma Xolair Launch Access MoH negotiated reimbursement only for patients who show improvement with Xolair; for all other patients Novartis will rebate full cost of treatment Stroke Apixaban Price A study was set-up which supported a non-transparent negotiation on the price reduction of Apixaban by ~ 60-70% as payers were not convinced of the clinical value of new anti-coagulants, especially given the good track record with patient INR control in the Netherlands Wet AMD Lucentis Ongoing access After a 2.5 year comparative effectiveness study, Lucentis was removed from the list of high cost hospital products as it did not demonstrate additional clinical value versus Avastin, before the release of CATT and IVAN RCT data Spain Therapy area Brand Lever Brief Description Oncology Iressa Launch Access Iressa was granted access in one hospital only, on the basis of outcomes collected as part of a contracting pilot project between AZ and Catalonia CV Ambrisentan Ongoing Access AZ entered into a pay for performance agreement with the hospital Virgen de las Nieves where patient improvement on ambrisentan would be analysed on key efficacy measures; AZ would provide up to a 20% discount for any patients that did not show improvement on the drug CV Lipitor Ongoing Access Remained on the list of non-recommended drugs due to insufficient data on CV mortality reduction Diabetes Lantus Ongoing Access Glargine was removed from the non-recommended list of drugs after patient satisfaction was higher with Lantus CV Altace Ongoing Access Altace was placed on list of recommended drugs due to improvement in hypertension lowering and reduced mortality COPD Spiriva Ongoing Access Remained on the list of non-recommended drugs due to lack of improvement with COPD patient mortality Other Neupogen Ongoing Access Manufacturer returns excess cost when rate of febrile neutropenia affects more than 10% of patients

27 27 Other Genotropin Ongoing Access Payers agreed to pay 13/mg for a max growth gain of 8.9 cm/year and 9.6 /mg for a min growth gain of 4 cm/year MS Sativex Ongoing Access Payers agreed to pay full price as long as more than 50% of patients respond to therapy Sweden Therapy area Brand Lever Brief Description Oncology Zytiga Launch Access Access conditional on enrolment in study at launch aimed to understand whether the drug is used for the right patient CV Atacand Ongoing Access Atacand maintained reimbursement and formulary status based on evidence showing higher survival rates and lower resource utilization costs CV CV Drug eluting stents Simvastatin & atorvastatin Ongoing Access Use Risk of death found to be higher with drug-eluting stents, informing reimbursement, usage and global treatment guidelines A study on statin use found that use was low which informed recommendations to physicians to increase prescribing RA Anti-TNFs Launch Access Launch access was contingent on mandatory registration in ARTIS registry (Antirheumatic Therapies in Sweden) CNS Blinded Ongoing Access The increase in sales of a CNS drug led the TLV to question its price and reimbursement status; but a retrospective study showed that initiating this drug reduced healthcare costs removing any restrictions on access Parkinson Levodopa Launch Access TLV reimbursed Levodopa at a premium price and granted provisional reimbursement, conditional on the collection of RWE HIV Reyataz Launch Access Reyataz was granted 3 years reimbursement to support claims of reduced GE side effects and reduced CV events through RWE studies; reimbursement was renewed based on improved outcomes and QoL Obesity Acomplia Launch Access Interim reimbursement status was granted for two years until long term effectiveness and cost-effectiveness were proven using RWE studies Other Nitrazepam Use Overall medication burden for elderly patients was considered too high which informed an overall reduction in prescriptions from real world studies Narcolepsy Xyrem Use Paediatric patients developed narcolepsy in response to the swine flu vaccine; while Xyrem did not have a paediatric label, Swedish authorities agreed to recommend its use conjunction with the collection of RWE

28 28 UK Therapy area Brand Lever Brief Description Oncology Iressa Launch Access AZ agreed cost-sharing scheme based on outcomes collection due to Iressa s high cost and unproven advantage over platinum therapy Oncology Navelbine Use Navelbine use reduced outpatient visit time by 90% leading to preference for oral over IV formulations CV Lipitor Ongoing Access Pfizer refunds the NHS if atorvastatin failed to reduce LDL levels to pre-specified targets CV Clopidogrel Use Study on the early discontinuation of oral anti-platelet therapies informed clinical guidelines on the appropriate duration of treatment COPD Daxas Label Suicidal behavior was reported in patients without a history of depression, informing a label safety warning Asthma ICS/LABAS Use Off-label prescribing was shown to be an economically wasteful practice and informed greater adherence to clinical guidelines Pain Lyrica Launch Access Lyrica was not included in hospital formularies due to higher rate of side effects, frequency of outpatient visits, and daily cost of therapy Pain Lyrica Use Lyrica revealed to fill an unmet need after patient database study demonstrated high DDIs with T2D neuropathic pain treatments Wet AMD Avastin Use Avastin was used off-label to treat wamd in the real-world, leading to even greater numbers of ophthalmologists using it in the place of Lucentis RA Cimzia Use Cimzia s lower response rate informed its removal from hospital formularies Cystitis Cystistat Launch Access Cystistat was granted conditional access, even though it did not have compelling evidence, pending PRO collection by physicians who pushed for its use Dermatology Emollients Ongoing Access A PCT switched to single company for all emollient needs based on satisfaction data from 100 patients RA Enbrel Use Enbrel was preferred over Humira for patients at higher risk of TB after real-life study informed appropriate usage of RA biologics in defining subpopulations LEMS Firdapse Ongoing Access PCTs refused access to the first licensed treatment for LEMS because of real world use of an unlicensed therapy MS Interferon beta or glatiramer acetate Launch Access Coverage with evidence development, but scheme failed despite data collection

29 29 Dupuytren s contracture Xiapex Use Funding decision for Xiapex was based on a study investigating a reduction in surgical intervention rates USA Therapy area Brand Lever Brief Description Oncology N/A Ongoing Access Pay for performance pilots in oncology where the manufacturer covers the cost of treatment in case of no response as defined by improvements in progression free survival Oncology Oncotype DX test Launch Access United Healthcare reimbursed Genomic Health s Oncotype Dx test at the list price following a study where clinical effectiveness was verified in breast cancer patients for 18 months Oncology Tysabri Label Tysabri was initially withdrawn from market due to serious adverse events but was then re-introduced under CED as real world studies contributed to demonstrating that benefits outweigh risks Osteoporosis Actonel Ongoing Access The cost of non-spinal bone fractures were reimbursed, delaying generic competition and helped Actonel in achieving preferred formulary position compared to competitor Boniva Osteoporosis Boniva Ongoing Access Boniva moved to a non-preferred tier after it was ranked lowest on WellPoint s real world analysis of 26,000 members Diabetes Byetta Ongoing Access BCBS tracked HbA1c levels for patients on Byetta versus other drugs and informed a decision to move Byetta from a medical to a pharmacy benefit due to better results CV Effient Ongoing Access Medco study demonstrated that Effient is not cost effective relative to Plavix which informed a non-coverage decision on the Medco Medicare closed formulary Asthma ICS/LM Ongoing Access Healthcore s analysis of WellPoint claims showed that patients on leukotriene modifiers (LM) had better adherence and fewer events, leading WellPoint to keep LM on a preferred tier and remove PA, contrasting RCT evidence which indicated that inhaled corticosteroids (ICS) were better than LMs Diabetes Januvia/Janumet Ongoing Access Cigna lowered patient co-pay for Januvia and Janumet after Merck fixed the cost and offered discounts for patient adherence to drug regimen and control of blood sugar CV Lipitor Use National claims database study showed superior outcomes for Lipitor versus generics in non-cvd patients, broadening the target population of Lipitor

30 30 GI Nexium Ongoing Access Nexium was withdrawn from United Healthcare s formulary after internal retrospective study showed Nexium was not cost-effective Depression Paxil Label Studies with US and Nordic databases determined that Paxil was associated with increased risk of congenital malformations; given that the benefits of therapy outweighed potential risks, Paxil was only re-labelled CV Plavix Label Medco study on Warfarin led to an FDA labeling change providing dose recommendations based on genetic test results CV PPI/Plavix Label FDA black box warning on Plavix with concomitant PPI use post-medco study Depression Prozac Use Group Health conducted a RWE study measuring outcomes where Prozac was found to be no more expensive than treatment with generic desipramine, imipramine when total treatment cost was considered Depression Seroquel Ongoing Access Seroquel was moved from T3 to T2 on both commercial and Medicare Part D plans due to demonstrated real world utilization that showed increased adherence more strictly to professional guidelines than competitors post-launch COPD Spiriva Ongoing Access Spiriva is on T2 at WellPoint, as a preferred brand, due to a study showing prevention of expensive events and lower pharmacy and medical overall costs compared to other interventions Erectile Dysfunction Viagra Ongoing Access Viagra regained formulary status after six years, replacing Bayer s Levitra and Staxyn after sharing cost effectiveness data MS Rebif Ongoing Access Merck agreed to provide rebate payments for MS drug Rebif tied to the number of hospital visits, as a result of relapses with Cigna and Prime Therapeutics RA Remicade Ongoing Access Prior-authorization for infliximab was removed based on compliance and outcomes demonstration, relative to the injectables Humira and Enbrel, in a study conducted by BCBS (other RA biologics continued to have a PA) Other N/A Use Analysis of NIS hospital database faciliated product entry and use in an effort to understand budget impact of rapid screening and prophylaxis for S. aureus colonization

31 31 Methodology and summary comparison tables We examined countries supply of RWD and demand for RWE in terms of frameworks on how to create and use RWE and the application of RWE as evidence that its demand drove actual decisions. Each dimension is explained with its key sub-components below. A scoring system of 0-5 was applied for data supply and frameworks and 0-10 for application, indicating the importance placed on using RWE to make decisions. We have provided an indicative example of what each of these levels means relative to the advancement on each sub-component. SUPPLY The ability to access quality patient-level data and apply either simple or sophisticated analyses to it, is a pre-requisite for capturing the value of medicines from RWE. As such, RWD supply can be understood to encompass the following: Usefulness Underlying data capture: the extent of routine electronic capture of rich clinical data, such as through electronic medical records, payment infrastructures and patient registries Data quality: the reliability and consistency of the data recorded Coverage: the coverage of the data in terms of the proportion of the population and care settings Link-ability: the extent of explicit (single database) or implicit (unique patient IDs across databases) linking of datasets to enable a single view of a patient in their interaction with the health system Access: legal and information governance mechanisms for direct or indirect access across stakeholders for appropriate uses of the data Research output (as a proxy): the volume of peer-reviewed publications developed from datasets in the country Using these components, an indicative example of scoring would be 0 = Limited underlying electronic healthcare data capture 1 = Significant pockets of electronic healthcare data capture of sufficient quality 2 = Electronic data capture for a significant proportion of the population across settings 3 = Ability to link data across different sources 4 = use of linked datasets through appropriate access mechanisms 5 = Extensive use of linked datasets through appropriate access mechanisms resulting in high research output

32 32 DEMAND: FRAMEWORKS Data availability in itself is insufficient to drive value. Creating meaningful insight from RWE depends on the ability of multiple stakeholders to understand and agree on the significance of that insight, in addition to creating a process to apply it. As such, insight has a number of requirements: Evaluation: a base understanding across stakeholders of the additional insights, methods, tools, and issues associated with RWE use and an overall positioning of RWE in decision making (e.g. a clear evidence hierarchy, clarity on where in the process RWE will be used, and transparency decisions made) Measurement: a common understanding of what to measure (e.g. clear direction on comparator sets, cost and disease burden factors to assess, end-points to measure, and potential summary value measures such as QALYs) and regular use of a standard set of RWE related indicators to ensure prescribing to guidelines Dissemination: engagement of all stakeholders on RWE, including prescribers and patients (e.g. appropriate framework for dissemination of RWE to prescribers) and impact on clinical guidelines Using these components, an indicative example of scoring would be 0 = Limited capability or use across all areas 1 = Awareness of RWE and basic framework for its incorporation in decision making 2 = Evaluation framework using RWE consistently applied 3 = Evaluation framework using RWE consistently applied and consistently measured 4 = Evaluation framework using RWE consistently applied, extensively measured, and flexibly disseminated 5 = Strong capability or use across all areas; RWE embedded in operational decision making DEMAND: APPLICATION Meaningful insight must be turned into action for RWE to create value. The application assessment is based on the evidence that RWE is used to make product and product group decisions affecting label, launch access, ongoing access, price and use: Label: the influence of RWE on indications that can be legally marketed Launch Access: the influence of RWE on enabling access at launch, including maximizing a product s potential compared to its label Ongoing Access: the influence of RWE on enabling/restricting ongoing access for the product e.g. formulary listing may be withdrawn based on unfavorable post launch cost effectiveness data Price: the extent to which RWE is used to negotiate a product s list or net price Use: the influence of RWE on how a product is used in clinical practice

33 33 This category was the hardest to score since much of the product-specific data is not in the public domain, so we used a combination of published data, interviews, and IMS expertise. For the overall assessment, we considered three elements of a country s case studies: Volume: we took the number of case studies identified within the research as one indicator of the overall level of RWE application in each individual country. Countries with an average number of case studies (around 10) were scored as medium, while countries with less than 6 were ranked low and over 15 high Variety: we looked at the number of different categories the case studies covered within an individual country and the level to which the distribution was skewed in any one direction. Countries with an even distribution and a coverage of at least three out of five categories were marked as medium, with countries diverging significantly from this number marked as either low or high Impact: case studies vary in impact, with national level examples having a higher impact than regional ones. Impact can also be increased by many regional level cases collectively covering a large area. Impact is also affected by the degree of change in label, access, price or use caused. Like supply and frameworks, these components are not always fully independent of each other. Specifically, volume is the pre-requisite for variety and also supports overall impact. Nevertheless, each component was assessed independently, with the assessments aggregated into an overall score. Of the three categories, we most heavily weighted impact. A score of zero represents rare, ad hoc usage of RWE with limited impact. A score of 10 represents a systematic approach consistently applied across all five opportunity areas and reflected in high volume, variety, and impact marks.

34 34 Data supply comparison table Country Underlying data capture Data Quality Research Coverage Linkage Access Research Output* Score UK 100% EMR in primary care 100% in hospital discharge ~70% hospital EMR Incentivized for quality (QOF, HRG) 15% primary care 85% hospital discharge No hospital EMR / national claims Linkage project underway Well defined framework and procedures for stakeholder access ~2000 studies 3 Sweden ~100 % Data capture integrated into healthcare system across different settings Long-standing culture of electronic data capture 100% for claims and national registries Variable levels for disease specific registries Good linkage across different data sources via unique national ID Ethics approval & publication plane required Application can take 3-6 months ~450 studies 4 Netherlands ~100% EMR use in primary care Hospital EMR high and increasing ~100% hospital discharge Some incentives of data capture Varies by dataset (30-100%) ~200k fully linked patients and increasing Direct access low, but strong capabilities for commissioned studies ~400 studies 3 USA 69% EMR in primary care, er EMR use in secondary care Multiple large claims data sets EMR use incentivized in meaningful use ~ 100% Claims including Medicare/caid Dependent on purchasing and linking datasets Mainly claims & Lab data. EMR integration in progress Commercial market for data studies 4 France 70% EMR primary care; ~33% Hospital EMR National claims dataset (SNIIRAM) Physicians recently incentivized in primary care 100% for Claims EMR ~7% PMSI 100% hospital episodes Extensive (claims-pmsi-emrdeath registry) Extremely limited private access except PMSI ~220 individuals in public sector studies 2 Italy EMR adoption variable by region, lower in secondary care Extensive regional administrative data National initiative to increase eprescribing ~12% for administrative data at regional level er and more variable EMR coverage Data protection laws acting as a barrier Limited with patient consent required for the majority of data processing ~50 studies 2 Denmark ~ 100% Data capture integrated into healthcare system across different settings Long-standing culture of electronic data capture 100% for claims and national registries Variable levels for disease specific registries Linkage possible across different data sources, but cumbersome Partnership with Danish academic group required for access ~500 studies 3 Germany Extensive claims data Good primary care EMR coverage but more limited in secondary care ~38% hospital EMR Includes linkage to some lab data Claims data ~20% eg BIPS 10% Primary care EMR Date protection laws are a barrier to linking data silos Good access for timely primary care data across stakeholders Access to secondary care data very limited studies 2 Canada 52% EMR in primary care Longitudinal Rx and claims Not known Will become clearer with use of new datasets Good for claims (without prescriptions) 3% for EMR (with prescriptions) Little linkage Well defined framework and procedures for stakeholder access studies 2 Spain Varies by region in both in primary and secondary care settings 83% hospital EMR national hospital discharge capture Not known Quality varies by region, physicians not incentivized EMR databases available in selected regions only Hospital discharge 75% national coverage Very limited with strict data protection laws acting as a barrier Generally limited and fragmented throughout the different regions studies 1 * Based on a pragmatic search of pubmed for retrospective database studies example search strings available on request

35 35 Demand frameworks comparison table Country Awareness UK Strategic appreciation of RWE insights due to historical use (NICE/ HTA, GPRD) Sweden Good understanding of potential insights offered by RWE Netherlands RWE incorporated into cost-benefit assessment guidelines USA Variable across different individual stakeholder Landscape comprises leaders, followers and non-engagers France Emerging: Used cost-effectiveness analysis since 2008; Payer performing ad-hoc studies Italy Understanding of potential benefits of RWE insights Denmark Cautious acceptance of possible RWE insights Canada Emerging: CADTH continues to evaluate mainly on RCT plus BIA. Provincial PLAs and HTA in QC are more progressive Germany strategic awareness narrow view of potential insights from RWE Spain Little attention given to database research Evaluation (HTA/Pricing) Long-standing HTA approach RWE included and assessed on own merit National HTA using RWE in the evidence framework RWE impacts pricing/access by TLV Explicit inclusion of RWE in HTA process 4-year drug re-evaluation in hospitals No national framework or HTA body, HTA varies by payer CER focused on non-pharmaceutical interventions and PROs New regulation since 2012 explicitly encourages RWE in CE analysis 5-year assessments enabling RWE generation RWE incorporated into HTA process Use of CED/P4P for market access Voluntary use of HTA Long-standing HTA approach With CADTH. RWE uncommonly included but increasing. AMNOG legislation places RWE at a low level in the evidence hierarchy Only 1 year to develop RWE at launch HTA historically weak Incorporation of RWE in new framework unclear Measurement Dissemination Score Selected indicators on prescribing; e.g. QOF Decisions disseminated via NICE guidelines Any actor can use RWE with prescribers 4 Some physician monitoring carried out but limited scope Published RWE studies can be directly presented to physicians 3 Indicators reported or some orphan drugs Different stakeholders able to present published RWE to physicians RWE used informally to influence future clinical practice 3 No national quality indicators reported Restrictions on directly communicating the results of RWE studies to physicians 1 Selected indicators on prescribing; none RWE based Guideline development issued by HAS er flexibility for other actors to engage using RWE 3 Indicators not routinely measured or reported Can disseminate RWE directly to physicians RWE used in guideline development through systematic review 2 Standard value metrics not used RWE can be directly communicated to physicians by different stake holders 1 selected indicators on prescribing; none RWE based Decisions disseminated by CADTH and INESSS (QC) listing recommendations Flexibility for any actor to use RWE with prescribers 1 Currently not used for regular reporting Used internally by some payers (disease management) Limited RWE use in guideline development Restrictions on disseminating the results of RWE studies to physicians 1 Indicators not routinely measured or reported RWE not actively incorporated into guideline development 0

36 36 Application case study comparison table Country Volume Variety Impact Score UK 17 case studies identified Case studies in 4 out 5 categories Distribution marginally skewed towards Use : 8 cases Overall distribution (1 to 5 to 3 to 8) Medium National level impact of NICE recommendations, but not systematic due to capacity constraints 4 Sweden Medium 11 case studies identified Case studies in 3 out 5 categories Even distribution (5 to 3 to 3 split) Medium National level impact mostly on prescribing behavior 2 Netherlands 4 case studies identified Case studies in 4 out 5 categories Even distribution (1 to 1 to 1 to 1 split) Medium Material national level impact of cases studies identified, but overall impact limited frequency of use 3 USA 21 case studies identified Medium Case studies in 4 out 5 categories Distribution skewed towards Ongoing Access : 13 out of 21 cases Medium While fragmented, the high frequency of use drives overall impact However overall impact is limited as stakeholders generally only want to rely on their own data 3 France 3 case studies identified Ad hoc and limited to highest budget impact items Case studies in 3 out 5 categories Even distribution (1 to 1 to 1 split) National level impact e.g. on guidelines, but rarity of use limits overall impact 1 Italy 27 case studies identified Systematic use for high cost drugs Case studies in 2 out 5 categories Distribution strongly skewed towards Launch Access : 26 cases Medium Impact limited to launch access, where they are used to reduce the net price Broadly used at the national level for expensive medication 2 Denmark 2 case studies identified Case studies in 1 out 5 categories Application only observed for Ongoing Access Impact limited to launch access, where they are used to reduce the net price 1 Canada Medium 9 case studies identified Medium Case studies in 3 out 5 categories Even distribution (4 to 3 to 2 split) No impact from national level RWE, as this only serves as guidance for provinces Limited use at provincial level with Ontario the most prolific 0 Germany 3 case studies identified Medium Case studies in 3 out 5 categories Even distribution (1 to 1 to 1 split) Very low Impact of examples very limited as the evidence type is only accepted for limited application 0 Spain Medium 9 case studies identified Case studies in 2 out 5 categories Distribution strongly skewed towards Ongoing Access : 8 cases No impact at the national level almost nonexistent Impact limited to individual regions, mostly Catalonia and products in big primary indications 1

37 37 This assessment is based on the following case base: Market Label Launch Access Ongoing Access Price Use Total UK Sweden Netherlands USA France Italy Denmark Canada Germany Spain Total

38 38 KEY CONTRIBUTORS Matthew Radford Maria Kosmaoglou Michael Opel Murray Aitken Zofia Rokicki Josh Hiller Vernon Schabert Consultant, Real World Evidence Solutions & HEOR, IMS Health Consultant, IMS Consulting Group Senior Consultant, IMS Consulting Group Executive Director, IMS Institute for Healthcare Informatics Associate Consultant, IMS Consulting Group Senior Principal, Real World Evidence Solutions & HEOR, IMS Health Senior Principal, Real World Evidence Solutions & HEOR, IMS Health Acknowledgments The development of this work has been a collaborative effort from many individuals across a range of backgrounds and settings. The authors would like to sincerely thank the contributions from numerous payers, clients, members of the global IMS HEOR and IMSCG teams and others for their expert knowledge and insights, which were invaluable in the development of this work.

39 39 FURTHER READING Research Databases Martin-Latry & Begaud Pharmacoepidemiological research using French reimbursement databases: yes we can! Hospipharmacoepidemiology and drug safety, 19: Hoffmann, F Review on use of German health insurance medication claims data for epidemiological research. Pharmacoepidemiology and drug safety 18: Herrett et al. (2010). Validation and validity of diagnoses in the General Practice Research Database: a systematic review. British Journal of Clinical Pharmacology. Br J Clin Pharmacol Jan;69(1):4-14. Furu et al. (2009) The Nordic Countries as a Cohort for Pharmacoepidemiological Research. Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 106, National Healthcare Quality Registries in Sweden. Swedish Association of Local Authorities and Regions, Stockholm ISBN Tricco AC, Pham B, Rawson NSB (2008) Manitoba and Saskatchewan administrative health care utilization databases are used differently to answer epidemiologic research questions. Journal of Clinical Epidemiology 61: Takahashi et al., 2010 Utilization of health care databases for pharmacoepidemiology. Eur J Clin Pharmacol. DOI /s Aljunid et al., Health-Care Data Collecting, Sharing, and Using in Thailand, China Mainland, South Korea, Taiwan, Japan, and Malaysia. Value in Health, 15 S Pharmacoepidemiology, Fifth Edition, Chapter 14: US Government Claims Databases wiley.com/doi/ / ch14/summary Administrative and claims records as sources of health care cost data. Med Care Jul;47(7 Suppl 1):S51-5 Pharmacoepidemiology, Fifth Edition, Chapter 17: Canadian Provincial Databases wiley.com/doi/ / ch17/summary Use of Health Care Databases in Pharmacoepidemiology, Basic & Clinical Pharmacology & Toxicology 2006, 98, Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care Aug;40(8 Suppl):IV-3-18 Data resources in the Department of Veterans Affairs. Diabetes Care May;27 Suppl 2:B22-6 Demand framework and application case studies International survey of methods used in health technology assessment (HTA): does practice meet the principles proposed for good research? Comparative Effectiveness Research 2012: Market access agreements for pharmaceuticals in Europe: diversity of approaches and underlying concepts. Jarosławski and Toumi BMC Health Services Research 2011, 11:259 Experiences and Impact of European Risk-Sharing Schemes Focusing on Oncology Medicines. Jaime Espín, Joan Rovira and Leticia García. Andalusian School of Public Health. The European Commission, Directorate-general Enterprise and Industry International Society for Pharmacoeconomics and Outcomes Research.

40 IMS HEALTH EUROPE & WORLDWIDE 210 Pentonville Road London, N1 9JY United Kingdom Tel: +44 (0) THE AMERICAS 200 Campus Drive Collegeville, PA USA Tel: ASIA-PACIFIC 8 Cross Street #21-01/02/03 PWC Building Singapore Tel: JAPAN Toranomon Towers Office Toranomon, Minato-ku Tokyo Japan Tel: ABOUT IMS HEALTH IMS Health is a leading worldwide provider of information, technology, and services dedicated to making healthcare perform better. With a global technology infrastructure and unique combination of real-world evidence, advanced analytics and proprietary software platforms, IMS Health connects knowledge across all aspects of healthcare to help clients improve patient outcomes and operate more efficiently. The company s expert resources draw on data from nearly 100,000 suppliers, and on insights from 39 billion healthcare transactions processed annually, to serve more than 5,000 healthcare clients globally. Customers include pharmaceutical, medical device and consumer health manufacturers and distributors, providers, payers, government agencies, policymakers, researchers and the financial community. Additional information is available at IMS Health Incorporated and its affiliates. All rights reserved. Trademarks are registered in the United States and in various other countries. RWEWHI0513/MIC3030