Data and marketing exclusivity for pharmaceuticals in the European Community

Food and Drug Law Journal

Volumn 55, Issue 2, 2000, Pages 209-223

  Kingham, Richard F ^a   Castle, Grant H ^a  

^a Department of International Practice   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ORPHAN DRUG; DRUG;

DRUG INDUSTRY; DRUG LEGISLATION; DRUG MARKETING; EUROPE; HEALTH CARE POLICY; LAW; REVIEW; TOXICITY TESTING; ARTICLE; COMMERCIAL PHENOMENA; DRUG APPROVAL; EUROPEAN UNION; FINANCIAL MANAGEMENT; HUMAN; INTERNATIONAL COOPERATION; LEGAL ASPECT; PATENT; STANDARD;

COMMERCE; DRUG APPROVAL; EUROPEAN UNION; HUMANS; INTERNATIONAL COOPERATION; MARKETING OF HEALTH SERVICES; PATENTS; PHARMACEUTICAL PREPARATIONS;

EID: 0033627076     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (76)

1. As used in this article, the term "data protection" means a period of protection against submission or approval of marketing authorization applications that do not contain full safety or efficacy data, but refer (without the innovator's permission) to data contained in the marketing authorization application for an innovative product (e.g., the periods of protection against approval of abbreviated new drug applications under section 505(j) of the Federal Food, Drug, and Cosmetic Act of 1938, Pub. L. No. 75-717, 52 Stat. 1040 (1938) (codified as amended 21 U.S.C. § 355(j) (1994)). "Marketing exclusivity" means a period of protection against approval of marketing authorization applications for similar products, even if they are supported by full safety and efficacy data (e.g., the seven-year period of exclusivity afforded to orphan drugs under 21 U.S.C. § 360cc).
2. Regulation (EC) No. 141/2000 of the European Parliament and of the Council on Orphan Medicinal Products, 2000 O.J. (L 18) 1 [hereinafter Orphan Drug Regulation].
3. Council Directive 65/65/EEC of January 26, 1965 on the approximation of provisions laid down by law, regulation, or administrative action relating to proprietary medicinal products, Council Directive 65/65, 1965 O.J. (No. 22) 368, reprinted in 1965-1966 O.J. Spec. Ed. 20 (1972). The Commission has proposed a recodification of the medicines directives, under which all directives issued since 1965 will be consolidated and their provisions renumbered. Proposal for a European Parliament and Council Directive on the Community Code Relating to Medicinal Products for Human Use, COM(1999)315 final.
4. Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products. Council Directive 75/318, 1975 O.J. (L 147) 1.
5. Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products. Council Directive 75/319, 1975 O.J. (L 147) 13.
6. Council Directive 87/21/EEC of 22 December 1986 amending Directive 65/65/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products. Council Directive 87/21, 1987 O.J. (L 15) 36.
7. Council Directive 87/22/EEC of 22 December 1986 on the approximation of national measures relating to the placing on the market of high-technology medicinal products, particularly those derived from biotechnology. Council Directive 87/22, 1987 O.J. (L 15) 38.
8. Council Directive 93/39/EEC of 14 June 1993 amending Directives 65/65/EEC, 75/318/EEC and 75/ 319/EEC in respect of medicinal products. Council Directive 93/39, 1993 O.J. (L 214) 22.
9. Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products. Council Regulation 2309/93, 1993 O.J. (L 214) 1.
10. For a discussion of the centralized and mutual recognition procedures, see Richard F. Kingham, Peter Bogaert & Pamela Eddy, The New European Medicines Agency, 49 FOOD DRUG COSM. L.J. 301 (1994).
11. Proposal for a European Parliament and Council Regulation (EC) on Orphan Medicinal Products, 1998 O.J. (C 276) 7.
12. See Orphan Drug Regulation, supra note 2.
13. Pub. L. No. 98-417, 98 Stat. 1585 (codified at 15 U.S.C. §§ 68b-c, 70b (1994); 21 U.S.C. §§ 301 note, 355, 360cc (1994); 28 U.S.C. § 2201 (1994); 35 U.S.C. §§ 156, 271, 282 (1994)). See Upjohn Mfg. Co. v. Schweiker, 681 F.2d 480 (6th Cir. 1982); Burroughs Wellcome Co. v. Schweiker, 649 F.2d 221 (4th Cir. 1981).
14. Scotia Pharmaceuticals Ltd. v. National Drugs Advisory Board, unreported (on file with authors).
15. The proposed codification of Directive 65/65 changes the wording of 4.8a(ii).
16. Commission Directive 1999/83/EC of 8 September 1999 amending the Annex to Council Directive 75/ 318/EEC on the approximation of the laws of the Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products. Commission Directive 1999/ 83, 1999 O.J. (L 243) 9); see also Directive 75/318/EEC, supra note 4. Directive 1999/83/EC amends Part 3 of the Annex to Directive 75/318/EEC by insertion of a new section I into that Annex.
17. There is no specific allowance for new uses of old substances or new pharmaceutical forms, although these might receive additional periods of data protection under Regulation 2309/93 or the recent European Court of Justice interpretation of article 4.8a(iii). See sections V (C), (D)(7), infra. Thus, bibliographic applications still might be used as an alternative to true abridged applications.
18. Case C-440/93, Regina v. Licensing Authority ex parte Scotia Pharmaceuticals Ltd., 1995 E.C.R. I-2851.
19. Bristol-Myers Squibb B.V./het College ter Beoordeling van Geneesmiddelen, Rb., Utrecht, 22 April 1998, (ann. R.D.), unreported (transcript on file with authors). The district court's decision was stayed pending an appeal to the Afdeling Rechtspraak van de Raad van State, the highest administrative court in The Netherlands, and the case was subsequently dismissed by agreement of the parties.
20. EUROPEAN COMMISSION, THE RULES GOVERNING MEDICINAL PRODUCTS IN THE EUROPEAN UNION, NOTICE TO APPLICANTS-MEDICINAL PRODUCTS FOR HUMAN USE, PROCEDURES FOR MARKETING AUTHORIZATION, Vol 2A, at 6 (Office for Official Publications of the European Communities 1998) [hereinafter Notice to Applicants].
21. Commission Communication on the Community Marketing Authorization Procedures for Medicinal Products, 1998 O.J. (C 229) 4, 13 [hereinafter Commission Communication].
22. See supra note 16.
23. It is possible that these provisions are intended mainly to simplify use of bibliographic applications for herbal products and phytomedicines, but there is nothing in the directive to prevent their use in reviewing applications for other medicinal products.
24. Public Health Service Act, Ch. 288, 37 Stat 309 (codified at 42 U.S.C. §§ 201 et seq. (1994)), § 351, establishes a licensing requirement for vaccines and other biological products that is separate from the provisions for approval of new drugs in section 505 of 21 U.S.C. § 355.
25. Council Directive 89/342/EEC of 3 May 1989, extending the scope of Directive 65/65/EEC and 75/ 319/EEC and laying down additional provisions for immunological medicinal products consisting of vaccines, toxins, or serums and allergens, Council Directive 89/342, art. 1, 1989 O.J. (L 142) 14; Council Directive 89/ 343/EEC of 3 May 1989, extending the scope of Directives 65/65/EEC and 75/319/EEC and laying down additional provisions for radiopharmaceuticals, Council Directive 89/343, art. 1, 1989 O.J. (L 142) 16; Council Directive 89/381/EEC of 14 June 1898, extending the scope of Directives 65/65/EEC and 75/318/EEC on the approximation of provisions laid down by law, regulation, or administrative action relating to proprietary medicinal products and laying down special provisions for medicinal pro ducts derived from human blood or human plasma, Council Directive 89/381, art. 1, 1989 O.J. (L 181) 44; Council Directive 92/73/EEC of 22 September 1992, widening the scope of Directives 65/65/EEC and 75/318/EEC in the approximation of provision laid down by law, regulation, or administrative practice relating to medicinal products and laying down additional provisions on homeopathic medicinal products, Council Directive 92/73, 1992 O.J. (L 297) 8.
26. The status of processed cells and tissues of human origin remains unclear. There also are exceptions from the marketing authorization requirement for "magistral" and "officinal" formulas prepared by pharmacists and medicinal products supplied to named patients by physicians.
27. Notice to Applicants, supra note 20, at 8.
28. Id.
29. Id. A review of national laws suggests that the Notice to Applicants may be over-simplified. In Spain and Portugal, the authorities may in some circumstances apply a data protection period beyond the expiry of a patent protecting the original product.
30. See Council Directive 65/65/EEC supra note 3, at art, 4.8a(iii).
31. In Regina v. Licensing Auth. ex parte Monsanto PLC [1997] 3 C.M.L.R. 402, (Q.B. 1996), the English High Court rejected the argument that, in deciding whether to accept an abridged marketing authorization application, the UK Medicines Control Agency was required to determine whether the data submitted in support of an approval granted in Germany more than ten years previously were sufficient to meet the requirements of Directive 75/318. The court held that it was enough for the agency to determine that Germany had implemented the EC medicines directives when the approval was granted.
32. See Council Directive 65/65/EEC, supra note 3, art. 4.8a(iii).
33. The Swedish Medicinal Products Ordinance measures the period of data protection from the first approval in an EEA country. Medicinal Products Ordinance (SFS 1992:1752) (Official Translation, Ministry of Health and Social Affairs International Secretariat, 1992).
34. It is conceivable that marketing authorizations for immunologicals, radiopharmaceuticals, and blood derivatives granted before the "extension" directives took effect were not "in accordance with Community provisions in force," and that data protection periods did not begin until the EC marketing authorization requirement was imposed.
35. Notice to Applicants, supra note 20, at 7.
36. Id.
37. C-368/96, The Queen v. The Licensing Auth. established by the Medicines Act 1968 (acting by The Medicines Control Agency), ex parte Generics (UK) Ltd., The Wellcome Found. Ltd. and Glaxo Operations UK Ltd. and Others, 1998 E.C.R. I-7967.
38. 21 U.S.C. § 355(j).
39. Commission Regulation (EC) No. 541/95 of 10 March 1995, concerning the examination of variations to the terms of a marketing authorization granted by a competent authority of a Member State, Commission Regulation 54/95, 1995 J.O. (L 55) 7.
40. For example, anew application is required to add an indication in a "different therapeutic area," defined in terms of the third level of the WHO Anatomic Therapeutic Chemical Code.
41. Opinion of Mr. Advocate General Ruiz-Jarabo Colomer delivered on 22 January 1998. The Queen v. The Licensing Auth. established by the Medicines Act 1968 (acting by The Medicines Control Agency), ex parte Generics (UK) Ltd., The Wellcome Found. Ltd. and Glaxo Operations UK Ltd. and Others, 1998 E.C.R. I-7967, at para. 70. He suggested at para. 63 that an indication might be of such importance if it would have been eligible for centralized approval under Regulation 2309/93, was patentable under the Munich Convention or national patent law, or required testing similar in scope to that needed to secure approval of a new chemical entity.
42. See supra note 37.
43. Council of Europe, European Department for the Quality of Medicines, Pharmeuropa List of Standard Terms, (2d ed. 1998). The Council of Europe, an organization that is separate from the EC, prepared the publication at the request of the European Commission to assist in the application of provisions of Directive 75/318 that require use of "standard terminology" to describe the pharmaceutical form of a medicinal product in a marketing authorization application. The publication identifies twenty-one "standard terms" (e.g., oral preparations-solid forms), with specific dosage forms under each standard term (e.g., "capsules, hard"). In a recent case, the English High Court rejected the argument that another difference in formulation (use of a microemulsion versus a macroemulsion) constituted a different pharmaceutical form for the purposes of essential similarity. Judgment of Mr. Justice Hidden in Regina v. Licensing Authority ex parte Novartis Pharamceuticals UK Ltd., computer-aided transcript of the stenograph notes of Smith Bernai Reporting Ltd., Official Shorthand Writers to the Court (Q.B.D. Mar. 30, 2000).
44. The Commission's Notice to Applicants appears to adopt the view that different salts and esters are not essentially similar within the meaning of article 4.8.a(iii), because it includes them among products that may require additional data under the "proviso" for hybrid applications. Notice to Applicants, supra note 20.
45. CPMP, Draft Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/ EWP/QWP/1401/98 (1998); see Novartis, supra note 43. In the Novartis case, the court suggested that medical product agencies have some discretion to determine whether proof of bioequivalence is required for essential similarity. The case is somewhat unusual because the dosage of the drug in question (cyclosperin) must be adjusted for each patient.
46. 21 U.S.C. § 355(j).
47. Case 316/95, Generics B.V. v. Smith Kline & French Lab. Ltd., 1997 E.C.R. I-3929. The Dutch court enjoined sales of the generic product for 14 months, the average time then required to review an abridged marketing authorization application in The Netherlands.
48. According to the European Commission, samples are required routinely in Belgium, Italy, Luxembourg, The Netherlands, Portugal, Spain, and Sweden. They are submitted in other member states only when requested by the authorities. Notice to Applicants, supra note 20, at 154. The same is true in the centralized procedure.
49. Pub. L. No. 98-417, 98 Stat 1585 (codified in scattered sections of 15 U.S.C., 21 U.S.C., 28 U.S.C., and 35 U.S.C.).
50. 35 U.S.C. § 271 (e)(1). The rule was enacted in response to the decision in Bolar Pharmaceutical Co., Inc. v. Roche Products, Inc., 469 U.S. 856; 105 S. Ct. 183 (1984), which held that use of a patented medicinal product for bioequivalence tests required to support an ANDA was an act of infringement.
51. In a complaint to the World Trade Organization, the EC has taken the position that Canada's adoption of a Bolar rule, combined with an exception that permits generic manufacturers to "stockpile" medicinal products prior to patent expiry, is inconsistent with the Agreement on Trade-Related Aspects of Intellectual Property Rights, although no similar challenge appears to have been made against the original Bolar rule in the United States. Canada - Patent Protection of Pharmaceutical Products, complaint by the European Communities WT/ DS114/1 (last modified Mar. 23, 2000) .
52. FDA, APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE EVALUATIONS (18th ed. 1998).
53. Notice to Applicants, supra note 20, at 8. A recently issued WTO Dispute Panel Report has upheld the provision of Canadian law permitting research and development activities for generic versions of medicines to begin before the patent term has expired for the innovative product, but ruled against the other provision that permitted pre-expiry stockpiling of generic products.
54. 21 U.S.C. § 355(j)(5)-(6).
55. This issue was raised in Regina v. Medicines Control Agency ex parte Rhône-Poulenc Rorer Ltd., 46 B.M.L.R. 199 (Q.B. 1998). The innovator had withdrawn its old formulation from the market when a new, patented formulation was approved, but the Medicines Control Agency determined that both formulations were the "same product," and the court concluded that the question whether the reference product was "on the market" need not be decided.
56. Notice to Applicants, supra note 20, at 15.
57. Id. at 23.
58. Commission Communication, supra note 21, at 6.
59. Notice to Applicants, supra note 20, at 24, 153-55.
60. Commission Communication, supra note 21, at 6.
61. Article 3.5 of Regulation 2309/93 authorizes the Commission, acting with the member states in the Standing Committee on Medicinal Products for Human Use, to amend the lists of medicinal products for which centralized approval is required or permitted, and it is conceivable that the Commission may use this power to clarify the status of abridged applications for pre-1995 biotechnology products.
62. See supra note 9.
63. Notice to Applicants, supra note 20, at 10.
64. Id. at 6.
65. See Orphan Drug Regulation, supra note 2.
66. Id. art. 1.
67. 21 U.S.C. § 360bb(a).
68. See Orphan Drug Regulation, supra note 2, art. 3.2(b).
69. Id. art. 8.2.
70. Id art. 83.
71. Draft Commission Regulation laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts "similar medicinal product" and "clinical superiority." The Standing Committee on Medicinal Products for Human Use issued a positive opinion on the proposed Regulation on March 23, 2000, and final action is expected shortly.
72. Id. art. 3.3. A "similar active substance" is defined as an identical active substance or one that has the same principal features of molecular structure including (1) "isomers, mixtures of isomers, complexes, esters, salts, and covalent derivatives of the original active substance" or an active substance that has only minor differences in molecular structure from the original, e.g., a structure analogue; or (2) the same macromolecule or one that differs from the original only with respect to certain specified changes in the molecular structure; or (3) the same "radiopharamceutical active substance or on that varies from the original only in radionuclide ligand, site of labelling or molecule-radionuclide coupling mechanism linking the molecule and radionuclide provided that it acts via the same mechanism."
73. Id. art. 3.3.
74. This was, in fact, the original proposal advanced by the Commission, but was rejected later for political reasons. See Report from the Commission to the Council Concerning the Adoption of Certain Urgent Measures Intended to Facilitate the Development and Marketing of Medicinal Products Derived From Biotechnology and Other High Technology Medicinal Products in the Community, COM(84)437 final.
75. Agreement on Trade-Related Aspects of Intellectual Property Rights, Apr. 15, 1994, Marrakesh Agreement Establishing the World Trade Organization, Annex 1C, LEGAL INSTRUMENTS-RESULT OF THE URUGUAY ROUND, vol. 31; 33 I.L.M. 81 (1994).
76. Agreement on Trade-Related Aspects of Intellectual Property Rights, Apr. 15, 1994, Marrakesh Agreement Establishing the World Trade Organization, Annex 1C, LEGAL INSTRUMENTS-RESULT OF THE URUGUAY ROUND, vol. 31; 33 I.L.M. 81 (1994).