PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Ar thritis

Transcription

1 PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Ar thritis PRMA Insights provide in-depth understanding of current and future market access realities, developed by industry-experienced experts with comprehensive cross-functional knowledge. Critical insight into the clinical and payor landscape is supported by actionable strategic insights, providing a cornerstone on which to build a successful market access strategy.

2 Pricing and reimbursement success Achieving market success is becoming ever more challenging as payors seek to rationalize restricted budgets on increasingly numerous and frequently expensive products. Success requires a thorough understanding of the current P&R landscape, and how it is changing, and careful, strategic planning from as early as Phase 2. PRMA Insights are a key resource that provides the basis for your planning. We have analyzed the current treatment landscape in detail, and have identified the key issues that need to be addressed in developing the market access strategy. [email protected] Tel (UK): +44 (0) Tel (US): +1 (415)

3 1 Introduction The RA market is crowded, with eight biologics already available. However, up to a quarter of patients do not respond adequately to these drugs and thus unmet need remains. Whilst most of the biologics are reimbursed in the scope countries, use is heavily restricted by payors seeking to limit the budget impact of these expensive products. A robust market access strategy is key to commercial success Manufacturers face considerable challenges in terms of proving differentiation and defining a place for their products in the treatment paradigm. However, the biologics provide a strong argument in favor of earlier intervention in order to limit progression to joint damage and disability. This offers a potential an opportunity for manufacturers who can rise to the challenge of generating robust data to support this approach. Rheumatoid arthritis (RA) is a chronic, progressive, and ultimately destructive autoimmune disorder that, in a clinically established form, affects 0.5 1% of the population worldwide. The global RA market experienced strong growth during , due largely to the launch of biologics such as Enbrel, Remicade, Humira, and Rituxan, and fuelled further by the more recent launches of Simponi, RoActemra, Orencia, and Cimzia. In 2008, the global RA market was worth US$11.6 bn and accounted for 1.7% of global pharmaceutical sales. Moderate growth over the next 10 years will be driven by the expected launch of the eight products currently in Phase 3 development, offering new mechanisms of action and in some cases oral administration. However, growth will be tempered by patent expiries of the major biologics and the subsequent launch of biosimilars. Nevertheless, the market is expected to grow to US$27 bn by Although the biologics are disease-modifying compounds that slow the progression of joint damage, use is largely restricted to later lines of therapy, when conventional DMARDS such as methotrexate have failed. However, about a quarter of patients have disease that is not adequately controlled despite the wide range of treatment options available. Thus, unmet needs remain, even though the market is crowded. New products with novel mechanisms of action may meet some of this need. However, demonstrating differentiation is challenging, and head-to-head trials will be critical. The biologics offer a realistic possibility of slowing disease progression in RA, and intervention before signs of joint damage become manifest has the potential to reduce joint destruction and subsequent disability and also the comorbidities associated with RA, such as cardiovascular disease. However, for earlier treatment to become a reality for patients, a paradigm shift towards diagnosis of RA at a much earlier stage is needed. Some authorities are beginning to advocate earlier diagnosis and therefore intervention; however, the means by which this can become a reality are far from clear. prma insights

4 2 Manufacturers launching into this crowded market face considerable challenges in terms of demonstrating differentiation and value for money to increasingly demanding payors faced with budgetary restrictions. However, a shift towards earlier diagnosis and therefore treatment of RA could also represent an opportunity in terms of market access for both established and new products provided that manufacturers can rise to the challenge in terms of clinical development. Manufacturers need a clear understanding of how to design clinical trials and economic models in order to demonstrate the benefits of intervention at an earlier stage of the disease. Clearly, building the HTA strategy to support such an argument will need careful consideration. Because of their high budget impact, the biologics are high on payors priority lists for limiting expenditure, and the barriers to market access will continue to increase. Access to biologics is already restricted in most countries through budgetary caps and funding restrictions at the national and/or local levels, restrictive national guidelines, and inter-regional differences in either the availability of authorized prescribing centers or the procedures involved in prescription of these products. Payors will expect manufacturers to proactively offer financially based risk-sharing models, a strategy used by UCB to ensure a positive NICE recommendation when introducing Cimzia into a crowded UK market. Interestingly, this RSA was subsequently adopted by some Regions in Spain. Changes in the RA market are being played out against a backdrop of P&R reform across Europe, no more so than in Germany with the new AMNOG legislation. Value-based pricing seems inevitable in the UK when the current PPRS expires in 2014, and a royal decree in Spain in August 2011 has set out the requirement for cost-effectiveness analysis in the P&R submission. Manufacturers need to keep abreast of changes to P&R requirements in the scope countries and ensure that clinical development plans are flexible to accommodate changing requirements. A compelling evidence-based payor value proposition is required to overcoming market access hurdles, ideally including head-to-head clinical data. Generation of an evidence package that is consistent with a manufacturer s pricing and commercial ambitions requires early planning (from Phase 1) and broad cross-functional cooperation. Failure to adequately plan and invest in the market access strategy could lead to commercially disastrous consequences such as HTA and P&R rejections, lower achievable price, smaller-than-planned reimbursed population, and extensive market access delays. PRMA Insights: The Roadmap to Pricing and Reimbursement Success in Rheumatoid Arthritis This publication focuses on the P&R issues around the following scope treatments: Humira (adalimumab, Abbott) Enbrel (etanercept, Pfizer/Amgen) Remicade (infliximab, Merck) Simponi (golimumab, Centocor/Merck) Cimzia (certolizumab pegol, UCB Pharma) RoActemra (tocilizumab, Roche; marketed as Actemra in the US and Japan) Kineret (anakinra, Biovitrum AB) Orencia (abatacept, Bristol-Myers Squibb) MabThera (rituximab, Roche; marketed as Rituxan in the US). A backdrop of global P&R reform In planning a successful market access strategy, manufacturers need to understand and accommodate the reforms that are influencing regulatory requirements, HTA, and P&R across many of the major markets. This PRMA Insights strategic resource considers such issues, and highlights those that are likely to affect strategy development. How will the stringent benefit assessment in Germany introduced with the AMNOG legislation influence market access and prices here and further afield? What impact will greater centralized use of costeffectiveness analysis and collaborative HTA by the Regions have in Spain? How will measures such as comparative trials for marketing authorization included in the recent reform in France play out? How will value-based pricing be implemented in the UK and what will be the impact in terms of demonstrating cost-effectiveness in areas of high unmet need such as RA? How will the market access landscape in Japan change as an HTA framework is established and costeffectiveness analysis becomes more important?

5 3 6 steps for pricing and reimbursement success 1 Understanding the current treatment landscape Reviews of international, national, and local clinical guidelines Changing approaches and attitudes to treatment Regulatory indications for the scope products Pivotal trial data for the scope products and overview of key elements of clinical trial design, such as subpopulations, comparators, and endpoints Future treatment landscape products in Phase 3 and the likely challenges these products will face 4 Disease burden Epidemiology of the disease and relevant subpopulations Analysis of cost burden and presentation of relevant key data Measurement of utilities Critique of cost-effectiveness analysis and budget impact models Payors expectations relating to cost arguments, and how these are changing 2 Understanding the HTA and P&R environment Overview of the current P&R process in the scope countries (US, EU major 5, and Japan) Focus on areas that are changing and how this could affect strategy development 5 Understanding the role of PROs PROs as a potential differentiating factor What needs to be measured Suitable instruments Expectations of the regulatory and HTA agencies Strategies for inclusion of PRO claims on the product label 3 Comprehensive review and analysis of relevant HTAs and P&R decisions Critical analysis of reviews and decisions made by: > NICE > SMC > AWMSG > CEPS > TC > IQWiG > G-BA > DGFPS > CIPM > GENESIS > AIFA > MHLW > regional and hospital evaluations in Spain and Italy The value propositions and arguments that manufacturers submitted What worked and what didn t Payors criticisms and expectations 6 Designing the clinical development program to support market access Expectations of regulatory bodies and payors Choice of comparators in clinical trials to meet payors expectations Appropriate endpoints Importance of patient subpopulations and how these should be defined Measurement of PROs relevant tools and instruments Ways to achieve differentiation PRMA Strategic Insight Developed by our in-house experts, PRMA Strategic Insights provide critical advice to manufacturers in planning their market access strategy. They are listed together in each Chapter Summary and in the Executive Summary, as well as being located at relevant points in the text. Area to watch Issues that could affect strategy development and that need to be monitored are flagged as areas to watch. prma insights

6 4 Table of contents Each chapter starts with a Chapter Summary, PRMA Strategic Insights, and Areas to watch. Executive summary 1 Clinical overview 1.1 Disease overview The pre-articular phase 1.2 Pathogenesis T and B cells Cytokines Morphologic manifestations Inflammatory mediators as new therapeutic targets 1.3 Etiology Genetics Risk factors 1.4 Clinical presentation and diagnosis 1.5 Classification criteria ACR criteria ACR/EULAR criteria 1.6 Measurement of severity Joint counts Radiography Disease Activity Score SDAI and CDAI ACR classification of functional status HAQ-DI 1.7 Disease progression 1.8 Prognostic factors Biomarkers in RA 1.9 Extra-articular manifestations of RA 2 Epidemiology of rheumatoid arthritis 2.1 Incidence 2.2 Prevalence Prevalence by country 2.3 Epidemiology of early RA 2.4 Impact of RA on morbidity and mortality Extra-articular manifestations Other comorbidities Burden of comorbidities Mortality 3 Patient-reported outcomes 3.1 Patient-reported outcomes 3.2 Definitions PROs HRQoL 3.3 Importance of PROs Why measure PROs in RA? 3.4 PRO instruments in RA Generic instruments Rheumatology-specific PRO instruments PRO instruments used to measure symptoms of RA 3.5 Impact of RA on HRQoL and other PROs France Germany Italy Japan Spain UK US 3.6 Guidance on use of PROs FDA guidance EMA guidance on the measurement of HRQoL 3.7 EMA and FDA guidance on PROs in RA Achieving a PRO claim Label claims Appendix A: PRO instruments used in RA A.1 Rheumatology-specific instruments A.1.1 AIMS/AIMS2 A.1.2 MACTAR A.1.3 QoL-RA Scale A.1.4 RAID A.2 Symptom-specific instruments A.2.1 Pain A.2.2 Productivity A.2.3 Fatigue A.2.4 Sleep A.2.5 Depression 4 Treatment of rheumatoid arthritis 4.1 Overview 4.2 Non-drug interventions 4.3 Pharmacologic interventions NSAIDs Glucocorticoids Non-biological DMARDs Biological DMARDs Paradigm shift in treatment towards early intervention Impact of treatment delay 4.4 Clinical guidelines ACR clinical guidelines EULAR clinical guidelines BSR/BHPR clinical guidelines 4.5 Measurement of response to RA therapies in clinical trials ACR response criteria EULAR response criteria (DAS28) BSR definitions of response Radiographic outcomes Remission 4.6 Label claims for RA products FDA guidance EMA guidance Overview of label claims 4.7 Biologics approved for the treatment of RA Enbrel Humira Remicade Simponi MabThera/Rituxan Orencia RoActemra/Actemra Cimzia Kineret 4.8 Key characteristics of RA trials 4.9 Safety of the biological DMARDs Withdrawals Infections Tuberculosis Malignancies and lymphoma 4.10 Products in development Tofacitinib Ofatumumab Sarilumab Fostamatinib Iguratimod Secukinumab LY Masitinib 5 Economic impact of rheumatoid arthritis 5.1 National annual costs of RA Direct and indirect costs

7 France Germany Japan Spain UK US Cost of RA by functional status 5.2 Utilities Utilities in rheumatoid arthritis 5.3 Pharmacoeconomic evaluations Assumptions used in the models Cost-effectiveness studies for biologics 6 Pricing and reimbursement in the US 6.1 Key stakeholders 6.2 Healthcare reform The Affordable Care Act Effect of healthcare reform on RA Biosimilars 6.3 Pricing of pharmaceuticals in the US Pricing of infused and injectable drugs Pricing of oral drugs Prices and OOP burden depend on type of insurance Government regulation of drug prices Manufacturer contracting in RA 6.4 Obtaining formulary listing 6.5 Formulary management Tiering Injectable products Other utilization management techniques Management of the pharmacy benefit Coverage of drug costs 6.6 Payor mix for RA Importance of RA biologics for employers 6.7 Formulary status of therapies for RA Commercial and Medicare Part D formularies Medicaid state formularies Coverage policies for biologics differ between MCOs 6.8 Current dynamics in RA Impact of novel oral agents entering the RA market Patient advocacy Infusion nurses Patient assistance programs Use of health technology assessment Comparative effectiveness research AHRQ guidance on RA MCOs are requesting Phase 4 naturalistic studies Risk evaluation and mitigation strategies 6.9 Annual costs of scope products in the US 7 Pricing and reimbursement in the UK 7.1 Key stakeholders 7.2 The pricing and reimbursement process 7.3 Free pricing in the UK within the context of the PPRS Value-based pricing likely from Data requirements for market access Drugs and Therapeutics Committees 7.4 NICE Selection of technologies to be evaluated Single versus multiple technology appraisals Single technology appraisals NICE can make one of four decisions Patient access schemes Scientific advice scheme 7.5 NICE clinical guidelines 7.6 NICE clinical guidelines in RA NICE commissioning guides in RA Quality and Outcomes Framework 7.7 BSR Biologics Register 7.8 NICE assessments of biologics in RA Humira, Enbrel, and Remicade are recommended for patients with RA Biologics recommended after inadequate response to a TNFI Cimzia is approved for the treatment of RA RoActemra is recommended for the treatment of RA Simponi is recommended for the treatment of RA in patients who have inadequately responded to DMARDs Orencia is not recommended for the treatment of RA following inadequate response to DMARDs including MTX Kineret is not recommended for the treatment of RA 7.9 Future NICE appraisals in RA 7.10 The Scottish Medicines Consortium Horizon scanning The SMC has a disproportionate influence Patient access schemes 7.11 SMC assessments in RA MabThera Orencia RoActemra Cimzia Kineret 7.12 All Wales Medicines Strategy Group 7.13 Summary of HTA decisions in the UK 7.14 Annual costs of scope products in the UK 8 Pricing and reimbursement in France 8.1 Key stakeholders 8.2 P&R process, key timings, and data requirements 8.3 TC clinical evaluation The evaluation of actual medical benefit the SMR Public health interest Incremental benefit ASMR is the key determinant of subsequent pricing ASMR versus SMR Target population Médicament d exception restriction 8.4 Hospital versus community funding T2A exemption Retrocession pharmaceuticals 8.5 Pricing Pricing for community products CEPS negotiations Pricing for retrocession and T2A-exempt products price notification process Pricing for hospital-only products Pricing for non-reimbursable drugs 8.6 A range of P&R controls apply beyond product launch 8.7 Proposed regulatory reform 8.8 National treatment framework Guidelines within the ALD scheme Other clinical guidelines Health networks Patient registries 8.9 Overview of TC assessments of scope products Remicade Kineret Enbrel Humira MabThera RoActemra Orencia Cimzia Simponi Overview of TC comments on scope products 8.10 Annual costs of scope products in France 9 Pricing and reimbursement in Germany 9.1 Key stakeholders 9.2 The German healthcare system Statutory health insurance prma insights

8 6 9.3 The new market access landscape in Germany 9.4 Benefit assessment by the G-BA The benefit dossier The assessment process and timelines G-BA scientific advice Determination of the appropriate comparator Cost data Definitions of additional benefit Indication/line extensions Assessments of drugs already marketed 9.5 The changing role of IQWiG Cost benefit assessments Benefit assessment 9.6 Pricing and reimbursement Expenditure controls Free pricing at launch Price negotiation with the GKV-Spitzenverband Indication/line extensions Arbitration Individual contracting with SHI funds Reference pricing Reimbursement and cost coverage in hospitals Long-term impact of AMNOG legislation on prices 9.7 RA in Germany Treatment guidelines G-BA therapy recommendations AKdÄ guideline DGRh guidelines IQWiG assessment of biological DMARDs 9.8 RABBIT registry 9.9 Pricing landscape in RA 9.10 Annual costs of scope products in Germany 10 Pricing and reimbursement in Spain 10.1 Key stakeholders The central Government The Regions The hospitals 10.2 P&R process, key timings, and data requirements The pricing and reimbursement processes are combined Fast-track process for innovative products Reimbursement Pricing negotiations The use of cost-effectiveness Cost-containment measures 10.3 Treatment guidelines for RA SER GUIPCAR clinical practice guidelines Health plans 10.4 National P&R status of key treatments Monitoring use of biologics 10.5 Regional and local reviews of RA treatments Cimzia Enbrel Humira Kineret Orencia RoActemra Simponi 10.6 Key issues highlighted by local and regional reviews of RA products 10.7 Annual costs of scope products in Spain 11 Pricing and reimbursement in Italy 11.1 Key stakeholders The central Government The Regions Local health units and hospitals 11.2 P&R process, key timings, and data requirements The P&R processes are combined Therapeutic innovation can lead to a premium price Determination of therapeutic innovation 11.3 Regional HTA Regional reviews Budgetary responsibilities Payback measures Risk-sharing agreements Pharmacovigilance Discounts are applied at hospitals Generics and reference pricing 11.4 Overview of RA in Italy 11.5 Management of RA National initiatives Regional initiatives Clinical guidelines Regional guidelines Adherence to clinical guidelines Use of the scope products in Italy 11.6 P&R status of the scope products 11.7 Economic evaluation of scope products Economic studies HTA/economic assessments by the Regions Overview of HTAs Regulation of biologics 11.8 Annual costs of scope products in Italy 12 Pricing and reimbursement in Japan 12.1 Key organizations and stakeholders 12.2 P&R process, key timings, and data requirements Data requirements for reimbursement 12.3 Pricing process 12.4 Pricing methods for patented products The comparator pricing method The cost calculation method Inter-strength adjustment Foreign price adjustment Analysis of methods used to calculate prices 12.5 Pricing of generics 12.6 Key current P&R issues Biennial price revisions Generic substitution 12.7 Future trends that will affect market access Improved regulatory approval timelines Price revision reforms The use of pharmacoeconomic data in price determination 12.8 Overview of the RA market in Japan Epidemiology Cost 12.9 Management of RA in Japan Availability of products Treatment guidelines P&R status of biologics for RA Remicade Enbrel Humira Actemra Orencia Simponi Cimzia Products in development Tofacitinib Iguratimod P&R issues identified from recent approvals The time lag between Japan and the US/EU Indication sequencing Annual costs of scope products in Japan 13 International price comparison 13.1 Introduction and methodology 13.2 Dosage regimens 13.3 Unit prices 13.4 International treatment cost comparison Annual cost of treatment Annual cost of treatment rebased to US prices References

9 7 Author profiles PRMA Insights are developed by consultants with wide-ranging experience of all aspects of market access, pricing, and reimbursement and are validated by national and international opinion leaders. Sotiria Papanicolaou Sotiria has more than 10 years experience in the pharmaceutical industry in corporate leader ship, EMA and global strategic market access teams, and a European health outcomes research group, where she developed health economics and outcomes strategies to support local P&R negotiations for new products. Jacqui Buchanan Jacqui has 10 years experience in clinical and health economic assessment. She has worked in strategic marketing and health policy, health economics and pricing. She also has wide-ranging experience in technology assessment and costeffectiveness consulting across the US, UK, and Australia. Dr Helen Barham Helen is managing editor at PRMA Consulting and has led content development of all the PRMA Insights series. She has more than 15 years experience in medical publishing, with expertise in a wide range of therapeutic areas and broad-ranging knowledge of market access and P&R. David Sykes (strategic advisor) David is the founding partner of PRMA Consulting. He has more than 15 years experience in P&R, market access, and health outcomes and has held senior leadership roles. David has developed European and global P&R and market access programs to quantify, capture, and communicate product value, including several products launched across multiple therapy areas. Professor Deborah Saltman AM (medical advisor) Deborah has worked in the pharmaceutical industry for more than 15 years, and has 20 years experience in leadership positions in academic medicine, delivering education programs for health workers in Europe, Asia, and Australia. She also has extensive experience in health research, postgraduate medical education, and medical publishing. Deborah is currently Honorary Professor in the Faculty of Medicine at the University of Sydney. Deborah was made a member of the Order of Australia in 2004, and was awarded the Rose Hunt Medal by the RCGP (UK) in prma insights

10 8 Monika Behrens Monika has more than 15 years experience in the pharmaceutical industry and statutory health insurance and has been responsible for market access strategy for GlaxoSmithKline in Germany, the UK, and Europe for a broad range of disease areas. Monika has an in-depth knowledge of the German healthcare system, particularly the AMNOG legislation. She holds a diploma in national economics and an MSc in health economics from York University. Vanessa Mirsky Vanessa has more than 10 years experience in healthcare and life sciences commercialization strategy, with a strong background in managed markets, including reimbursement dynamics among public and private payors in the US. Vanessa has worked with multinational pharmaceutical companies and small boutique firms in the US, and has significant experience in oncology and biologics. Cécile Matthews Cécile has 13 years experience in pharmaceutical consultancy, covering a broad range of strategic issues and therapeutic areas. She has specialist knowledge of European pricing and reimbursement issues that affect the pharmaceutical industry, particularly in France. Dr Divyagiri Seshagiri Divyagiri is a qualified physician and has over 6 years experience in the healthcare industry, including clinical practice and clinical research and all stages of the healthcare system, from prescribing through to drug research and public health setup in India and various European countries. Dr Alicia Gil Alicia has more than 14 years experience in the pharmaceutical and biotechnology industry, having held global, regional, and local positions where she was involved in the development and execution of regulatory affairs and market access strategies through all phases of drug development and commercialization, in a range of therapeutic areas. Alicia has an in-depth understanding of the Spanish healthcare system and market access challenges that it presents. Dr Alberto Redaelli Alberto has more than 25 years experience in the pharmaceutical industry. He has been an international manager in P&R and outcomes research, with broad experience in business planning, market research, and new product development at corporate level. Alberto has published numerous articles and reviews relating to the health economics of oncology in international peerreviewed journals, and has an in-depth understanding of the Italian healthcare system and market access challenges.

11 Sample pages 9 1 Clinical overview PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Arthritis 3 Patient-reported outcomes PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Arthritis difficult to assess. The BATTER-UP consortium is undertaking a prospective study of a biomarker panel that might predict response to TNFIs. Extra-articular manifestations of RA occur in 40 50% of patients and can affect the CV system, skin, eyes, blood, mucosa, and pulmonary system, and contribute to morbidity and mortality. Incidence increases with disease duration. PRMA Strategic Insights: Clinical overview 1i 1ii Defining RA is currently a moving target. Trials to date have used the 1987 ACR criteria for case recognition, which are based on features of established RA. However, the 2010 ACR/EULAR criteria provide a standardized approach to the identification of patients with early RA and thus the framework for trials to investigate earlier intervention. This will have an impact on trial design and the comparability of trial outcomes. The majority of data on disease progression currently available are based on patient cohorts before the widespread use of biological DMARDs. However, the pattern of disease progression has changed, as TNFIs effectively suppress the pathophysiological mechanisms associated with cartilage degradation and bone erosion, slowing radiographic progression. As the treatment paradigm shifts towards earlier intervention, the need to predict disease progression at the pre-articular phase becomes important, particularly if intervention at this stage can avoid initiation of the disease process. RF and ACPA can be used as diagnostic tools for early RA as well as prognostic factors. Areas to watch Interest in biomarkers as predictors of disease progression and treatment response is increasing. Various potential biomarkers have been proposed but further work is needed to establish any role in clinical practice (Section 1.8.1). The BATTER-UP consortium is due to publish a validation of eight biomarkers as predictors of the response to TNFIs in April 2012 (Section ). Algorithms to predict response to treatment on the basis of clinical indices have been proposed and a mathematical model for predicting response to TNFI therapy after 2 weeks of treatment has been developed. The likely value of such algorithms remains to be seen (Section ). approval for a new therapy on the basis of a PRO claim. It is imperative that concepts match the claims sought, and that the PRO instrument is developed and validated for the target population. The multidimensionality of PROs is exemplified in the variety of outcomes that have been included in FDA labeling claims: of PRO labels for drugs approved in 2007 and 2008, 75% of claims were granted for signs and symptoms, 13% for activity limitations, and 13% for HRQoL (Doward et al., 2010). PRMA Strategic Insight 3i Why measure PROs in RA? Given that there is no cure for RA, the aim of treatment is to slow disease progression and lessen the impact of the disease on patients lives. Measurement of PROs in people with RA is important because it: encourages patient-centered care can define the severity of the condition and inform decision-making determines the effectiveness of treatments and improvement of RA in routine practice can be used to assess quality of care is recommended by the EMA and FDA (see Section 3.6) is used as a decision-making tool for policy makers who need to allocate limited resources. PRO claims are important for helping to secure market access. 3.4 PRO instruments in RA In the absence of clinical superiority data, PRO benefits may be key to differentiation of a new product. A well-designed and robust PRO strategy is therefore essential, especially as most of the existing products have PRO claims in the labels. In addition to the standard physical function (HAQ) and generic PRO instruments, instruments that evaluate pain, fatigue, productivity, and quality of sleep should be considered. The PRO strategy should be developed and externally validated with payors and key opinion leaders from Phase 1 onwards, in order to identify the instruments that should be included in Phase 2/3 programs. Many generic and disease-specific instruments are used to assess PROs in RA. These are discussed in the following sections. Details of individual instruments are given in Appendix A (page 89) Generic instruments Generic instruments enable comparisons across groups and interventions. All pivotal clinical trials of new therapeutics in RA now include at least one generic instrument, usually the HAQ-DI (see Section 1.6.6) to assess function and/or the SF-36 to assess HRQoL (Tugwell et al., 2007). These instruments have proven validity and sensitivity for assessment of changes in health status or HRQoL in clinical trials of DMARDs and biologics. These and other generic PRO instruments that are widely used in trials of RA therapeutics are summarized in Table Rheumatology-specific PRO instruments Rheumatology-specific instruments are designed to address problems specific to the RA population. The Arthritis Impact Measurement Scale (AIMS) was one of the first PRO measures developed to evaluate HRQoL in RA (Meenan et al., 1980). AIMS2 is a more comprehensive and sensitive version of this questionnaire (Meenan et al., 1992). Use of the AIMS2 instrument is recommended by both the FDA and EMA (see Section 3.7), although it has not yet been widely used in clinical trials of investigational drugs for RA. The RA Impact of Disease (RAID) is new patient-derived composite response score recently developed by EULAR for use in clinical trials as a measure of the impact of RA on HRQoL (Gossec et al., 2011). EULAR s aim in developing RAID was to bring additional information into the assessment of RA that accounts for discordance between the patient s and the physician s perspective. Current standard assessments of RA include some dimensions or domains assessed by PROs (patient assessment of This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions. 38 This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions Treatment of rheumatoid arthritis PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Arthritis 5 Economic impact of rheumatoid arthritis PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Arthritis Table 4.38: Summary of the RAPID-1 trial of Cimzia References Keystone et al. (2008) Certolizumab pegol plus MTX is significantly more effective than placebo plus MTX in active rheumatoid arthritis: findings of a fifty-two-week, Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 58: Strand et al. (2009) Rapid and sustained improvements in health-related quality of life, fatigue, and other patient-reported outcomes in rheumatoid arthritis patients treated with certolizumab pegol plus MTX over 1 year: results from the RAPID 1 randomized controlled trial. Arthritis Res Ther 11: R170 Study 52 week Phase 3 multicenter randomized double-blind placebo-controlled parallel-group trial design Sample size 982 Treatment Cimzia 400/200: Cimzia 400 mg at weeks 0, 2, and 4, then Cimzia 200 mg every 2 weeks + MTX and dosing weekly Cimzia 400/400: Cimzia 400 mg at weeks 0, 2, and 4, then Cimzia 400 mg every 2 weeks + MTX weekly Placebo + MTX Patient Active rheumatoid arthritis despite MTX population Endpoints Primary ACR 20 response rate at week 24 Mean change from baseline in mtss at week 52 Major secondary Mean change from baseline in mtss at week 24 Mean change in HAQ-DI score at week 52 ACR 20, 50, and 70 response rates at week 24 Results ACR 20: Cimzia 400/200, 58.8%; Cimzia 400/400, 60.8%; placebo, 13.6% Mean change in mtss at week 52: Cimzia 400/200, 0.4; Cimzia 400/400, 0.2; placebo, 2.8 Mean improvement in HAQ-DI: Cimzia 400/200, 0.6; Cimzia 400/400, 0.63; MTX, 0.18 ACR 50: Cimzia 400/200, 37.1%; Cimzia 400/400, 39.9%; placebo, 7.6% ACR 70: Cimzia 400/200, 21.4%; Cimzia 400/400, 20.6%; placebo, 3.0% P < Cimzia groups vs placebo for all results HRQoL SF-36 PCS: Cimzia 400/200, 7.8; Cimzia 400/400, 8.6%; placebo, 1.7 SF-36 MCS: Cimzia 400/200, 6.4; Cimzia 400/400, 6.4; placebo, 2.1 Fatigue Assessment Scale: Cimzia 400/200, 2.6; Cimzia 400/400, 2.5; placebo, 0.8 All values are mean change from baseline at week 52; P < Cimzia groups vs placebo for all results Safety and Treatment-emergent AEs: Cimzia 400/200, 96.6; Cimzia 400/400, 94.5; placebo, tolerability The most frequent non-infectious AEs were headache, hypertension, and back pain Serious AEs: Cimzia 400/200, 14.8; Cimzia 400/400, 15.2; placebo, 12.0 AEs leading to study withdrawal: Cimzia 400/200, 5.6; Cimzia 400/400, 7.0; placebo, 3.3 Malignancy: Cimzia 400/200, 2.3; Cimzia 400/400, 1.3; placebo, 1.1 All rates are incidence per 100 patient-years Conclusions Compared with placebo plus MTX, Cimzia 200 or 400 mg plus MTX reduced signs and symptoms of rheumatoid arthritis in a rapid and sustained manner, inhibited structural damage, and improved physical function Abbreviations: ACR 20/50/70, 20/50/70% improvement in number of tender or swollen joints and three of five other American College of Rheumatology criteria; AE, adverse event; HAQ-DI, Health Assessment Questionnaire disability index; HRQoL, healthrelated quality of life; MCS, mental component summary; mtss, modified total Sharp score; MTX, methotrexate; PCS, physical component summary; SF-36, Short-form (36) Health Survey PRMA Consulting 2012 PRMA Strategic Insights 5i Drug costs and hospitalizations account for the greatest proportion of direct costs; however, many published studies have not considered high-cost biologics. To build the value proposition, new observational and costing studies are needed to assess the clinical and economic impact of these agents. Relevant data need to be collected to allow stratification of results according to disease severity, functional status, and comorbidities. 5ii Existing registries may present an opportunity to characterize treatment patterns and resource utilization profiles to inform costing and cost-effectiveness studies. Figure 5.2: 25,000 20,000 15,000 10,000 5, ,069 Source: Lundkvist et al., ,463 21,908 22,458 16,441 15,417 16,502 US Europe France Germany Italy Spain UK Indirect Informal care Non-medical Medical (excluding drugs) Drugs Several studies have assessed the total per-patient costs associated with RA, summarized in Table 5.1. Some studies have included both direct and indirect costs. Few studies have evaluated the cost of RA in recent years and some studies date back to the early 1990s. (Only full key papers published in English are considered in this discussion.) France Kobelt and colleagues reported costs associated with RA from a sample of 1,487 patients who completed an anonymous mail survey, summarized in Table 5.2 (page 174). From a societal perspective, productivity losses were the major cost (24%), followed by hospitalization (21%), medication (20%), and informal care (16%). From the perspective of public payors, hospitalization was the largest cost (34%), followed by drugs (26%) and indemnities (20%) (Kobelt et al., 2008). The mean cost per patient in this latter perspective was estimated at 11,658 and represented only 54% of total societal costs, which amounted to 21,690. Direct medical and non-medical costs represented a high proportion of total costs (77% in the societal perspective and 80% in the public payor perspective), reflecting the high age of the sample, and consequently low indirect costs. Use of biological treatments was higher than the expected use 27% of patients in the sample (Enbrel, 48.1%; Remicade, 26.5%; Humira, 25.7%; Kineret or MabThera, 3%). This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions. 152 This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions. 172 prma insights

12 This report is a licensed product and is not to be reproduced 10 Sample pages 5 Economic impact of rheumatoid arthritis PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Arthritis 7 Pricing and reimbursement in the UK PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Arthritis measured by the HAQ-DI (P 0.001) and both approaches (HUI-3 and the EQ-5D utilities) showed decreasing utility values as RA severity increased (Table 5.8). Table 7.9: Cost-effectiveness results for Cimzia, based on the manufacturer s model Area to watch Table 5.8: HUI-3 and EQ-5D utility values according to disease severity assessed by the HAQ-DI 0.5 HAQ-DI 1.1 HAQ-DI 1.6 HAQ-DI HAQ-DI 0.5 < 1.1 < 1.6 < 2.1 HAQ-DI 2.1 HUI ± ± ± ± ± 0.20 (n = 62) (n = 56) (n = 31) (n = 34) (n = 23) EQ-5D 0.87 ± ± ± ± ± 0.42 (n = 68) (n = 66) (n = 39) (n = 35) (n = 27) Values are mean ± SD (valid n) Abbreviations: EQ-5D, EuroQol five-dimension questionnaire; HAQ-DI, Health Assessment Questionnaire disability index; HUI-3, Health Utilities Index; SD, standard deviation Source: Carreno et al., 2011 PRMA Consulting 2012 Adams and colleagues used regression analysis to calculate utility scores from the HAQ-DI and the DAS28 in an RA sample (n = 345) at baseline and after 12 months of biological therapy (Adams et al., 2010). A 1 point reduction in the HAQ-DI was associated with a gain in QALYs per annum of 0.24 using the EQ-5D but only 0.08 using the SF-6D. In addition, a 1 point reduction in the DAS28 score was associated with a gain in QALYs per annum of using the EQ-5D and using the SF-6D. These differences highlight that comparison of cost-effectiveness is problematic when utility scores have been derived using different methods. In acknowledgement of the heterogeneous nature of RA, work is now starting to address different HAQ-DI trajectories for different levels of sustained disease activity. HAQ-DI is mainly influenced by disease activity in the early stages of disease but by joint damage in established disease. Thus DMARDs and biologics can have a greater influence on the HAQ-DI during early disease stages but less effect in established disease. According to recent feedback from advisors in our network, this is particularly important when the HAQ is mapped to utility scores and costs per QALY in health economic evaluations. A recently published league table of utility scores in various diseases showed RA to be associated with the worst HRQoL (Figure 5.8) (Currie et al., 2005; Lundkvist et al., 2008; Orme et al., 2007). Clinical trials in RA have not typically collected generic preference-based utility measures, so methods of estimating utility values from diseasespecific instruments have been developed. Formulas to map the HAQ-DI to the EQ-5D and SF-6D have been developed in order to estimate the average utility of a cohort (Bansback et al., 2007; Hurst et al., 1997). The use of mapping techniques, while not based on the primary collection of data, is a practical solution when no utility measure has been collected. The mapping technique proposed by Hurst and colleagues (from a Scottish cohort of RA patients) has been used in economic evaluations of TNFIs and PRMA Strategic Insight 5v Different instruments and methodologies have been used to derive utilities in RA. For example, a 1 point reduction in the HAQ-DI or DAS28 has been associated with higher QALY gains if the EQ-5D rather than the SF-6D is used. Thorough research on this area is needed before defining the PRO strategy and health outcomes research. was used in the Birmingham RA Model (BRAM) which evaluated the cost-effectiveness of Enbrel, Humira, and Remicade for the treatment of RA (Chen et al., 2006b). Bansback and colleagues estimated EQ-5D and SF-6D scores from HAQ-DI items using linear regression models. The HAQ-DI Incremental utility Incremental cost Cost per QALY Treatment Comparator BC/revised BC/revised BC/revised Not including PAS Cimzia + Enbrel / ,675/2,993 Cimzia less effective and MTX MTX more costly/ 46,192 Cimzia + Humira / ,563/3,124 34,930/12,937 MTX MTX Cimzia + Remicade / ,468/ 6,441 Dominated/dominated MTX MTX Cimzia Humira 0.127/ ,347/1,223 42,197/5,687 Cimzia Enbrel 0.047/ / 517 6,341/Cimzia less effective and less costly Including PAS Cimzia + Enbrel / / 582 Cimzia less effective and MTX MTX less costly/dominated Cimzia + Humira / / 451 Dominated/dominated MTX MTX Cimzia + Remicade / ,043/ 10,016 Dominated/dominated MTX MTX Cimzia Humira 0.127/ ,772/ 2,352 13,982/dominated Enbrel Cimzia 0.047/ ,872/ 4,092 82,695/31,582 In all cases, dominated means Cimzia was more effective and less costly Abbreviations: BC, base case; MTX, methotrexate; PAS, patient access scheme; QALY, quality-adjusted life-year Source: NICE, 2010c PRMA Consulting 2012 Cimzia monotherapy compared with Humira monotherapy gave a QALY gain of and incremental costs of 1,223, resulting in an ICER for Cimzia of 5,687 per QALY gained. Cimzia monotherapy was less effective and less costly than Enbrel monotherapy. The revised economic model including the PAS for combination therapy showed that Cimzia dominated Enbrel, Humira, and Remicade. Cimzia monotherapy also dominated Humira monotherapy. The ERG outlined the following concerns regarding the methodology used for the indirect comparison. The ERG questioned the appropriateness of using an indirect treatment comparison in which only multiple two-way comparisons between biological DMARDs was possible, rather than using a mixed-treatment comparison. The method used for selecting the studies to be included in the indirect treatment comparison was unclear. It was possible that relevant information from several excluded studies, including one of Cimzia plus MTX versus placebo plus MTX (C87014 trial), could have been used. The inclusion of data from the included studies was not consistent. There was insufficient consideration and exploration of underlying heterogeneity among the studies included in the indirect comparison. Of the 10 trials used in the indirect comparison for combination therapy, participants in the two Cimzia trials at 6 months had a low previous exposure to DMARDs compared with participants in trials of comparator treatments. Also, the mean MTX dosage at the time of entry to the 10 trials was lowest in the Cimzia trials. This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions. 186 This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions Pricing and reimbursement in Spain PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Arthritis 12 Pricing and reimbursement in Japan PRMA Insights: Pricing and Reimbursement Success in Rheumatoid Arthritis Reviewers and decision-makers have criticized the lack of real-world evidence and costeffectiveness studies. In the absence of such studies, economic evaluations are performed on the basis of daily treatment, cost of complete treatment, and incremental cost versus alternatives. Evaluations may also consider an estimation of the number of patients likely to receive a treatment per year, annual costs, and annual efficacy units. The reviewers criticized the general lack of data relevant to clinical practice in Spain (e.g., comparison with the treatments used locally, rather than the international perspective) this has important consequences since, in most cases, products are approved/introduced with restrictions over their approved indication and reimbursement conditions. Finally, while increased efforts are being made to standardize approaches and methodology, discrepancies in conclusions reached after evaluating the same data set still remain, which can be confusing for manufacturers. PRMA Strategic Insight 10xiv Regional reviewers have criticized the lack of data relevant to clinical practice in Spain, which has resulted in restrictions over their approved indication and reimbursement conditions. Manufacturers need to understand local clinical practice in Spain, and ensure that relevant comparators (those actually used in clinical practice) are included in studies Annual costs of scope products in Spain Figure 10.3 shows the annual cost of treatments of RA with the scope products in Spain. The methodology used to calculate these prices is described in Section Figure 12.1: Overview of the pricing and reimbursement process in Japan Discussion New drug approval HPB EAD Applicant Applicant s draft price Reimbursement discussed with HIB MED Japan Medical Association and Japan Pharmaceutical Association HIB s draft price In principle within DPO (1st) days Applicant submits 1. Presence of similar drugs appeal statement 2. Suitability of similar drugs 3. Necessity of applying premium 4. Validity of cost DPO (2nd) Draft pricing report Added to NHI price list Chuikyo: final decision on price/approval Abbreviations: DPO, Drug Pricing Organization; EAD, Economic Affairs Division; HIB, Health Insurance Bureau; HPB, Health Policy Bureau; MED, Medical Economics Division; NHI, national health insurance Source: adapted from JPMA, 2012 PRMA Consulting 2012 Figure 10.3: Annual costs of scope products for rheumatoid arthritis in Spain Cost of treatment per patient per year (US$) 25,000 20,000 15,000 10,000 5, ,881 Cimzia 17,216 18,675 13,500 14,492 21,124 15,861 20,345 18,712 Enbrel Humira Kineret MabThera Orencia Remicade RoActemra Simponi Costs are for the first year of treatment, based on the regimens defined in Table 13.1, calculated ex-factory prices, and the following exchange rates (27 July 2011; US$1 = 0.61, 78, 0.69 Source: PRMA Consulting, 2011 PRMA Consulting 2012 applications to the NHI drug list has decreased significantly over time. For example, in the late 1990s almost 50% of applications included some form of economic evaluation, compared with fewer than 10% in An industry survey published in 2008 reported that manufacturers chose not to submit health economic data because such studies are not considered by the authorities as they are not part of the formal reimbursement process, and there are insufficient data for robust analyses (Koike et al., 2007; Toshiya and Sannomiya, 2008) Pricing process The pricing process in Japan is based on a series of rules and there is limited scope for manufacturers to influence or negotiate price. This section outlines the steps for achieving a price on the NHI drug list. This process is illustrated in Figure Once a manufacturer achieves regulatory approval, it submits a pricing proposal to the EAD in the Health Policy Bureau. The price proposal needs to justify the pricing method, the choice of comparator, and any price premium proposed (these methods are discussed in further detail in Section 12.4). The EAD submits a recommendation to the Medical Economics Division (MED) in the Health Insurance Bureau; the MED then sends its own proposal to the manufacturer. If the manufacturer is satisfied with the proposal, the MED will consult with the DPO on the basis of this proposal. If the manufacturer is not satisfied with the proposal, it is allowed to submit its original proposal to the DPO. In this case, both the manufacturer and the MED present their separate proposals at a meeting with the DPO and both are allowed to respond to questions from the DPO. The manufacturer can be accompanied by an expert at this meeting. The DPO s price proposal that goes to Chuikyo is based on its assessment of the following: the existence of similar drugs (the validity of either the comparator pricing method or the cost calculation method) This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions. 388 or photocopied without the appropriate permissions. 438

13 11 Ways to use PRMA Insights PRMA Insights provide a key resource for development of your P&R and market access strategy. This diagram illustrates just a few of the many ways that this can support your planning. Development of an HEOR strategy and evidencegeneration plan Development of a PRO strategy Development of a preference-based utility strategy Critical understanding of existing HE models All chapters Chapter 3 Chapter 5 Chapter 7 (UK) Chapter 5 Country-specific chapters (6 12; particularly 7 [UK]) Understand: Competitor data packages Adverse-effect profiles Indirect comparisons Existing utility estimates Registries in the scope countries (data captured and how these can be used) Supporting development of economic models Evidence gaps and future evidence generation Understand: Role of PROs in product differentiation Impact of PROs on HTA and P&R submissions Existing PRO data for marketed products and label claims Evolution of a PRO strategy Understand: Existing utility estimates in the literature and how these have been applied to cost-effectiveness models of competitor products Mapping to EQ-5D to generate utilities How such estimates map onto different symptoms that may be able to drive utility differences Understand: Critically assess existing models, assumptions, and inputs (cost, utility, and clinical) Competitor AE profiles Inform clinical development program (endpoints, subgroups) Inform HTA strategy Inform cost-effectiveness model Develop and inform value propositions Chapter 4 and country-specific chapters All chapters Chapters 3 5 Country-specific chapters Understand: Impact of AEs in economic models HTA feedback on relevant AEs to include in models Understand: Competitors HTA and clinical development strategies (existing products and products in development) Benefits according to different subgroups and definitions used in trials Feedback from payors and HTA agencies on submitted evidence and needs for future research Understand the value propositions of competitors and their acceptance by payors Provide the basis for the global value dossier of a new product Internal education All chapters Use as educational materials to enable colleagues to rapidly become familiar with a new therapy area and the market challenges Cross-functional collaboration All chapters Ensure common understanding across the organization in order to develop a single coherent strategy that meets various stakeholders needs in: Market access challenges and opportunities HEOR strategy development Clinical development strategy Regulatory expectations in terms of indication, clinical trial design, and PROs Accurate forecasting of the market opportunity A consistent value proposition that supports both market access and marketing prma insights

14 8 Pricing and ordering PRMA Insights Focus: Pricing and Reimbursement in Germany under AMNOG ($19,000) Market Access Success for Companion Diagnostic Drug Pairings in Oncology ($79,000) Pricing and Reimbursement Success in: NSCLC (2nd edition) ($69,000) Renal Cell Carcinoma ($59,000) Metastatic Breast Cancer ($59,000) Rheumatoid Arthritis ($69,000) Psoriasis ($59,000) Type 2 Diabetes ($59,000) COPD ($59,000) PRMA Insights Focus series PRMA Insights Market Access series PRMA Insights Pricing and Reimbursement series Each PRMA Insights license provides: Unlimited access to the electronic version across the organization Two copies of the PRMA Insights pack A teleconference with authors from the PRMA Consulting team to: Talk you through the content Highlight key market access themes Discuss strategic implications for your assets To order, or for more information, call +44 (0) or [email protected] prma insights

15 Order form PRMA Consulting Pricing, reimbursement, and market access p I would like to order PRMA Insights Focus: Pricing and Reimbursement Success in Rheumatoid Arthritis $69,000 global user license* (unlimited use within entire organization) *Reports will be digitally rights managed, restricting forwarding, printing, scanning, and saving to USB outside the organization, see PRMA Insights standard terms and conditions (/termsandconditions); reports will not be dispatched before full payment has been received p Please invoice my company Name Job title Department Company Address Postcode/ZIP Country Telephone Mobile Please quote PO number NB: EU companies (excl UK) must supply VAT/BTW/ MOMS/MWST/IVA/FPA number: UK sales are subject to VAT at the current rate Complete your details p Please tick if same as above Name Job title Department Company Address Postcode/ZIP Country Telephone Mobile Please sign and date to confirm your order DATE Send your order Fax this order form to +44 (0) or scan and to [email protected] Invoice payment terms: 30 days For more information about PRMA Insights and to see all the titles in the series, visit [email protected] Tel (UK): +44 (0) Tel (US):

16 PRMA Consulting PRMA Consulting are experts in pricing, reimbursement, and market access. We work in close partnership with our clients to deliver integrated and innovative solutions to market access. Strategy development our creative but pragmatic market access strategies are founded on early planning and strategic thinking to understand the challenges. Evidence generation the broad cross-functional expertise and thought leadership of our 75+ strong consultancy team enables us to deliver novel and scientifically rigorous payor-focused evidence generation solutions that meet the needs of both global and affiliate groups. Value communication we develop innovative ways to communicate the value proposition of products to payors and other stakeholders. For further details, visit Join our webinars We regularly host webinars on issues that we consider to be of critical importance in market access, such as companion diagnostics, benefit assessment in Germany, and the increasingly important role of PROs in oncology. Meet us face to face Join us at one of the international conferences that we regularly attend and discuss your market access challenges face to face. To learn more and to register for forthcoming webinars and events, visit Follow us Learn about forthcoming PRMA consulting events Keep up to date with pricing, reimbursement, and market access issues Watch our informative industry-related webinars and short vidoes prma-consulting-ltd prmaconsulting1 prmaconsultingvideo Tel (UK): +44 (0) Tel (US): +1 (415) IFAMNOG

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