EU orphan regulation - Ten years of application

Food and Drug Law Journal

Volumn 65, Issue 4, 2010, Pages

  Michaux, Geneviève ^a,b  

^a Department of International Practice   (United Kingdom)

^b Life Sciences Department   (United Kingdom)

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[No Author keywords available]

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EID: 84880009178     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (106)

1. Regulation 141/2000, 2000 O.J. (L18) 1-5 (EC) of the European Parliament and of the Council of 16 December 1999 on Orphan Medicinal Products.
2. Veterinary products are not subject to an orphan regime. See written parliamentary question of January 12, 2000 and answer of 22 February 2000, E-2613/99, O.J., C 280 E, pp.81 and 82.
3. Orphan medicines in numbers. The success often years of orphan legislation, EMA, 3 May 2010.
4. The EMA report indicates 760 positive COMP opinions, 16 negative COMP opinions, and 269 withdrawals of applications for orphan designation.
5. Commission Regulation 847/2000, 2000 O.J. (L103) 5-8 (EC) 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'.
6. www.ema.europa.eu.
7. Communication from the Commission on Regulation (EC) No 141/2000 of the European Parliament and of the Council on orphan medicinal products, O.J. C 178/2. In June 2006, the Commission also published a report on the effect of the Orphan Regulation: Commission Staff Working Document on the experience acquired as a result of the application of Regulation (EC) No 141/2000 on orphan medicinal products and account of the public health benefits obtained - Document on the basis of Article 10 of Regulation (EC) No 141/2000 (26 June 2006).
8. Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another, Commission, July 9, 2007.
9. General information for Sponsors of Orphan Medicinal Products - Q&A, EMA, January 29, 2009, regularly updated.
10. 21 U.S.C. § 360bb(a).
11. Footnote 8, p.3.
12. Orphanet was launched in 1997 by the French Ministry of Health and the Institut National de la Santé et de la Recherche Médicale (INSERM). Its objective is to contribute to the improvement of the diagnosis, care and treatment of patients with rare diseases. Orphanet includes a Professional Encyclopaedia, a Patient Encyclopaedia, and a Directory of Expert Services, which includes information on relevant clinics, clinical laboratories, research activities and patient organizations.
13. 21 C.F.R. § 316.20(b)(1) & (6).
14. Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation. EMA. March 2010.
15. Recital 3 of the Council Recommendation on action in the field of rare diseases (June 9, 2009; see below), indicates that "A more refined definition based on updated scientific review, taking into account both prevalence and incidence, will be developed using the Second Community Health Programmes resources."
16. Pursuant to Article 8 of Protocol 1 on Horizontal Adaptations to the European Economic Area Agreement (1994 O.J. (L1) 3), the term "Community" refers to the EEA in the pieces of legislation to which this Agreement applies.
17. Switzerland is not part of the EEA.
18. Points to Consider on the Calculation and Reporting of the Prevalence of a Condition for Orphan Designation, EMA, March 26, 2002.
19. Footnote 5.
20. In Liechtenstein, medicinal products may be marketed on the basis of either a MA granted under Liechtenstein law or a Swiss MA that is recognized in Liechtenstein under a Customs Agreement between Switzerland and Liechtenstein. Until 2005, Liechtenstein automatically recognized Swiss MAs. As of June 1, 2005, the recognition of Swiss MAs in Liechtenstein is no longer automatic but delayed by one year so that the company has time to elect not to have the Swiss MA recognized in Liechtenstein. As a result of the automatic recognition, a Swiss MA is the MA for Liechtenstein and thus possibly for the EEA.
21. To assist applicants, the EMA published a "Data providers and sources to identify existing authorised medicinal products in the European Union and the European Economic Area" (June 2009).
22. Moreover, the Member States (organized in the Co-ordination Group for Mutual Recognition and Decentralised Procedure or CMD(h)) published a "Best practice guide for the exchange of regulatory and administrative information regarding orphan medicinal products between the EMEA and the national competent authorities" (Feb.2007).
23. Footnote 9. Assumptions must be replaced by evidence at the time of approval (see below).
24. The General Court (formerly the Court of First Instance) has jurisdiction over the Commission's decisions. Appeal against the General Court's decisions may be brought before the Court of Justice (formerly the European Court of Justice or ECJ).
25. GC, September 9, 2010, T-74/08, Now Pharma v. Commission, § 134.
26. Footnote 25.
27. Summary COMP opinion, June 24, 2009;
28. Summary COMP opinion, May 11, 2009;
29. Summary COMp opinion, May 6, 2010.
30. Summary COMP opinion, June 21, 2010: "[...] high-dose formulation will allow patients to sake only one tablet instead of multiple tablets they take with the currently available formulations."
31. A Community MA is a MA granted by the European Commission and valid for the entire EU (i.e. in each the Member State). Community MAs are granted on the basis of Regulation 726/2004, 2004 O.J. (L136) 1-33 (EC) of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.
32. In June 2010, Raptor Pharmaceuticals Europe was granted an orphan designation for cysteamine bitartrate (gastroresistant) for the treatment of cystinosis. The COMP opinion has not yet been published, but it seems that the significant therapeutic benefit results from the pharmaceutical form (delayed release rather than immediate release), which could reduce dosing frequency and gastrointestinal side effects.
33. Summary COMP opinion, December 7, 2009.
34. Summary COMP opinion. July 1, 2008.
35. Summary COMP opinion, May 11, 2009.
36. Summary COMP opinion, February 23, 2010.
37. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for pediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004.
38. Footnote 7, p.4.
39. In the past, orphan products could be approved through a mutual recognition procedure, i.e. nationally.
40. Footnote 23.
41. Where a generic product differs from the originator product, the generic applicant must file a hybrid application rather than an abridged application (the EU equivalent of an ANDA). The application is "hybrid" because it refers to the originator dossier but also contains new, own data from the applicant that is designed to bridge the difference with the originator product.
42. This guideline is a short list of practical issues and information for sponsors planning to submit an application for designation of a medicine as an orphan medicinal product.
43. Footnote 25, § 77.
44. CJ, September 9, 2010, Case T-264/07, CLS Behring v. Commission and EMA. The limited scope of this article does not allow commenting extensively on the various law issues analyzed and addressed by the Court.
45. Procedural advice on appeal Procedure for Orphan Medicinal Product Designation, EMA, March 4, 2008.
46. Footnotes 25 and 41.
47. Footnotes 3 and 4.
48. Note for guidance on the format and content of the annual report on the state of development of an orphan medicinal product, EMA, April 20, 2010.
49. The Procedure for Orphan Medicinal Product Designation - General Principles, EMA, June 13, 2008;
50. Common EMA/FDA application form for orphan medicinal product designation, EMA, Nov. 2007.
51. Market exclusivity relates to the orphan therapeutic indication, which can be narrower than the orphan indication.
52. For example, Levodopa/carbidopa; beta-artemether/lumefantrine.
53. In a nutshell, under the mutual recognition procedure (MRP), a MA is granted by one Member State (called the Reference Member State) and the MAH asks other Member States of his choice (called Concerned Member States) to recognize the scientific assessment and product information approved by the Reference Member State. Thus, the product is approved separately by each Member State that participates in the procedure. In the centralized procedure, the product is approved by the Commission and the so-called 'Community' MA is valid in all the Member States.
54. If the applicant opted for the mutual recognition procedure, the product had to be approved in all the Member States to benefit from market exclusivity.
55. To the best of our knowledge, only one orphan product was approved through a mutual recognition procedure rather than through a centralized procedure (Duodopa).
56. Regulation 726/2004, 2004 O.J. (L136) 1-33 (EC) of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.
57. Regulation 726/2004 amended and replaced Regulation (EEC) No 2309/93 (Council Regulation 2309/93, 1993 O.J. (L214) 1-21 (EEC) 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).
58. An abridged application is the EU equivalent of an ANDA. A consent application is a MA application filed with a reference letter from the MAH of the reference product indicating authorization to cross-reference the MA dossier of the reference product.
59. Another alternative is to waive the orphan designation and then vary the MA to include the new non-orphan indication.
60. Template - Sponsor's report on the maintenance of the designation criteria at the time of marketing authorisation application, EMA, June 2010.
61. The EMA started publishing the documents on review of orphan designation in September 2010. Before such publication, it was difficult to track down medicinal products that had been but were no longer designated as orphans.
62. "When an application is submitted for a marketing authorisation in respect of medicinal products for human use which are of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure. The request shall be duly substantiated. If the Committee for Medicinal Products for Human Use accepts the request, the time-limit laid down in Article 6(3), first subparagraph, shall be reduced to 150 days." (Article 14.9 Regulation 726/2004, 2004 O.J. (L136) 1-33 (EC)).
63. Following consultation with the applicant, an authorisation may be granted subject to certain specific obligations, to be reviewed annually by the Agency. The list of these obligations shall be made publicly accessible. By way of derogation from paragraph 1, such authorisation shall be valid for one year, on a renewable basis. The provisions for granting such authorisation shall be laid down in a Commission Regulation adopted in accordance with the procedure referred to in Article 87(2)." (Article 14.7 Regulation 726/2004, 2004 O.J. (L136) 1-33 (EC);
64. Commission Regulation 507/2006, 2006 O.J. (L92) 6-9 (EC) of 29 March 2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation 726/2004,
65. 2004 O.J. (L136) 1-33 (EC) of the European Parliament and of the Council).
66. In exceptional circumstances and following consultation with the applicant, the authorisation may be granted subject to a requirement for the applicant to introduce specific procedures, in particular concerning the safety of the medicinal product, notification to the competent authorities of any incident relating to its use, and action to be taken. This authorisation may be granted only for objective, verifiable reasons and must be based on one of the grounds set out in Annex I to Directive 2001/83/EC. Continuation of the authorisation shall be linked to the annual reassessment of these conditions." (Article 14.8 Regulation 726/2004,2004 O.J. (L136) 1-33 (EC)).
67. Data exclusivity is the EU equivalent of the market exclusivity.
68. Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on Rare Diseases: Europe's Challenges, November 11, 2008.
69. 21 U.S.C. § 360 cc and C.F.R. § 316.31 (a).
70. The issue of whether a medicinal product qualifies as a 'new' medicinal product under the general pharmaceutical rules (Directive 2001/83/EC and Regulation (EC) 726/2004) is very complex. Based on the current legal provisions and guidelines and on the Commission's and EMA's practice, it seems that an active substance qualifies as a 'new' active substance where the applicant demonstrates that it significantly differs from an approved active substance with regard to safety or efficacy. For example, the European Commission granted a MA for Lunivia but considered that eszopiclone (Lunivia) was the same active substance as zoplicone (imovane/zimovane) because "[t]he applicant failed to prove relevant and clinically meaningful differences between eszopiclone and the racemate zopiclone in an adequate planned clinical trial with direct head to head comparison. No relevant differences have been demonstrated in properties with regard to safety or efficacy." (See T-275/09, Sepracor v. Commission, pending before the General Court).
71. Footnote 43.
72. Guideline on the aspects of the application of Article 8(1) and (3) of Regulation No 141/2000: Assessing similarity of medicinal products versus authorised orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity, Commission, September 19, 2008.
73. CHMP assessment report for Atriance, "The CHMP concluded that, having considered the arguments presented by the applicant, the Rapporteurs assessment, and the conclusions of the Quality working Party, there are differences in the mechanism of action of nelarabine and clofarabine. The two active substances are considered not to be similar as regards mechanism of action since they act on different pharmacodynamic targets (DNA polymerases α and β, DNA polymerases α and ribonucleotide reductase, for nelarabine and clofarabine, respectively). However, the CHMP concluded that nelarabine and clofarabine are similar in terms of molecular structural aspects since both molecules share the same principal molecular structural features and the changes in molecular structure are only minor."
74. CHMP assessment report for Tasigna, "The CHMP is of the opinion that Tasigna is similar to Glivec within the meaning ofArticle 3 of Commission Regulation (EC) No. 847/200. See appendix 5.1. Tasigna and Glivec share the same principal molecular structural features, both containing a N-(2-methylphenyl)- 4(3-pyridinyl)-2-pyrimidinamine part, rendering half of the molecules identical. In addition, due to the flexibility and reversibility of amide bridges, the common part may be extended to include the phenyl group linked to the amide bridge. If a molecule is 50% identical with the possibility of even more additional similarity it is enough to conclude structural similarity. The CHMP is of the opinion that Tasigna is not similar to Sprycel within the meaning of Article 3 of Commission Regulation (EC) No. 847/200. See appendix 5.2. Tasigna and Sprycel do not share the same principal molecular structural features and the only major common element is the aniline-amide portion of the molecules, which corresponds to 22% of Tasigna and to 24% of Sprycel as assessed by molecular weight." Tasigna was approved despite its similarity with Glivec because the MAH of Glivec gave its consent for a derogation to its market exclusivity (see below).
75. CHMP assessment report for Thalidomide Celgene, "The CHMP concluded that, having considered the arguments presented by the applicant, the Rapporteurs assessment and the conclusions of the Quality Working Party, Thalidomide Pharmion was similar, in terms of molecular structure (as defined in Article 3 of Commission Regulation (EC) No 847/ 2000) to the orphan medicinal product Revlimid authorised for a condition relating to the proposed therapeutic indication. However, Thalidomide Pharmion and Revlimid did not share the same therapeutic indication, according to article 8 of Regulation (EC) No. 141/2000."
76. Commission 2003 Communication; See also Question 4 of EMA Q&A.
77. Footnote 63.
78. Article 81 of Regulation 726/2004.
79. Guideline on aspects of the application of Article 8(2) of Regulation (EC) No 141/2000: Review of the period of market exclusivity of orphan medicinal products, Commission, September 17, 2008.
80. An interesting issue is the validity of a national MA granted to a similar product for a same therapeutic indication but before accession to the EU. Does that MA become invalid on the date of accession due to the 'acquis communautaire' which includes the Community MA for the orphan product and the associated market exclusivity protection?
81. For further explanation of the Paediatric Regulation, see G. Michaux, Pediatric Exclusivities in Europe - A Quest for the Grail, FDLJ 2009, Vol. 64, p. 1-32.
82. SPCs are regulated by Council Regulation 1768/92, 1992 O.J. (L182) 1-5 (EEC) of 18 June 1992, concerning the creation of a supplementary protection certificate for medicinal products. The SPC is the EU equivalent of the patent term extension.
83. Regulation 1768/92 defines a 'basic patent' as "a patent which protects a product as defined in (b) as such, a process to obtain a product or an application of a product, and which is designated by its holder for the purpose of the procedure for grant of a certificate."
84. The submission of pediatric data is optional for approved medicinal products that are not or no longer protected by a patent or an SPC. If the MAH of such product decides to submit pediatric data (generated in accordance with a PIP agreed upon by the EMA), he may be granted a 'paediatric use marketing authorisation' (PUMA) and the new pediatric data are protected by data exclusivity.
85. The EMA 2010 report (see footnote 5) indicates that 8,4% of the COMP positive opinions concern exclusively pediatric medical conditions and 49,8% concern adult and pediatric medical conditions.
86. Footnote 7 in Guideline on aspects of the application of Article 8(2) of Regulation (EC) No 141/2000: Review of the period of market exclusivity of orphan medicinal products (see footnote 63): "For products falling under Article 37 of the above-cited paediatric regulation the reduced period under Article 8(2) of Regulation (EC) No 141/2000 will be equally six years; Article 37 of the paediatric regulation only affects the calculation of the period referred to in Article 8(1) of Regulation (EC) No 141/2000.
87. Commission Recommendation 2003/361/EC of 6 May 2003. Most companies filing for orphan designation are SMEs although larger pharmaceutical companies seem increasingly interested by those niche products.
88. Public Statement on Fee Reductions for Designated Orphan Medicinal Products, EMA,February 4, 2009. In 2007, the aggregate fee reductions and waivers amounted to around 6,000,000 €.
89. Recently, the Netherlands implemented a scheme intended to help companies planning to submit applications for orphan designation. See I. Schofield, Dutch move to boost orphan drug development, RAJ Pharma, August 2010.
90. Orphan medicinal products supported by the FP7 includes, for example, ibuprofen, methotrexate, thiotepa.
91. The High Level Group on Health Services and Medical Care brings together experts from all the Member States and works in seven main areas: cross border healthcare purchasing and provision; healthcare professionals; centres of reference; health technology assessment; information and e-health; health impact assessment and health systems; and patient safety.
92. Eurordis is a non-governmental patient-driven alliance of patient organizations and individuals active in the field of rare diseases, dedicated to improving the quality of life of all people living with rare diseases in Europe. It comprises more than 434 members in more than 43 countries as well as 11 national rare disease alliances. For more information, see www.eurordis.org.
93. "Improving Access to Orphan Medicines for All Affected Citizens" (Oct. 2008). Pricing and reimbursement issues are also highlighted in the Eurordis' 2007 Survey on Orphan Drugs Availability in Europe. In 2004, the Commission also commissioned a report on the prices of orphan drugs.
94. The High Level Pharmaceutical Forum is a high-level political platform that is supported by a Steering Committee and three expert Working Groups (Working Group on Information to Patients, Working Group on Pricing, and Working Group on Relative Effectiveness). The Pharmaceutical Forum aims at improving the performance of the pharmaceutical industry in terms of its competitiveness and contribution to social and public health objectives. It brings together Ministers from all Member States and representatives of the European Parliament, pharmaceutical industry, healthcare professionals, patients, and insurance funds.
95. Communication from the Commission to the European Parliament, the Council, the European Economic and Social Committee and the Committee of the Regions on Rare Diseases: Europe's Challenges, Commission, November 11, 2008.
96. Council Recommendation on European Action in the field of Rare Diseases, June 9, 2009.
97. Eurordis press release, December 9, 2009, www.eurordis.org.
98. In the EU, the biotech industry is primarily represented by two trade associations: EuropaBio and European Biopharmaceutical Enterprises (EBE), a branch of EFPIA (European Federation of Pharmaceutical Industries and Associations).
99. Together for Health: A Strategic Approach for the EU 2008-2013, Commission, Oct. 2007.
100. At the end of November 2009, the Commission established the EU Committee of Experts on Rare Diseases, which replaces the Rare Disease Task Force and comprises representatives of Member States, patient's organizations, the pharmaceutical industry, and EU experts in the field of rare diseases. The Rare Diseases Task Force had been created in January 2004 to assist the Commission Public Health Directorate in promoting the optimal prevention, diagnosis and treatment of rare diseases in Europe, and to provide a forum for discussion and exchange of views on issues related to rare diseases. It published several reports in support of Commission's actions in the area of rare diseases (Overview of current Centres of References on rare diseases in the EU (2005);
101. Contributions to policy shaping: For a European collaboration on health services and medical care in the field of rare diseases (2006);
102. Centres of Reference for rare diseases in Europe - State-of-the-art in 2006 and Recommendations of the Rare Diseases Task Force (2007);
103. How Many Drugs for How Many Patients? Recommendations of the Rare Diseases Task Force (2007);
104. Assessing the added-value of European Reference Networks in the Field of Rare Diseases (2008);
105. Health Indicators for Rare Diseases (2008);
106. Patient Registries and Databases in the Field of rare Diseases: Technical, legal and Ethical Issues (2008).