Outline of Final Report

1. Outline of Final Report • Introduction • Background • Goals • Market covered • Methodology • Desk research • Review literature • Develop interview guide • Conduct telephone interviews • Identify Analogues

2. Outline of Final Report • Individual Results for Italy, France and United Kingdom • Reimbursement Environment • Reimbursement submission and approval process • Assessment of Pricing and Reimbursement challenges • Interview Results • Key learnings • Analogues in each country

3. Outline of Final Report • Recommendations and Conclusions • Key learnings which are a common denominator across markets • Recommendations on how to minimize the risks and maximize the opportunities of optimal pricing and reimbursement for Product X

4. Background • New pharmaceutical approach in the primary treatment of Type 1 Diabetes • A humanized monoclonal antibody that modulates the immune system by acting on T effector cells and/or generating T regulatory cells • Genzyme is interested in evaluating the key pricing and reimbursement issues that this product may face in key European markets

5. Goals • Ascertain the Pricing and Reimbursement challenges for the Product for three major markets in Europe through qualitative interviews • An assessment of the Pricing and Reimbursement challenges for the Product in France, Italy, and United Kingdom • A set of recommendations on how to minimize the risks and maximize the opportunities of optimal pricing for the Product

6. Focus On Key European Countries • France • 1 health economist • 1 • Italy • 1 health economist • 1 current member of the AIFA • United Kingdom • 1 health economist • 1 Clinician specializing in Diabetes

7. Candidate Selection Criteria • Candidates for interviews had to be: • Well informed about formal pricing and reimbursement processes in the targeted country • Possibly involved – either as actual or former decision makers or advisors • Or well informed about drug utilization decisions

8. France

9. Executive summary France With a highly centralised healthcare system, national decisions currently have most impact in France • Price agreements: price is negotiated nationally with the Pricing committee (CEPS) taking into account the prices of drugs in the same class/therapeutic use, improvement in medical benefit over comparators, projected sales volume and any conditions that might be set on usage • Price-volume agreements: theseare often applied to high-cost, innovative products and restrict product sales within agreed and defined parameters. Manufacturers are obliged to give the government rebates if volumes are exceeded* • Generic reference pricing: The use of generics is being strongly encouraged - they currently have a mandatory 30-40% discount to the brand at launch and brands are referenced priced to this level after 1-2 years if generics gain less than 50-60% market share (this could change in the new social security finance law for 2006 ) * NB Rebates can be tiered, with the %age increasing as revenues rise above target

10. Reimbursement EnvironmentFrance • High debts increase the focus on P&R • In order to reduce the overall healthcare spending, a range of reforms and P&R controls have been implemented • Reforms: Patient co-payment, PCP gatekeeper system, Diagnosis-related group (DRG) system to manage hospital healthcare expenditure • P&R controls: volume limitations, reference pricing, taxes and levies

11. Reimbursement EnvironmentFrance • Recent reorganization of the P&R process with 2 new authorities mediating P&R • HAS: evaluates medical benefit of drugs • UNCAM: decides on reimbursement rates within a 10% margin

12. Reimbursement EnvironmentFrance • Transparency Commission (part of HAS) determines the reimbursement level for a drug based on SMR (Service Medical Rendu) and ASMR (Amélioration du SMR) • SMR: based on drugs’ medical benefit • Effectiveness and possible side effects • Drug’s place in the therapeutic process vs alternative therapies • Seriousness of the disease being treated • ASMR: based on therapeutic benefit vs other drugs for same indication • HAS produces recommendations on the rational with conditions for reimbursement

13. The output of the Transparency Commission evaluation is a recommendation on the reimbursement • The Transparency Commission evaluates the benefits of a new compound (SMR: Service Medical Rendu): • 3 levels:

14. I II • Major • therapeutic • advance III Significant improvement in therapeutic and/or reduction in side effects IV Modest improvement in efficacy or safety V Minor improvement No improvement The output of the Transparency Commission evaluation is also a recommendation Medical Added Value (ASMR) of the new compound • ASMR: Improvement of Clinical Benefit versus existing comparators • ASMR: is associated with a specific target population in the therapeutic strategy

15. Pricing Decision In France • Pricing is essentially based on the ASMR rating:

16. Reimbursement EnvironmentFrance • Innovative drugs go through an accelerated P&R setting procedure (dépôt de prix)

17. The idea...

18. The Market Access Process Market Access

19. Key FindingsFrance • Prof de Pouvourville suggested that the company design the trial so even after the end of the phase III trail patients are followed to obtain long term data.  Eventhough this information will not be able at time of filing it is good to include this in the submission to show that the company is committed to prove their assumption about the effect of the product long term is true.

20. Italy

21. Executive summary Italy Regional and hospital controls pose the greatest challenge in Italy • Generic (reference) pricing: only exists for generic and off-patent products. Products are grouped by active ingredient. Generics (and biosimilars) have to be priced 20% below the originator • Budgetary controls/restrictions on reimbursement: Regional health authorities, ASLs and hospitals are all responsible for budgets and may use formularies/guidelines to restrict usage. The national pricing committee (AIFA) can limit reimbursed indications through prescribing guidelines (Note) and can limit where a product is used by designating Class A (ambulatory) or Class H (hospital-only) status • Health technology assessment: AIFA require a pharmacoeconomic submission for all new products, however budget impact is of greater interest • Prices are negotiated at national level: Manufacturers have to enter new negotiation for extensions of indication (this will be important for denosumab)

22. Reimbursement EnvironmentItaly • Italian healthcare system racked by debt makes it very difficult for drug companies to generate profit • Italy has one of the lowest expenditures suggesting the Italian healthcare system is cost efficient • Although, drug spending accounts for a higher percentage of overall healthcare spending in Italy compared with the seven major markets (EU5, US and Japan)

23. Reimbursement EnvironmentItaly • To contain drug expenditure, Italy uses a wide range of P&R tools • Charges, co-payments, reimbursement restrictions, prescription limitations, reference pricing • The key centralized healthcare stakeholder is AIFA (Agenzia Italiana del Farmaco) aimed to reform the way drugs are approved, priced and reimbursed

24. Reimbursement EnvironmentItaly • AIFA determines the reimbursement levels depending on the degree of therapeutic advantage a drug confers • Cost effectiveness analysis (CEA) is playing an increasingly prominent role in Italian P&R and is part of the evaluation process. • CEA takes into account • The reference price for the therapeutic drug class • The cost of a defined daily dose (DDD) for drugs with the same threapeutic indication.

25. Reimbursement EnvironmentItaly • Although there is a formalized reimbursement structure, reimbursement is based on negotiations • Drugs are group into classes to determine reimbursement levels • A: totally reimbursed • C: not reimbursed but still subject to cost containment pressures • H: reimbursed but only in hospitals • LOUISE (need to add or not on the complex reimbursement issues of class C? See p.117 of Datamonitor Presentation)

26. Reimbursement EnvironmentItaly • Schemes have been put in place to restrict government’s exposure to expensive drug payment (e.g., Avastin - oncology monoclonal antibody) • Risk-sharing agreements have been introduced for expensive therapies or drugs requiring greater levels of proof of cost effectiveness (e.g., Antares - rheumatoid arthritis)

27. United Kingdom

28. United Kingdom Executive summary Health technology assessments will be the central issue driving uptake in the United Kingdom • Health technology assessments: NICE (England only) regularly conduct health technology assessments of selected products and therapeutic areas. Products are chosen on the basis of clinical importance and expected cost per patient/budget impact. The SMC (Scottish Medicines Consortium) review all new products at launch and a negative opinion will block use in Scotland. A positive review from both agencies is essential for Amen product uptake but does not guarantee it • Budgetary controls: budgets are strictly controlled at local level through PCTs (Primary Care Trusts) who are responsible for budgets for both primary and secondary care. Health authorities have a duty to provide resources to allow implementation of positive NICE guidance but up take still depends on individual prescribers and varies widely • Restrictions on reimbursement: guidance from HTA bodies such as NICE may restrict usage to patient sub-populations. This guidance can be further restricted at local level through formularies and protocols

29. Reimbursement EnvironmentUnited Kingdom • Wide range of trusts and authorities are involved in United Kingdom healthcare provision, making it a fragmented market with a number of P&R stakeholders • Primary Care Trusts (PCTs) are the key stakeholders • NHS is increasingly focused on evidence-based medicine and utilizing pharmacoeconomics (PE) to justify formulary access

30. Reimbursement EnvironmentUnited Kingdom • A modernization program of the NHS adopted back in 2000 will impact P&R • Increase decentralization of healthcare provision and budgeting towards PCTs • Change the prescription dynamics by allowing “specialist” GPs such as nurse and pharmacist prescribers prescribe any licensed drug • Renew the focus on disease prevention boosted by the evolving role of community pharmacists who are monitoring patients and compliance • National Service Frameworks (NSFs) initiatives established to set guidelines for treating specific diseases such as diabetes

31. Reimbursement EnvironmentUnited Kingdom • NICE is responsible for producing evidence-based guidelines that include significant PE analysis • Quality-adjusted Life Years (QALYs) form the basis of NICE’s PE analysis to determine the value of treatments with a limit of £30,000/QALY to classify a drug as cost effective • Broadly speaking, Europe is prepared to spend less per QALY than the US

32. Reimbursement EnvironmentUnited Kingdom • Compared with the rest of Europe, the P&R environment in the United Kingdom is relatively non-restrictive with few direct pricing controls. • Unlike many other European countries, there is no system whereby a drug price is set and then reimbursement re-negociated

33. Reimbursement EnvironmentUnited Kingdom • Pharmaceutical Price Regulation Scheme (PPRS) is the principal method of governmental P&R regulation in the United Kingdom • The PPRS is a profit control system based on a drug manufacturer’s return on capital employed (ROCE) and not to exceed a profit level of 21%

34. United Kingdom pricing and reimbursement process Regulatory approval Apply to DoH for price Dept of health 4 weeks later Price agreed Launch Prices maintained unless modified in PPRS If no NICE review 3 months post launch submit to SMC PCTs budget holders allow prescribers Possible NICE HTA review At any time +/- NICE guidance 12 to 13 months for HTA desision NICE STA review Possible NICE guidance 1-3 years for guideline decision 6 month process for decision

35. Recommendations and Conclusions

36. Conclusion • European P&R is a difficult environment to generate a strong ROI • European market is complex and the P&R environment is continually changing • Drug companies need to understand the market, track it and maintain a market presence • Most P&R governmental bodies take considerable time to assess a drug • Drug companies should enter into greater dialogue with the P&R bodies to make sure the data submitted answer all the questions raised by these bodies

37. Conclusion • Regulators and P&R bodies have different goals • Data submitted to the regulator and the P&R body must be different • Regulators need safety and efficacy clinical data and can accept surrogate endpoint data • P&R bodies need longer-term data showing effectiveness in a real-world setting that demonstrate improved efficacy • Head-to-head studies with the gold standard • Demonstration of non-inferiority • Studies that does not include placebo-controlled data (don’t get this one???)

38. Conclusion • Most European Healthcare Government bodies are focusing on cost containment and therefore to secure strong pricing and reimbursement, new drugs need to be qualified as “innovation” • Innovation can be defined by a number of parameters: • Releasing other health care resources • Improving quality and duration of life • Reducing drug-interaction problems • Improving safety • Tolerability and side-effect profile • Improving patients’ convenience

39. Conclusion • PE analysis has a relatively low profile in France and an increasingly high profile in Italy and particularly in the United Kingdom • Different types of analysis should be submitted to different P&R bodies • Health economics, PE analysis at national level (e.g. NICE) • Budget impact analysis at the local level (e.g. PCTs)

40. Conclusion • To optimize the European markets’ P&R level, drug companies need • Negotiation skills and open communication with a strong, clear central message with P&R bodies • Clear P&R strategy depending on the drug’s characteristics • Integrate P&R analysis into the clinical trial process • Understand the payers’ needs in terms of data - tailored to specific countries • Determine the optimal launch sequence across Europe • Historically United Kingdom and Germany have been viewed as the optimal markets to launch in because of the relatively free pricing and the immediate reimbursement

41. IMPORTANT NOTES • Visibility of drugs companies and their drugs is restricted in France as it is in much of Europe • DTC is not allowed • Number of restrictions limit the effectiveness of sales forces and physician contact is reduced • Taxation used to restrict promotional spending totaling less than 6.5% of revenue

42. QUESTIONSPAYER PERSPECTIVE • From a payer perspective, who are the comparators for product x? On pricing? On efficacy? • How might this situation change with new entrants? • What restrictions could be put into place for Product X? • How could product x be differentiated from competitors? • What are potential consequences for patients if payers do not fund product x post-launch?

43. QUESTIONSGHE PLANNING • What are the competing priorities between the EU and US in terms of GHE planning and how should they be addressed (e.g. subgroup trials and outcomes)? • What are important endpoints for product x? • What contingencies should GHE be prepared to face during development of product x?

44. Reference Pricing: Europe • European Reference Prices • Germany • United Kingdom • Spain • Italy • Analysis of prices and expected volumes

45. Cost Containment Savings in Key European markets