PRMA Insights: Pricing and Reimbursement Success in Renal Cell Carcinoma

Transcription

1 PRMA Insights: Pricing and Reimbursement Success in Renal Cell Carcinoma 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 supplement brochure included

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. info@prmainsights.com Tel (UK): +44 (0) Tel (US): +1 (415)

3 1 Introduction Renal cell carcinoma (RCC) is an uncommon tumor, accounting for 2 3% of all cancers; 80 90% of kidney cancers are RCC. The peak incidence of RCC is at years of age, with a median age at diagnosis of metastatic disease of 64 years; an estimated 27.5% of patients with RCC have metastases at diagnosis. The worldwide and European incidence of RCC have increased by 2 3% per year over the last decade. A major factor in this increase has been the advent of modern imaging techniques, which has led to a stage migration, with tumors now being detected at earlier stages. More than half of new RCC cases are found incidentally and are not associated with disease-specific symptoms. A robust market access strategy is key to commercial success Oncology is now the leading therapy area by value, with global sales of US$52.4 bn in 2009, an 8.8% increase from the previous year. The oncology market is expected to double in size by This is driven by a number of factors, including the rising incidence of cancer, the increasingly high prices of new oncologics, and the absolute number of oncologics being developed. Of 861 oncologics currently in clinical development, 44 are for kidney cancer. However, budgetary pressures, exacerbated by the global economic crisis, are resulting in greater scrutiny from payors around the world as reimbursement for products is sought. The RCC market is estimated to be worth over US$1 bn and, with six molecularly targeted therapies already marketed, is highly competitive. Significant growth is expected as a result of the new targeted therapies and an increase in the numbers of patients being treated. For many manufacturers, RCC is the tumor used to demonstrate proof of concept and is likely to be the lead indication. Despite the scientific attractiveness of this approach, however, commercial barriers to success in RCC are increasing at the market-access level, which will require early planning and adequate investment. Given the increasingly competitive treatment landscape, combined with the difficulty of demonstrating clear benefits in overall survival because of crossover in trials, demonstration of maintenance of health-related quality of life (HRQoL) becomes a critical differentiation point. It must be demonstrated using validated instruments that improvements in progression-free or overall survival are not achieved at too high a cost in terms of impact on HRQoL. As they make their reimbursement decisions, payors will also be asking searching questions about appropriate treatment sequencing and the value that combinations of targeted therapies may offer. Although requirements differ across the major markets, one trend is clear: the evidence requirements to achieve reimbursement and market access are increasing, requiring use of cost-effectiveness data, HTAs, risk-sharing agreements, real-world naturalistic data, and head-to-head comparative effectiveness data. In response, a manufacturer launching a new product into an increasingly competitive market will have to provide a compelling evidence-based payor value proposition in order to support price premiums, achieve reimbursement, and gain market share. The probability of commercial success will inevitably be compromised by failure to adequately plan the market access strategy and to systematically evaluate and deliver on evidence requirements reduced price, reimbursement rejections, smaller-than-planned reimbursed population, and extensive market access delays are all commercially disastrous consequences of poor planning. Key decisions during the development process will affect the P&R opportunity, including the tumor subtype to be studied, patient subpopulation, choice of comparator, inclusion of patient-reported outcome data, and choice of endpoint (progression-free or overall survival). Generating an evidence package that is consistent with the manufacturer s pricing and commercial aspirations requires early planning and broad cross-functional cooperation. In RCC, where HRQoL will become an increasingly important point of differentiation, this planning will need to occur from Phase 1 onwards. PRMA Insights: The Roadmap to Pricing and Reimbursement Success in Renal Cell Carcinoma focuses on the P&R issues around the following scope treatments: Avastin (bevacizumab; Roche [marketed by Chugai in Japan]) Nexavar (sorafenib; Bayer/Onyx) Sutent (sunitinib; Pfizer) Torisel (temsirolimus; Pfizer) Afinitor (everolimus; Novartis) Votrient (pazopanib; GlaxoSmithKline). prma insights

4 2 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.

5 3 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. David Sykes 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 at Lilly and J&J. 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. David has published extensively in the area of health economics. Professor Bernard Escudier Professor Escudier is head of the Immunotherapy Unit at the Gustave Roussy Institute in Paris, where he works in the immunotherapy of RCC, particularly high-dose interleukin, and the development of new strategies (antiangiogenic drugs, gene therapy). He was the principal investigator in several pivotal RCC trials, including AVOREN, TARGET, and TORAVA. He also led the ESMO working group that developed the clinical practice guidelines for RCC. Sotiria Papanicolaou Sotiria has more than 10 years experience in the pharmaceutical industry. She has worked in the corporate leadership team of Janssen-Cilag, Greece, and in a number of EMA and global strategic market access teams. Sotiria was also part of the European Health Outcomes Research group at Lilly, where she developed health economics and outcomes strategies to support local P&R negotiations for new products. Dr Marcus Healey MBA Marcus is the principal medical writer at PRMA Consulting and has more than 8 years experience in medical communications and 20 years experience across numerous therapeutic areas and markets. Marcus has co-authored and edited books and numerous journal articles. Dr Jan Geldmacher Dr Geldmacher has over 30 years experience in the German healthcare system. He is a member of the drug committee of the G-BA (Federal Joint Committee), the expert advisory committee on prescription-only products of the German Health Ministry, and the drug commission of the German Medical Association (AKDÄ). He also represents AKDÄ on the drug safety committee of the BfArM (Federal Institute for Drugs and Medical Devices). Dr Mark Larkin Mark has over 10 years experience in strategy consulting and finance. He has been involved in strategy development across a broad range of therapeutic areas, at both European and global levels, and has extensive experience of advising North American and European developers on P&R and market access strategies, for both in-house launches and to support business development objectives. Vanessa Mirsky Our in-house US expert, Vanessa has more than 10 years consultancy 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. 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. Albert has an indepth understanding of the Italian healthcare system and market access challenges. prma insights

6 4 Table of contents Each chapter starts with a Chapter Summary and PRMA Strategic Insights. Executive summary 1 Clinical overview 1.1 Disease definition 1.2 Classification Histology of renal cancer Histology of RCC 1.3 Characteristics of different subtypes Clear cell RCC Papillary RCC Chromophobe RCC Collecting duct carcinoma Sarcomatoid RCC 1.4 Etiology 1.5 Risk factors Obesity Tobacco smoking Hypertension Genetic and hereditary factors Age Sex Other factors Summary of risk factors 1.6 Presenting symptoms Incidental finding Stage at diagnosis 1.7 Diagnostic workup 1.8 Staging 1.9 Prognostic factors Performance status Prognostic systems Metastases Molecular biomarkers 2 Burden of RCC 2.1 Epidemiology Incidence of kidney cancer Prevalence of kidney cancer Incidence of RCC Mortality Survival 2.2 Burden of RCC 2.3 Patient-reported outcomes Definition and importance of PROs, QoL, and HRQoL FDA guidance EMA guidance HRQoL in cancer Why measure PROs in RCC? Domains and items of interest in RCC Instruments used to measure PROs in RCC Effect of the individual therapies on HRQoL Quality-adjusted survival Utilities 2.4 Economic burden of RCC Costs in the US Costs in Europe Indirect costs of RCC Pharmacoeconomic evaluations in RCC 3 Treatment of RCC 3.1 Overview of treatment 3.2 Surgery Radical nephrectomy Partial nephrectomy Cytoreductive nephrectomy Metastasectomy 3.3 Neoadjuvant therapy 3.4 Adjuvant therapy MTTs in the adjuvant setting 3.5 Systemic treatment strategies for advanced RCC and MRCC Chemotherapy, hormonal therapy, and radiotherapy Immunotherapy 3.6 Molecularly targeted therapeutics Avastin Nexavar Sutent Torisel Afinitor Votrient 3.7 Summary of the MTTs in metastatic RCC 3.8 Current treatment strategies Clinical guidelines Sequential therapy with MTTs Combination therapy with MTTs 3.9 Products in development Axitinib Tivozanib Trials for additional indications 4 Pricing and reimbursement in the US 4.1 Key stakeholders 4.2 Pricing of pharmaceuticals in the US 4.3 Obtaining formulary listing Oral products

7 Injectable products Other utilization management techniques Formulary management Reimbursement for off-label use Payor mix for renal cell cancer 4.4 Formulary status of therapies for RCC 4.5 Current US payor dynamics in RCC Reliance on national cancer guidelines Research in the adjuvant setting Economics of IV versus self-injectable/oral therapies Increasing presence of specialty pharmacy Increase in service contracts among oncology drug manufacturers Personalized medicine Use of health technology assessment Comparative effectiveness research Importance of endpoints in oncology Cost shifting 4.6 Federal healthcare reform Implications for consumers Implications for pharmaceutical pricing 4.7 Costs of scope treatments for RCC in the US 5 Pricing and reimbursement in the UK 5.1 Key stakeholders 5.2 Pricing and reimbursement process Free pricing in the UK within the context of the PPRS Data requirements 5.3 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 End-of-life treatments Scientific advice pilot Top-up care 5.4 NICE assessments in advanced and/or metastatic RCC Sutent wins NICE approval as first-line treatment NICE rejects targeted therapies NICE rejects Afinitor for second-line treatment of advanced RCC NICE plans to review five RCC drugs in The Scottish Medicines Consortium Horizon scanning The SMC has a disproportionate influence Patient access schemes 5.6 SMC assessments in RCC Avastin Sutent Nexavar Afinitor 5.7 All Wales Medicines Strategy Group (AWMSG) 5.8 AWMSG appraisals in RCC 5.9 Summary of HTA decisions in the UK 5.10 Costs of scope treatments for RCC in the UK 6 Pricing and reimbursement in France 6.1 Key stakeholders 6.2 P&R process, key timings, and data requirements 6.3 TC HTA is the pivotal market access hurdle for innovative ambulatory drugs Public health impact and target population SMR denotes level of actual benefit Incremental benefit ASMR is the key determinant of subsequent pricing A range of P&R controls exists beyond product launch Almost all new hospital oncology products will be included on the T2A-exempt list 6.4 National guidelines for metastatic RCC 6.5 TC assessments of molecularly targeted therapeutics for RCC Afinitor Avastin Nexavar Sutent Torisel 6.6 P&R status of immunotherapies for RCC in France 6.7 Costs of scope treatments for RCC in France 7 Pricing and reimbursement in Germany 7.1 Key stakeholders 7.2 P&R process and key timings Officially pricing is unregulated but the reality is price controls 7.3 IQWiG performs evidence-based evaluations, but not in oncology IQWiG s scope of activity has widened but does not include oncology 7.4 Reference pricing and possible co-pays 7.5 P&R reform Measures to curb expenditure A new assessment framework for innovative drugs Long-term changes Implications for manufacturers Cancellation of proposed special drug list 7.6 DRG tariffs and NUB (innovation) scheme for hospital products 7.7 No national treatment recommendations for RCC 7.8 No HTAs for RCC therapeutics 7.9 G-BA guidance on RCC therapeutics September 2009 draft guidance December 2009 draft guidance prma insights

8 IL-2 and IFN 7.10 Costs of scope treatments for RCC in Germany 8 Pricing and reimbursement in Spain 8.1 Key stakeholders The central government The Regions The hospitals 8.2 P&R process, key timings, and data requirements The P&R processes are combined Fast-track process for innovative products Hospital products are fully reimbursed but rationing controls exist Pricing negotiations The use of cost-effectiveness 8.3 National activities SNS cancer strategy Report on the cancer situation in Spain Report on the SNS quality plan Treatment guidelines SOGUG guidelines SEOM guidelines Local treatment guidelines 8.5 Regional activities Oncology health plans 8.6 National P&R status of key treatments 8.7 Reviews of key treatments HTA review of RCC treatments Avastin Nexavar Sutent Torisel Overview of key influencing factors 8.8 Costs of scope treatments for RCC in Spain 9 Pricing and reimbursement in Italy 9.1 Key stakeholders The central government The Regions Local health units and hospitals 9.2 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 Orphan drugs Pricing approval process Regional reviews can take on average 223 days Budgetary responsibilities Payback mechanisms and risk-sharing agreements Monitoring requirements Discounts are applied at hospitals Generics and reference pricing 9.3 Treatment guidelines for metastatic RCC 9.4 National P&R status of treatments for advanced and/or metastatic RCC Risk-sharing agreements 9.5 National and regional reviews of RCC treatments and influencing factors Avastin Nexavar Sutent Torisel 9.6 Pharmacoeconomic evaluations 9.7 Costs of scope treatments for RCC in Italy 10 Pricing and reimbursement in Japan 10.1 Key organizations and stakeholders 10.2 P&R process, key timings, and data requirements Data requirements for submission 10.3 Pricing process 10.4 Pricing methods The comparator pricing method The cost calculation method Foreign price adjustment Analysis of methods used to calculate prices 10.5 Pricing of generics 10.6 Key current P&R issues Biennial price revisions Generic substitution 10.7 Future trends that will affect market access Improved regulatory approval timelines Price revision reforms The use of pharmacoeconomic data in price determination 10.8 RCC in Japan 10.9 Treatment recommendations for metastatic RCC Overview of the RCC market in Japan P&R status of RCC products Nexavar Sutent Afinitor Torisel Avastin P&R issues exemplified from recent approvals The time lag between Japan and the US/EU Pricing issues Need for comparator studies Costs of scope treatments for RCC in Japan 11 International price comparison 11.1 Introduction and methodology 11.2 Dosage regimens 11.3 International cost comparison Cost of treatment Cost of treatment rebased to US prices References

9 Sample pages 7 2 Burden of RCC PRMA Insights: The Roadmap to Pricing and Reimbursement Success in Renal Cell Carcinoma 3 Treatment of RCC PRMA Insights: The Roadmap to Pricing and Reimbursement Success in Renal Cell Carcinoma Table 2.8: Summary of studies that measured health-related quality of life in patients with renal cell carcinoma Comparator Instruments arms used Results Reference Nexavar SF-36 Findings suggest that treatment-related adverse Miyake et al., 2010 events with Nexavar may not impair HRQoL in patients with MRCC and the efficacy of treatment may have a positive impact on HRQoL Nexavar vs FKSI-15 Superiority for Nexavar over IFN-α in FKSI-15, Szczylik et al., 2008 IFN-α TSQM significant delay in health status deterioration, greater overall satisfaction with treatment, fewer FACT-BRM kidney cancer-related concerns and symptoms, better overall QoL Nexavar vs FACT Patients receiving Nexavar reported significantly Bukowski et al., 2007a placebo FKSI-10 fewer symptoms and concerns: cough, fevers, shortness of breath, ability to enjoy life, worry about treatment effects Sutent vs EQ-5D Patients in the Sutent group experienced Castellano et al., 2009 IFN-α FACT-G significantly milder kidney-related symptoms and better cancer-specific HRQoL and general health FKSI status FKSI-DRS Sutent vs EQ-5D Patients in the Sutent group were favored in Cella et al., 2008 IFN-α FACT-G terms of energy, fatigue, shortness of breath, coughing, and bother with fever FKSI FKSI-DRS Sutent vs EQ-5D Patients in the Sutent group reported a Motzer et al., 2007 IFN-α FACT-G significantly better QoL than patients in the IFN-α group (P < 0.001). FKSI FKSI-DRS Sutent vs FACIT- Patients in the Sutent group had similar scores as Motzer et al., 2006 IFN-α Fatigue the general US population EQ-5D EQ-VAS Afinitor vs EORTC No significant changes reported by patients in Motzer et al., 2008 placebo QLQ-C30 the two groups as measurable effect on disease (Table 3.21) FKSI-DRS symptoms or QoL based on pre-established criteria for clinical meaningfulness Votrient vs EORTC Patients treated with Votrient did not have Hawkins et al., 2009 placebo QLQ-C30 clinically meaningful difference in QoL vs placebo even with the toxicities that may be expected with an active agent Axitinib EORTC Cytokine-refractory patients treated with Trask et al., 2008 QLQ-C30 axitinib reported significant post-treatment changes from baseline in HRQoL functioning and symptoms, although these were not meaningful deteriorations to the patients Abbreviations: EORTC QLQ-C30: European Organization for the Research and Treatment of Cancer Quality of Life Core Questionnaire; EQ-5D, EuroQol five-dimension questionnaire; FACT, Functional Assessment of Cancer Therapy (BRM, Biological Response Modifiers; G, General); FKSI, FACT Kidney Symptom Index (10 or 15 questions); FKSI- DRS, FKSI Disease-Related Symptoms; HRQoL, health-related quality of life; IFN, interferon; MRCC, metastatic renal cell carcinoma; QoL, quality of life; SF-36, short-form 36; TSQM, Treatment Satisfaction Questionnaire for Medication The mitogenic growth factors VEGF-A, PDGFβ, and TGF-α bind to multiple tyrosine kinase receptors on RCC cells. This binding triggers a signal transduction cascade that eventually leads to cell survival and proliferation (Patel et al., 2006). The TKIs Sutent, Nexavar, Votrient, axitinib (Pfizer), and cediranib (AstraZeneca) act by inhibiting this pathway. The mtor pathway is also involved in RCC tumorigenesis because it regulates the expression and stability of HIF1α; rapamycin inhibits the induction of HIF1α in response to hypoxia (Hudes, 2009; Patard et al., 2008). The HIF pathway can therefore be blocked with either distal inhibitors (i.e., inhibitors of VEGF, PDGF, TGF) or proximal inhibitors (i.e., inhibitors of mtor activity) (Patel et al., 2006). The new MTTs target these pathways in three ways (Schmidinger and Bellmunt, 2010). Avastin is a MAb that binds and neutralizes circulating VEGF (Presta et al., 1997). Sutent, Nexavar, and Votrient are TKIs (Bastien et al., 2009). Torisel and Afinitor are rapamycin derivatives that inhibit the mtor pathway (Bastien et al., 2009). Figure 3.2 summarizes the sites of action of the MTTs in RCC. Figure 3.2: Molecular targets of the agents used in renal cell carcinoma to inhibit tumorigenesis hypoxia cediranib Nexavar Sutent Votrient HIF Nexavar Sutent Votrient Afinitor Torisel mtor pathway VEGF PDGF EGF, TGF target of rapamycin; PDGF, platelet-derived growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; VHL, von Hippel Lindau Source: adapted from Di Lorenzo et al., 2009; Kaelin, 2004; Sosman and Puzanov, 2009 This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions. 68 This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions Treatment of RCC PRMA Insights: The Roadmap to Pricing and Reimbursement Success in Renal Cell Carcinoma 4 Pricing and reimbursement in the US PRMA Insights: The Roadmap to Pricing and Reimbursement Success in Renal Cell Carcinoma Table 3.13: Regulatory indications for Torisel in advanced renal cell carcinoma Figure 4.4: intravenous therapies Agency and approval date Indication Approved dose EMA For the first-line treatment of patients 25 mg infused IV over minutes with advanced RCC who have at least once a week Nov 2007 three of six prognostic risk factors FDA For the treatment of advanced RCC 25 mg infused IV over minutes, May 2007 once a week, until disease progression or unacceptable toxicity MHLW For unresectable or metastatic RCC 25 mg IV once a week May 2010 Reimbursement to physician burden Pharmacy benefit oral therapy 0% Typically 25 33% co-insurance cost can be upwards of US$1,000 per month Medical benefit IV therapy administered in the physician office ASP +6 10%, depending on payor US$20 per office visit Abbreviations: EMA, European Medicines Agency; FDA, Food and Drug Administration (US); IV, intravenous; MHLW, Ministry of Health, Labour and Welfare (Japan); RCC, renal cell carcinoma following predictors of short survival: less than 1 year from initial diagnosis to randomization; KPS 60 70%; hemoglobin less than the lower normal limit; corrected calcium greater than 10 mg/dl; lactate dehydrogenase greater than 1.5 times the upper normal limit; metastases in more than one organ (MSKCC criteria). The study had three arms: Torisel alone, IFN-α alone, and Torisel plus IFN-α. Details of the treatment protocol are given in Table Most patients had clear cell RCC (80%) and 67% had undergone nephrectomy. Approximately 80% of patients had a KPS of 60 70%, Table 3.14: Pivotal Phase 3 study of Torisel in the first-line treatment of patients with metastatic renal cell carcinoma Reference Hudes et al. (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356: Study design A three-arm randomized study in 626 patients with previously untreated metastatic RCC and poor prognosis Treatment and dosing Treatment groups: Torisel (n = 209), IFN (n = 207), Torisel + IFN (n = 210) Dosing regimens: Torisel, 25 mg as a 30 minute IV infusion once a week; IFN, 3, 9, and 18 MIU SC three times per week for the first, second, and third week, respectively; patients who could not tolerate 9 or 18 MIU received the maximum tolerated dose; combination treatment: Torisel, 15 mg as a 30 minute IV infusion, once a week,+ IFN, 3 MIU SC three times a week for week 1 and 6 MIU thereafter Endpoints Primary: OS Secondary: PFS, ORR, CBR a, safety Results Median OS: 10.9 (Torisel) vs 7.3 (IFN) vs 8.4 (Torisel/IFN) months ( b HR 0.73; 95% CI ; P = ) Median PFS: 3.8 vs 1.9 vs 3.7 months ( b HR 0.74; 95% CI ; P = ) ORR: 8.6 vs 4.8 vs 8.1% ( b P = ) CBR: 32.1 vs 15.5 vs 28.1% Safety Asthenia was the most common adverse event in patients receiving IFN Significant increase in the incidence of some grade 3/4 adverse events seen with combination treatment, including weight loss, anemia, neutropenia, thrombocytopenia, and mucosal inflammation Conclusion Torisel monotherapy improved OS compared with IFN monotherapy in patients with poor prognosis who have not received any prior systemic treatment; the combination of Torisel and IFN does not improve survival further, however a Defined as the proportion of patients with stable disease for at least 24 weeks or an objective response b From EMA and FDA summaries of product characteristics for Torisel Abbreviations: CBR, clinical benefit rate; CI, confidence interval; HR, hazard ratio; IFN, interferon-α; IV, intravenous; MIU, million international units; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma; SC, subcutaneous for both physicians and patients. However, this may become less attractive in the future as coinsurances are instituted for IV therapies across payors Increasing presence of specialty pharmacy Use of specialty pharmacies has been common practice for infused oncologics, largely because of the educational needs (i.e., for patients, nurses, practice managers, and physicians), and the administration and monitoring requirements for such drugs. The requirement for specialty pharmacy inclusion is now becoming a concern for manufacturers of oral agents, as some payors are requiring the use of specialty pharmacies for dispensing of oral as well as infused oncologics. Given the increasing prevalence of cancer and with specialty pharmacies moving in-house, reliance on specialty pharmacy to manage oncology as a whole will increase (i.e., way to cut costs). With large volumes of distribution and the ability to develop compliance programs, specialty pharmacies are able to negotiate lower product costs and higher product rebates based on market share or volume with manufacturers. In the near future, especially with increasing competition, manufacturers will need to develop programs with specialty pharmacies and provide cost reductions to ensure widespread use of their products. PRMA Strategic Insight 4xii Given the increasing prevalence of cancer and with specialty pharmacies moving in-house specialty pharmacies as a way to cut costs), the payor community is changing, which is likely to push manufacturers to develop programs with specialty pharmacies and provide cost reductions to ensure widespread use of their drugs Increase in service contracts among oncology drug manufacturers Historically, service contracts have been negotiated with manufacturers of growth-colonycontracting in oncology is currently limited, there is some evidence of service contracting, but products that are not under a traditional rebate contract, as a means to expand their pharmacy business and to achieve revenue from manufacturers in therapeutic areas where contracting is rare. Examples of such service contracts are direct-mail compliance and persistence programs This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions. 107 This report is a licensed product and is not to be reproduced or photocopied without the appropriate permissions. prma insights

10 8 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

11 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 info@prmainsights.com prma insights

12 Order form PRMA Consulting Pricing, reimbursement, and market access p I would like to order PRMA Insights Focus: Pricing and Reimbursement Success in Renal Cell Carcinoma $59,000 global user license* (unlimited use within entire organization; includes 2013 Supplement) *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 info@prmaconsulting.com Invoice payment terms: 30 days For more information about PRMA Insights and to see all the titles in the series, visit info@prmaconsulting.com Tel (UK): +44 (0) Tel (US):

13 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

14 PRMA Insights: Pricing and Reimbursement Success in Renal Cell Carcinoma 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. The 2013 supplement to this report summarizes and critically analyzes the consequences of recent changes, providing a completely up-to-date view of the current payor and treatment landscapes supplement

15 Pricing and reimbursement success Achieving market access 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 this is changing, and careful, strategic planning, from as early as Phase 2. PRMA Insights: the Roadmap to Pricing and Reimbursement Success in Renal Cell Carcinoma provides a comprehensive analysis of the market access landscape and the key issues that influence payors decisions. The 2013 supplement to this report summarizes and critically analyzes the consequence of recent changes, providing a completely up-to-date view of the current payor and treatment landscapes. Critical analysis of HTA and reimbursement decisions relating to Votrient and Inlyta, and the factors that influenced these decisions The current market dynamic and how this is changing Analysis of the clinical trial design and results for tivozanib, and learnings for manufacturers of other products Products in development and approaching launch Changes to treatment guidelines Changes to the US landscape Summary of changes to processes and systems across the EU major five markets, with critical insight into the likely future reimbursement landscape. PRMA Strategic Insight As in all our reports, the analysis is supported by PRMA strategic insights: critical advice to manufacturers in planning their market access strategy, developed by our cross-functional team. For more information about the PRMA Insights series, and to download the brochure for the full resource, visit

16 Table of contents for 2013 supplement The table of contents for the full resource can be downloaded from Executive summary PRMA Strategic insights 1 P&R landscape changes 1.1 US 1.2 UK 1.3 France 1.4 Germany 1.5 Spain 1.6 Italy 1.7 Japan 2 Currently approved therapies 3 Updates on existing therapies 3.1 Votrient Pivotal trial results: VEG COMPARZ and PISCES trials NICE SMC France 4 Newly approved therapies 4.1 Inlyta Regulatory indications Pivotal trial results: AXIS NICE SMC France Germany 4.2 Tivozanib Learnings from FDA rejection Pivotal trial results: TIVO-1 5 US reimbursement update 5.1 Medicaid 5.2 Comparative effectiveness research 5.3 Formulary updates 5.4 Coverage policies for biologics differ between MCOs 6 Updates to clinical guidelines 7 Products in development 7.1 Dovitinib 7.3 Cabozantinib 7.4 BMS Immunotherapy Appendix: summary of market access landscapes US UK France Germany Spain Italy Japan Pricing and ordering Pricing and Reimbursement Success in Renal Cell Carcinoma Supplement $20,000 Full resource $59,000 Combined $59,000 To order, or for more information, call +44 (0) or info@prmainsights.com prma insights

17 PRMA Consulting has rapidly become established as a leading consultancy specializing in: pricing, reimbursement, and market access health economics and outcomes research licensing due diligence. Our clients include leading pharmaceutical companies, biotechnology, medical device, and diagnostic companies, and venture capital and private equity firms. We work in close collaboration with our clients to develop integrated strategic, commercial, and technical-based solutions that overcome global, national, and local market access hurdles. Projects are executed to the highest standard, on time and to budget, whilst delivering flexibility and adaptability in recognition of changing situations and needs. Our 70-strong consulting team has expertise across all aspects of P&R, health outcomes, and market access in the major and key emerging markets, further supported by a network of specialists and national and international key opinion leaders. This enables us to deliver truly innovative and strategic recommendations for the most challenging market access problems. For further details, visit PRMA Consulting host webinars around the topics discussed in this resource. We also attend a range of international conferences, where you can view other titles in the series and discuss the resources with the team and how they can help you in planning your market access strategies. For more information visit info@prmainsights.com Tel (UK): +44 (0) Tel (US): +1 (415)