1. The new EU pharma legislation: who came out ahead? Generics or innovators? 6 th European Biotechnology Symposium, Copenhagen 13-15 November 2005 Linda Horton, JD, LLM Hogan & Hartson L.L.P. Brussels and Washington, DC Linda Horton, JD, LLM Hogan & Hartson L.L.P. Brussels and Washington, DC

2. Description of our session The new European pharmaceutical legislation enacted in 2004 included landmark provisions on regulatory data protection, generic drugs, and "biosimilars." Many issues are still being worked out in the new legislation, and there are many questions about the level of data needed to show comparability. Meanwhile, legislative changes are affected by legal challenges in the EU courts such as the Omnitrop case. Member States are required to implement the new laws this month. The new European pharmaceutical legislation enacted in 2004 included landmark provisions on regulatory data protection, generic drugs, and "biosimilars." Many issues are still being worked out in the new legislation, and there are many questions about the level of data needed to show comparability. Meanwhile, legislative changes are affected by legal challenges in the EU courts such as the Omnitrop case. Member States are required to implement the new laws this month.

3. Overview Relationship between regulatory exclusivity law and patent law Landmarks in Development of EU Medicinal Products Law relevant to topic Generics provisions Bolar provisions Biosimilar provisions Relationship between regulatory exclusivity law and patent law Landmarks in Development of EU Medicinal Products Law relevant to topic Generics provisions Bolar provisions Biosimilar provisions

4. Relationship of regulatory exclusivity law to patent law Both types designed to create incentives to innovation. Patent law provides a period of legal monopoly (20 years) in exchange for disclosure of the invention. Essence of a patent is the right to exclude others Both types designed to create incentives to innovation. Patent law provides a period of legal monopoly (20 years) in exchange for disclosure of the invention. Essence of a patent is the right to exclude others

5. Relationship of regulatory exclusivity law to patent law Regulatory exclusivity is a separate area of innovator protections recognizing: The extraordinary expense involved in testing new products Not all significant discoveries are patentable Established in EU and U.S. laws Established in trade agreements providing separate innovator protections: patents & exclusivity. Not to be confused with “data protection” under EU privacy law Regulatory exclusivity is a separate area of innovator protections recognizing: The extraordinary expense involved in testing new products Not all significant discoveries are patentable Established in EU and U.S. laws Established in trade agreements providing separate innovator protections: patents & exclusivity. Not to be confused with “data protection” under EU privacy law

6. Exclusivity: types With data exclusivity, there can be neither disclosure of regulatory data to a competitor nor regulatory reliance upon the data. However, unless a patent blocks the way, a competitor can reach the market by generating his own data on his version of the drug (“testing his way to market”). With marketing exclusivity, agency cannot allow a competing product to enter the market during a time period in which an innovator has a right of exclusivity Competitor cannot generate own data to get around the exclusivity With data exclusivity, there can be neither disclosure of regulatory data to a competitor nor regulatory reliance upon the data. However, unless a patent blocks the way, a competitor can reach the market by generating his own data on his version of the drug (“testing his way to market”). With marketing exclusivity, agency cannot allow a competing product to enter the market during a time period in which an innovator has a right of exclusivity Competitor cannot generate own data to get around the exclusivity

7. Landmarks in Development of EU Medicinal Products Law First European Community medicines law, Directive 65/65 Established framework requirements for authorization of medicinal products As amended in 1987: “The applicant shall not be required to provide the results of pharmacological and toxicological tests or the results of clinical trials if he can demonstrate…either that the medicinal product is ‘substantially similar’ to a product authorized in the country concerned...or by detailed references to published scientific literature… First European Community medicines law, Directive 65/65 Established framework requirements for authorization of medicinal products As amended in 1987: “The applicant shall not be required to provide the results of pharmacological and toxicological tests or the results of clinical trials if he can demonstrate…either that the medicinal product is ‘substantially similar’ to a product authorized in the country concerned...or by detailed references to published scientific literature… 1965 For Reference

8. Landmarks in Development of EU Medicinal Products Law …or that the medicinal product is essentially similar to a product which has been authorized within the Community, in accordance with Community provisions in force, for not less than six years and is marketed in the Member State for which the application is made; this period shall be extended to 10 years in the case of high-technology medicinal products …furthermore, a Member State may also extend this period to 10 years by a single decision covering all the products marketed on its territory where it considers this necessary in the interests of public health.” 1987 For Reference

9. Under 65/65 as amended, Member States were at liberty not to apply the six-year period past the date of expiry of a patent. 1768/92:Supplementary protection certificates (re patent term restoration up to 5 years, extending ordinary patent term of 20 years) Under 65/65 as amended, Member States were at liberty not to apply the six-year period past the date of expiry of a patent. 1768/92:Supplementary protection certificates (re patent term restoration up to 5 years, extending ordinary patent term of 20 years) 1992 Landmarks in Development of EU Medicinal Products Law For Reference

10. World Trade Organization Agreement on Trade- Related Intellectual Property Rights Article 39.3 protection for undisclosed data, including trade secrets World Trade Organization Agreement on Trade- Related Intellectual Property Rights Article 39.3 protection for undisclosed data, including trade secrets 1993 Landmarks in Development of EU Medicinal Products Law For Reference

11. Regulation establishing the European Agency for the Evaluation of Medicinal Products (EMEA) 10 years of exclusivity for centrally authorised products. Regulation establishing the European Agency for the Evaluation of Medicinal Products (EMEA) 10 years of exclusivity for centrally authorised products. 1993 Landmarks in Development of EU Medicinal Products Law For Reference

12. Orphan Medicinal Products Regulation141/2000 The first product to obtain an approval in the EU blocks for 10 years any existing marketing authorization for the “same therapeutic indication” in respect of a “similar medicinal product.” Unchanged by 2004 legislation Commission Regulation (EC) No. 847/2000. "similar medicinal product" and "clinical superiority" Orphan Medicinal Products Regulation141/2000 The first product to obtain an approval in the EU blocks for 10 years any existing marketing authorization for the “same therapeutic indication” in respect of a “similar medicinal product.” Unchanged by 2004 legislation Commission Regulation (EC) No. 847/2000. "similar medicinal product" and "clinical superiority" 2000 Landmarks in Development of EU Medicinal Products Law For Reference

13. In 2000, the WTO issued a panel report deciding on a challenge by the European Union (EU) vs. Canada to Canadian “Bolar” law. The WTO Panel concluded that Canada's law is a "limited exception" within the meaning of TRIPS Article 30 “[a]s long as the exception is confined to conduct needed to comply with the requirements of the regulatory approval process.” In 2000, the WTO issued a panel report deciding on a challenge by the European Union (EU) vs. Canada to Canadian “Bolar” law. The WTO Panel concluded that Canada's law is a "limited exception" within the meaning of TRIPS Article 30 “[a]s long as the exception is confined to conduct needed to comply with the requirements of the regulatory approval process.” 2000 Landmarks in Development of EU Medicinal Products Law For Reference

14. Community Code on Medicinal Products 2001/83: Human Use Directive codification of 65/65, 78/318, 75/319, 89/342, 89/341, 89/381, 92/25, 92/26, 92/27, 92/28, and 92/73 July 2001: Start of Review Process leading to legislation published April 30, 2004 Commission proposal: harmonise to 10 + 1 Community Code on Medicinal Products 2001/83: Human Use Directive codification of 65/65, 78/318, 75/319, 89/342, 89/341, 89/381, 92/25, 92/26, 92/27, 92/28, and 92/73 July 2001: Start of Review Process leading to legislation published April 30, 2004 Commission proposal: harmonise to 10 + 1 2001 For Reference Landmarks in Development of EU Medicinal Products Law

15. 2003/63:New Annex 1 to Directive 2001/83 (ICH Common Technical Document; different requirements for biologics) December 2003: EMEA CPMP Guidance documents on comparability 2003/63:New Annex 1 to Directive 2001/83 (ICH Common Technical Document; different requirements for biologics) December 2003: EMEA CPMP Guidance documents on comparability 2003 For Reference Landmarks in Development of EU Medicinal Products Law

16. The challenge to legislators Striking the balance between innovator rights, and generic opportunities, was one of the most contentious issues in the development of the recently enacted EU medicines legislation.

17. Exclusivity Provisions In the new Pharmaceuticals Legislation

18. Data Exclusivity before amendments centrally approved products and concertation products: 10 years nationally approved products: 10 years: Belgium, Germany, France, Italy, Netherlands, Sweden, the UK, and Luxembourg 6 years: Austria, Denmark, Finland, Ireland, Portugal, Spain, Greece (also Norway, Iceland) centrally approved products and concertation products: 10 years nationally approved products: 10 years: Belgium, Germany, France, Italy, Netherlands, Sweden, the UK, and Luxembourg 6 years: Austria, Denmark, Finland, Ireland, Portugal, Spain, Greece (also Norway, Iceland)

19. Data Exclusivity Changes Future System “8+2+1” 8 years data exclusivity: no generic applications fileable 2 years marketing protection: no generic applications approvable + 1 year: new indication(s) if it constitutes a significant clinical benefit For all products, regardless of nationally, via central or decentralized approval procedure Not retroactive; does not affect exclusivity periods for products authorized before effective date 8 years data exclusivity: no generic applications fileable 2 years marketing protection: no generic applications approvable + 1 year: new indication(s) if it constitutes a significant clinical benefit For all products, regardless of nationally, via central or decentralized approval procedure Not retroactive; does not affect exclusivity periods for products authorized before effective date

20. Other Exclusivity Provisions 1 year data exclusivity for a new indication for a well-established substance 1 year data exclusivity for change of the classification Orphan drug exclusivity unchanged New pediatric exclusivity under consideration 1 year data exclusivity for a new indication for a well-established substance 1 year data exclusivity for change of the classification Orphan drug exclusivity unchanged New pediatric exclusivity under consideration

21. U.S. Exclusivity Periods In the U.S. there is a: 5 year data exclusivity period for a new chemical entity, 3 year data exclusivity period for a new indication, 6 month data exclusivity period for pediatric indications as well as a 7 year marketing exclusivity period for a drug that FDA has designated as an orphan drug. In the U.S. there is a: 5 year data exclusivity period for a new chemical entity, 3 year data exclusivity period for a new indication, 6 month data exclusivity period for pediatric indications as well as a 7 year marketing exclusivity period for a drug that FDA has designated as an orphan drug.

22. U.S. Patent Term Restoration In addition to exclusivity periods, under the 1984 Hatch-Waxman Act, pharmaceutical patent owners are granted patent term restoration to restore part of the loss of potential patent life due to the need to develop, test, and seek regulatory approval of the product (35 USC 156). A company can get both patent term restoration and exclusivity. In addition to exclusivity periods, under the 1984 Hatch-Waxman Act, pharmaceutical patent owners are granted patent term restoration to restore part of the loss of potential patent life due to the need to develop, test, and seek regulatory approval of the product (35 USC 156). A company can get both patent term restoration and exclusivity.

23. Bolar provision In the new EU pharmaceuticals legislation

24. Art. 10 (5) – Bolar Provision “ Conducting the necessary studies and trials with a view to the application of paragraphs 1, 2, 3 and 4 to a generic medicinal product and the consequential practical requirements shall not be regarded as contrary to patent rights or to supplementary protection certificates for those medicinal products.” Providing samples is included in permissible activities Otherwise, patent law is unchanged. “ Conducting the necessary studies and trials with a view to the application of paragraphs 1, 2, 3 and 4 to a generic medicinal product and the consequential practical requirements shall not be regarded as contrary to patent rights or to supplementary protection certificates for those medicinal products.” Providing samples is included in permissible activities Otherwise, patent law is unchanged.

25. Why is this called “Bolar” provision? In Roche Products, Inc. v. Bolar Pharmaceutical Co. 733 F. 2nd 858, certiorari denied 469 U.S. 856 (1984), the court of appeals held that U.S. patent law was violated when a generic company (Bolar) tested its product against that of the pioneer (Roche) during the patent life of the latter’s pioneer product.

26. Hatch Waxman reversed court decision Subsequently, as part of the 1984 Hatch-Waxman law, the holding of the Bolar case was reversed in a provision dubbed the “Bolar” provision, 35 USC 271 (e)(1), which reads in part: It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention... solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products. Subsequently, as part of the 1984 Hatch-Waxman law, the holding of the Bolar case was reversed in a provision dubbed the “Bolar” provision, 35 USC 271 (e)(1), which reads in part: It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention... solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

27. In 2000, the WTO issued a panel report deciding on a challenge by the European Union (EU) vs. Canada to Canadian “extended Bolar” law which went beyond regulatory testing and allowed stockpiling. The WTO Panel concluded that Canada's law is a "limited exception" within the meaning of TRIPS Article 30 “[a]s long as the exception is confined to conduct needed to comply with the requirements of the regulatory approval process.” In 2000, the WTO issued a panel report deciding on a challenge by the European Union (EU) vs. Canada to Canadian “extended Bolar” law which went beyond regulatory testing and allowed stockpiling. The WTO Panel concluded that Canada's law is a "limited exception" within the meaning of TRIPS Article 30 “[a]s long as the exception is confined to conduct needed to comply with the requirements of the regulatory approval process.” 2000 The WTO Case, EU v. Canada, has a bearing on today’s EU Bolar provision For Reference

28. What the WTO said... Even though regulatory approval processes may require substantial amounts of test production to demonstrate reliable manufacturing, the patent owner's rights themselves are not impaired any further by the size of such production runs, as long as they are solely for regulatory purposes and no commercial use is made of resulting final products.

29. Stockpiling not “ small and narrowly bounded.” The WTO Panel concluded that the stockpiling exception in Canada’s law “constitutes a substantial curtailment of the exclusionary rights required to be granted to patent owners under Article 28.1 of the TRIPS Agreement….and cannot be considered a "limited exception" within the meaning of Article 30 of the Agreement.”

30. No stockpiling & no sale of drugs During the patent life of the pioneer drug, the generic competitor is allowed to make the drug only for regulatory review purposes: Stockpiling is not allowed. Selling drugs made during patent term is not allowed. During the patent life of the pioneer drug, the generic competitor is allowed to make the drug only for regulatory review purposes: Stockpiling is not allowed. Selling drugs made during patent term is not allowed.

31. Bolar provisions an exception to normal patent law A Bolar provision allows a generic product producer, during the patent life of the pioneer’s drug, to conduct certain testing of the generic product against the pioneer’s drug as needed to secure regulatory approval—but not to produce commercial quantities or fill the pipeline. Following the WTO case, the EU decided to switch sides on Bolar. The innovative industry hoped this was tied to “10+1” on exclusivity The 10 new prospective EU members expressed views! A Bolar provision allows a generic product producer, during the patent life of the pioneer’s drug, to conduct certain testing of the generic product against the pioneer’s drug as needed to secure regulatory approval—but not to produce commercial quantities or fill the pipeline. Following the WTO case, the EU decided to switch sides on Bolar. The innovative industry hoped this was tied to “10+1” on exclusivity The 10 new prospective EU members expressed views!

32. “Generics” provisions In new EU pharmaceuticals legislation

33. Amendments to the Community Code Directive: “generic medicinal product” Art. 10 (2) (b) “generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. … Art. 10 (2) (b) “generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. … For Reference

34. . Amendments to the Community Code Directive: “generic medicinal product” …The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of an authorised active substance must be supplied by the applicant. The various immediate- release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form. Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines.

35. “Generic medicinal product” can include all different salts, esters, ethers, isomers, etc. provided there is not a different safety or efficacy profile states that all immediate release oral forms are the same Refers to “global marketing authorization” (Art. 6 (1)). “Generic medicinal product” can include all different salts, esters, ethers, isomers, etc. provided there is not a different safety or efficacy profile states that all immediate release oral forms are the same Refers to “global marketing authorization” (Art. 6 (1)). Differences from Generics Case C-368/96 (European Court of Justice)

36. Abridged applications (for generic medicinal products) Reference product need not be approved in the Member State of application Member State agencies are expected to cooperate and share dossiers if necessary Bioavailability requirements are less strict “global marketing authorisation” concept to prevent innovators from “evergreening” their products with changes Effect: little reward to innovators for product improvements Reference product need not be approved in the Member State of application Member State agencies are expected to cooperate and share dossiers if necessary Bioavailability requirements are less strict “global marketing authorisation” concept to prevent innovators from “evergreening” their products with changes Effect: little reward to innovators for product improvements

37. Biosimilar provisions In new EU pharmaceuticals legislation

38. Why different from chemical drugs as to follow-on products For chemical drugs that can be exactly copied, the product is not so process-dependent, and copies can be produced through reverse engineering, good chemistry, tight specifications, and Good Manufacturing Practices for day-to-day consistency in actual production. For biological drugs, there are always differences among different manufacturers’ products, and “the process is the product, and the product is the process.” For chemical drugs that can be exactly copied, the product is not so process-dependent, and copies can be produced through reverse engineering, good chemistry, tight specifications, and Good Manufacturing Practices for day-to-day consistency in actual production. For biological drugs, there are always differences among different manufacturers’ products, and “the process is the product, and the product is the process.”

39. Biosimilars under EU Medicines Law “Biosimilars” are products that cannot meet the criteria for “generics,” generally because they are large- molecule proteins and one cannot be sure they are sufficiently close to the originator’s product. First EU regulatory pathway for biosimilars: June 2003 Commission Directive (2003/63/EC) amending the Community code on medicinal products establishing a new Annex on the required contents of an Application for Marketing Authorization. Article 4 of the revised Annex I, Part II, set forth the specific marketing authorization dossier requirements for “similar biological medicinal products.” “Biosimilars” are products that cannot meet the criteria for “generics,” generally because they are large- molecule proteins and one cannot be sure they are sufficiently close to the originator’s product. First EU regulatory pathway for biosimilars: June 2003 Commission Directive (2003/63/EC) amending the Community code on medicinal products establishing a new Annex on the required contents of an Application for Marketing Authorization. Article 4 of the revised Annex I, Part II, set forth the specific marketing authorization dossier requirements for “similar biological medicinal products.”

40. Biosimilars under EU Medicines Law 2 guidance documents were published in December 2003 by the key EMA committee responsible for product assessments, now called the Committee on Human Medicinal Products (CHMP). The new 2004 medicines legislation, amending the Community code on medicinal products for human use (Directive 2004/27/EC), continues and codifies this prior law. 2 guidance documents were published in December 2003 by the key EMA committee responsible for product assessments, now called the Committee on Human Medicinal Products (CHMP). The new 2004 medicines legislation, amending the Community code on medicinal products for human use (Directive 2004/27/EC), continues and codifies this prior law.

41. Biosimilars: Article 10.4 of the directive “Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. …

42. Biosimilars: Article 10.4 of the directive …The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I and the related detailed guidelines. The results of other tests and trials from the reference medicinal product’s dossier shall not be provided.”

43. Biosimilars under EU Medicines Law : continued Also various guidelines under the International Conference on Harmonization (ICH) are recognized by the EMEA March 2005 guidance from the EMEA on quality issues in biotech- derived biosimilars Also various guidelines under the International Conference on Harmonization (ICH) are recognized by the EMEA March 2005 guidance from the EMEA on quality issues in biotech- derived biosimilars

44. Biosimilars The European Commission has announced that the European Medicines Agency (EMEA) will be the only approval authority for biosimilars. Many, many details remain to be worked out: Guidance documents, beyond the 2 December 2003 guidance documents, such as product-class guidelines. Litigation (Omnitrop case in European Court of First Instance; and now a similar case in the U.S.!). In individual approvals? In both the EU and the U.S, there is more transparency for stakeholders where a public process and guidance documents are used (compared with approval process). The European Commission has announced that the European Medicines Agency (EMEA) will be the only approval authority for biosimilars. Many, many details remain to be worked out: Guidance documents, beyond the 2 December 2003 guidance documents, such as product-class guidelines. Litigation (Omnitrop case in European Court of First Instance; and now a similar case in the U.S.!). In individual approvals? In both the EU and the U.S, there is more transparency for stakeholders where a public process and guidance documents are used (compared with approval process).

45. What are the EMEA Guidelines? On May 16, 2005, the European Medicines Agency (EMEA) issued a final guideline describing general principles for clinical and non-clinical issues involved in the approval of similar biological medicinal products (biosimilars). The guideline is accompanied by 4 annexes providing more targeted guidance on approval requirements for these recombinant proteins: Erythropoietin (EPO), Granulocyte-colony stimulating factor (GCSF), Insulin, and Somatropin, i.e., human growth hormone (HGH). On May 16, 2005, the European Medicines Agency (EMEA) issued a final guideline describing general principles for clinical and non-clinical issues involved in the approval of similar biological medicinal products (biosimilars). The guideline is accompanied by 4 annexes providing more targeted guidance on approval requirements for these recombinant proteins: Erythropoietin (EPO), Granulocyte-colony stimulating factor (GCSF), Insulin, and Somatropin, i.e., human growth hormone (HGH).

46. What Do the Guidelines Say? (1) Require full quality dossier, extensive non-clinical and clinical studies, immunogenicity studies, ‘extensive’ comparability, comparative pharmacokinetics. For clinical safety and pharmacovigilance requirements, the guideline distinguishes: pre-approval phase: safety data from preauthorization studies, from the post-approval phase: close monitoring of the product. Require full quality dossier, extensive non-clinical and clinical studies, immunogenicity studies, ‘extensive’ comparability, comparative pharmacokinetics. For clinical safety and pharmacovigilance requirements, the guideline distinguishes: pre-approval phase: safety data from preauthorization studies, from the post-approval phase: close monitoring of the product.

47. What Do the Guidelines Say? (2) The applicant should include in the application: a "risk specification" (describing possible safety issues due to the manufacturing process being different from that of the innovator), a pharmacovigilance plan in accord with EU legislation/guidelines. The EMEA warns that compliance will be strictly monitored Penalties regulation in preparation in case of non- compliance =>Hefty requirements, certainly in relation to those for traditional generics The applicant should include in the application: a "risk specification" (describing possible safety issues due to the manufacturing process being different from that of the innovator), a pharmacovigilance plan in accord with EU legislation/guidelines. The EMEA warns that compliance will be strictly monitored Penalties regulation in preparation in case of non- compliance =>Hefty requirements, certainly in relation to those for traditional generics

48. …other points to note Each application will be handled on a case-by- case basis. Each biosimilar applicant must justify the approach taken and is encouraged to seek early discussions with the EMEA. The same reference product should be used for all aspects of the application (quality, safety, and efficacy). The EMEA recommends use, in the required clinical trials, of the test product produced with the final manufacturing process. Each application will be handled on a case-by- case basis. Each biosimilar applicant must justify the approach taken and is encouraged to seek early discussions with the EMEA. The same reference product should be used for all aspects of the application (quality, safety, and efficacy). The EMEA recommends use, in the required clinical trials, of the test product produced with the final manufacturing process.

49. What do the Guidelines Mean? Europe is serious about getting these biosimilars approved and wants to do so in the short-term. There is political pressure (access to cheaper drugs) as well as scientific pressure Several applications are pending (BioPartners, Sandoz) The guidelines likely represent an amalgamation or compromise of the content of those applications. Europe is serious about getting these biosimilars approved and wants to do so in the short-term. There is political pressure (access to cheaper drugs) as well as scientific pressure Several applications are pending (BioPartners, Sandoz) The guidelines likely represent an amalgamation or compromise of the content of those applications.

50. (Some) Un-answered Questions Data confidentiality : Can the regulators refer to innovator data files, and do they intend to? Safety: is the barrier sufficiently high—particularly if regulators are allowing safety to be shown post-marketing? Comparability: confusion between intra-company and inter-company Will product substitution be allowed? Is patient consent needed where pre-market trials were small? Data confidentiality : Can the regulators refer to innovator data files, and do they intend to? Safety: is the barrier sufficiently high—particularly if regulators are allowing safety to be shown post-marketing? Comparability: confusion between intra-company and inter-company Will product substitution be allowed? Is patient consent needed where pre-market trials were small?

51. And a Few Inconsistencies…. For example, the EPO annex calls for: Safety data from at least 300 patients is adequate in efficacy trials Postmarket reporting will add to this database. The applicant should provide at least 12-months immunogenicity data in biosimilar-treated patients. Retention of samples for both ‘titration’ and ‘maintenance’ studies is recommended. For the detection of anti-epoetin antibodies, a validated, highly sensitive assay should be used. For example, the EPO annex calls for: Safety data from at least 300 patients is adequate in efficacy trials Postmarket reporting will add to this database. The applicant should provide at least 12-months immunogenicity data in biosimilar-treated patients. Retention of samples for both ‘titration’ and ‘maintenance’ studies is recommended. For the detection of anti-epoetin antibodies, a validated, highly sensitive assay should be used.

52. Yet EMEA is proposing to excuse erythropoietin biosimilars from many safety studies that had been carried out by the innovator companies More worrying, the EMEA is requiring testing on just one indication to get all authorized indications! Yet EMEA is proposing to excuse erythropoietin biosimilars from many safety studies that had been carried out by the innovator companies More worrying, the EMEA is requiring testing on just one indication to get all authorized indications!

53. What is going to happen next? The odds are that these guidelines, or something near, will be approved. Comment period open until October 31, 2005. The EMEA is co-sponsoring a workshop in Paris on biosimilars, organized by the Drug Information Association (DIA) and scheduled for December 8 and 9, 2005. The odds are that these guidelines, or something near, will be approved. Comment period open until October 31, 2005. The EMEA is co-sponsoring a workshop in Paris on biosimilars, organized by the Drug Information Association (DIA) and scheduled for December 8 and 9, 2005.

54. Should Innovators Challenge Biosimilar Authorizations? Case-law precedents on “generics” generally pro-generic Will judges understand how biosimilars differ from generics (biosimilars are neither “essentially similar” or the “same”)? Will the clause on intellectual property help? How will judges view regulatory reference to innovator data? How will they view shortcuts based on “what is known” How will it play out when everyone is operating in the dark? Case-law precedents on “generics” generally pro-generic Will judges understand how biosimilars differ from generics (biosimilars are neither “essentially similar” or the “same”)? Will the clause on intellectual property help? How will judges view regulatory reference to innovator data? How will they view shortcuts based on “what is known” How will it play out when everyone is operating in the dark?

55. Biosimilar applicants have not seen the innovator’s reference product dossier Innovators have not seen the biosimilars’ dossiers Regulators do not produce pharmaceuticals, and the dossiers they have in hand present only a subset of the know-how on biotech biological production Reference products were approved long ago; regulatory standards have changed and many changes made in production of the reference product Biosimilar applicants have not seen the innovator’s reference product dossier Innovators have not seen the biosimilars’ dossiers Regulators do not produce pharmaceuticals, and the dossiers they have in hand present only a subset of the know-how on biotech biological production Reference products were approved long ago; regulatory standards have changed and many changes made in production of the reference product

56. Action May Shift Post- Approval Even if products do get approved, questions of price (not likely much lower) reimbursement (which countries will reimburse?), switching (will it be allowed?). Will physicians/ patients perceive biosimilars as less safe? Innovators can be expected to leverage their reputation/ brand/safety data to discourage switching. => Perceptions of safety may play out against price Even if products do get approved, questions of price (not likely much lower) reimbursement (which countries will reimburse?), switching (will it be allowed?). Will physicians/ patients perceive biosimilars as less safe? Innovators can be expected to leverage their reputation/ brand/safety data to discourage switching. => Perceptions of safety may play out against price

57. New Pathway Redundant? Are stringent data requirements for biosimilars, plus risks & uncertainties around post-approval marketing forcing biosimilar firms into developing improved biologics, distinguishable from the original in dosage, convenience, freedom from human serum albumin etc.? Which raises the question: how useful will the new regulatory pathway be after all? Are stringent data requirements for biosimilars, plus risks & uncertainties around post-approval marketing forcing biosimilar firms into developing improved biologics, distinguishable from the original in dosage, convenience, freedom from human serum albumin etc.? Which raises the question: how useful will the new regulatory pathway be after all?

58. US-EU Issue :: Proprietary Data Protected Or Not? May a regulatory reviewer rely on a reference product’s data in reviewing biosimilar application? What about innovator’s trade secret methods or processes? See Genentech Petition to FDA When Pfizer challenged FDA’s approval of a 505(b)(2) application of a recombinant Human Growth Hormone product, FDA informed the court that it had discovered that FDA staff had relied upon Pfizer data in the approval decision and FDA asked for a “time out” to investigate whether any improprieties had occurred May a regulatory reviewer rely on a reference product’s data in reviewing biosimilar application? What about innovator’s trade secret methods or processes? See Genentech Petition to FDA When Pfizer challenged FDA’s approval of a 505(b)(2) application of a recombinant Human Growth Hormone product, FDA informed the court that it had discovered that FDA staff had relied upon Pfizer data in the approval decision and FDA asked for a “time out” to investigate whether any improprieties had occurred

59. Use of Innovators’ data in Regulatory Reviews of Biosimilars? Is Regulatory Reliance on Reference Product Data Allowed in EU? Article 10.4 of the EU community code on medicinal products, as amended: … “The results of other tests and trials from the reference medicinal product’s dossier shall not be provided” Is Regulatory Reliance on Reference Product Data Allowed in EU? Article 10.4 of the EU community code on medicinal products, as amended: … “The results of other tests and trials from the reference medicinal product’s dossier shall not be provided”

60. Right of Reference CONTRAST Article 10c Following the granting of a marketing authorisation, the MAA may allow use to be made of the documentation contained in the file, with a view to examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form WITH Article 10.4 “The results of other tests and trials from the reference medicinal product’s dossier shall not be provided” CONTRAST Article 10c Following the granting of a marketing authorisation, the MAA may allow use to be made of the documentation contained in the file, with a view to examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form WITH Article 10.4 “The results of other tests and trials from the reference medicinal product’s dossier shall not be provided”

61. Concerns with March 2005 EMEA Guidance on Quality The EMEA continues to use “comparability” to describe both intra-company comparability—where the use is proper—and also inter-company comparison—where “similarity” would be better In contrast, the ICH guideline (accepted in the US, Europe and Japan) on comparability deals specifically with comparability in the context of a single manufacturer The EMEA continues to use “comparability” to describe both intra-company comparability—where the use is proper—and also inter-company comparison—where “similarity” would be better In contrast, the ICH guideline (accepted in the US, Europe and Japan) on comparability deals specifically with comparability in the context of a single manufacturer

62. The EU Process Has Been Closed CPMP and EMEA Working Groups meet behind closed doors Who wrote which document? Guideline development: opportunity for comment, but Where are the responses to previous comments? CPMP and EMEA Working Groups meet behind closed doors Who wrote which document? Guideline development: opportunity for comment, but Where are the responses to previous comments?

63. Should people re-comment? No other EMEA public process to date except through conferences sponsored by other organisations 1:1 discussions between biosimilar applicants and CHMP and/or rapporteur Should people re-comment? No other EMEA public process to date except through conferences sponsored by other organisations 1:1 discussions between biosimilar applicants and CHMP and/or rapporteur

64. For further information please contact... Linda R. Horton Partner View Building rue de l'Industrie 26 B-1040 Brussels Belgium Tel: +32.2.505.0931 (Brussels) Tel:+1.202.637.5795 (Washington, DC) Mobile: + 1.202.250.9880 Email: lrhorton@hhlw.com... or visit www.hhlaw.com

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