Pediatric exclusivities in Europe - A quest for the grail?

Food and Drug Law Journal

Volumn 64, Issue 4, 2009, Pages 631-662

  Michaux, Geneviève ^a  

^a Department of International Practice   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

GENERIC DRUG; HOMEOPATHIC AGENT;

DRUG APPROVAL; DRUG CONTROL; DRUG EFFICACY; DRUG INDICATION; DRUG INDUSTRY; DRUG LEGISLATION; DRUG MARKETING; DRUG RESEARCH; DRUG SAFETY; EUROPE; HUMAN; PATENT; PEDIATRICS; REVIEW;

EID: 73849135920     PISSN: 1064590X     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (83)

1. Regulation 1901/2006, 2006 O.J. (L378) 1-19 (EC) on medicinal products for paediatric use and amending: Regulation 1768/92, 1992 O.J. (L182) 1-5 (EEC); Directive 2001/20, 2001 O.J. (L121) 34-44 (EC); Directive 2001/83, 2001 O.J. (L311) 67-128 (EC); and Regulation 726/2004, 2004 O.J. (L136) 1-33 (EC).
2. The Paediatric Regulation entered into force on 26 January 2007 and became applicable to off-patent approved products on 26 July 2007, to new products on 26 July 2008, and to on-patent approved products on 26 January 2009 (See Question 5 of the FAQ on Regulatory Aspects of the Paediatric Regulation, European Medicines Agency (EMEA), 2 Sept. 2008). For purposes of this article, the term "Europe" will refer to the European Union (which currently comprises of 27 Member States).
3. For purposes of this article, we will use the term " formulation" rather than "pharmaceutical form".
4. The EMEA is a decentralized body of the European Union composed of members of all EU and EEA-EFTA states with headquarters in London. Its main responsibility is the protection and promotion of public and animal health, through the evaluation and supervision of medicinal products for human and veterinary use.
5. In Europe, medicinal products may be approved at the Community level through the centralized procedure or at the national level through the decentralized procedure, the mutual recognition procedure or, where approval is sought only in one Member State, the purely national procedure. The centralized procedure leads to the grant of a marketing authorization by the European Commission, which is valid in all the Member States. The decentralized and mutual recognition procedures lead to the grant of a national marketing authorization by each Member State involved in the procedure, which is valid in the granting Member State.
6. Regulation 469/2009, 2009 O.J. (L152) 1-10 (EC) (the "SPC Regulation"). This regulation codifies and replaces Regulation 1768/92, 1992 O.J. (L182) 1-5 (EEC) concerning the creation of a supplementary protection certificate for medicinal products.
7. Regulation 141/2000, 2000 O.J. (L18) 1-5 (EC) on orphan medicinal products (the "Orphan Regulation").
8. Many guidelines have been adopted by the Commission and the EMEA. The most important guidelines are the Commission Guideline, 2008 O.J. (C243) 1-12 on the Format and Content of Applications for Agreement or Modification of a Paediatric Investigation Plan and Requests for Waivers or Deferrals and Concerning the Operation of the Compliance Check and on Criteria for Assessing Significant Studies (the "Commission Guideline") and the EMEAs Procedural Advice on Paediatric investigation plans, waivers, and modifications, which is regularly updated.
9. Article 1(2) of Directive 2001/83, 2001 O.J. (L311) 67-128 (EC) on the Community code relating to medicinal products for human use defines the term "medicinal product". In Europe this term covers both drugs and biologicals.
10. Article 1 of the SPC Regulation defines a "basic patent" as "a patent which protects a product [...] 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."
11. Where a generic product differs from the originator product, the generic applicant must file a so-called 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. In the U.S., hybrid applications are section 505(b)(2) applications.
12. The Paediatric Regulation defines a PUMA as "a marketing authorisation granted in respect of a medicinal product for human use which is not protected by a supplementary protection certificate under Regulation (EEC) No 1768/92 or by a patent which qualifies for the granting of the supplementary protection certificate, covering exclusively therapeutic indications which are relevant for use in the paediatric population, or subsets thereof, including the appropriate strength, pharmaceutical form or route of administration for that product."
13. "When a medicinal product has been granted an initial marketing authorisation in accordance with the first subparagraph, any additional strengths, pharmaceutical forms, administration routes, presentations, as well as any variations and extensions shall also be granted an authorisation in accordance with the first subparagraph or be included in the initial marketing authorisation. All these marketing authorisations shall be considered as belonging to the same global marketing authorisation, in particular for the purpose of the application of Article 10(1)."
14. 2005 Rules Governing Medicinal Products in the European Union (Eudralex), Vol. 2 - Pharmaceutical Legislation, Notice to Applicants and Regulatory Guidelines for Medicinal Products for Human Use, Vol. 2A, Chp 1, Section 2.3.
15. The term a "new medicinal product" is not legally defined and is determined by the authorities on a case by case basis. For purpose of this article, and on the basis of European Court of Justice ("ECJ") case law and the Notice to Applicants, we will define the term "new medicinal product" as a "new active substance."
16. The last part of Article 6(1) of EC Directive 2001/83 shows that the concept of global MA was primarily developed for abridged applications purposes.
17. 1994 O.J. (L1) 3
18. As of 1 June 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.
19. New indications are determined in light of the Commission guideline on the extra year of data exclusivity protection (Guidance on a new therapeutic indication for a well-established substance - Nov. 2007) and the guideline on new therapeutic indications for well-established substances. (Guidance on elements required to support the significant clinical benefit in comparison with existing therapies of a new therapeutic indication in order to benefit from an extended (11 year) marketing protection period - Nov. 2007). They include new pediatric indications (existing indications extended to one or more subsets of the pediatric population).
20. New pharmaceutical forms are determined in light of the guideline on the categorization of extension applications versus variation applications (Guideline on the categorization of Extension Applications (EA) versus Variations Applications (V) - Oct. 2003).
21. ICH Topic E 11, Clinical Investigation of Medicinal Products in the Paediatric Population.
22. See footnote 9.
23. The Commission Guideline defines "condition" as "any deviation(s) from the normal structure or function of the body, as manifested by a characterised set of signs and symptoms (typically a recognised distinct disease or a syndrome.)" In practice, conditions are normally determined on the basis of the World Health Organisation (WHO) E10 International Classification of Diseases.
24. The criteria for a waiver are the following: the specific medicinal product or class of medicinal products is likely to be ineffective or unsafe in part or all of the pediatric population; the disease or condition for which the specific medicinal product or class is intended occurs only in adult populations; and the specific medicinal product does not represent a significant therapeutic benefit over existing treatments for pediatric patients. Unlike the U.S., the circumstance that the studies are impossible or impracticable is not a valid criterion for a waiver. In such case, however, the EMEA seems to rely on a broad interpretation of the third criterion (no significant therapeutic benefit).
25. See the Nycomed cases, Cases T-52/09, Nycomed Danmark v EMEA, 2009 O.J. (C141) 43 and T-52/09 R. Nycomed filed an action for annulment of the EMEA decision rejecting its request for a waiver on the grounds that (i) waivers must be tied to the adult indication(s) envisaged by the applicant for the MA application and (ii) the EMEA misuses its powers by requesting paediatric data for indications that are not those envisaged by the applicant for the MA application. On 24 April 2009, the President of the European Court of First Instance rejected the application for interim measures filed by Nycomed. The application for annulment of the EMEA decision is still pending before the Court of First Instance (Case T-52/90 R, Nycomed Danmark v EMEA).
26. The SmPC is the official ID of a medicinal product. Article 11 of EC Directive 2001/83 lists the information to be included in the SmPC. Pursuant to Article 21(3) of EC Directive 2001/83, the competent regulatory authorities must make the SmPC publicly available without delay. In practice, however, some do not. The SmPC should not be mistaken with the package leaflet. The package leaflet is a leaflet containing information for the user which accompanies the medicinal product" (Article 1(26) of EC Directive 2001/83) and thus the EU equivalent of the package insert. It must be drawn in accordance with the SmPC and be included in each box of the medicinal product unless the information it contains is already on the labeling.
27. If the unsuccessful studies related to a new pediatric formulation or route of administration the study does not need to be included in the SmPC because it is not relevant to patients or healthcare professionals.
28. E. Sergheraert and A. Soetemont, Obtaining Paediatric SPC Extensions in the European Union, RAJ Pharma 365 (2009).
29. Record of the Meeting of National Experts held on 3 February 1995.
30. Record of the Second Meeting of National Supplementary Protection Certificates (SPC) Experts held on 9 October 2006 in Brussels.
31. Record of the Third Meeting of National Supplementary Protection Certificates (SPC) Experts held on 26 September 2008 in London at the EMEA.
32. Article 28 (3) of the Paediatric Regulation.
33. Article 36(2) of the Paediatric Regulation.
34. The German Article 36(3) uses the term "Arzneimittel." The Spanish Article 36(3) uses the term "medicamento."
35. For example, the French Article 36(3) uses the term " produit", the Dutch Article 36(3) uses the term "produkt" , the Italian Article 36(3) uses the term "prodotto", the Swedish Article 36(3) uses the term "produkten", and the Polish Article 36(3) uses the term "produkt".
36. An application for a variation (new indication) or a line extension (new formulation or route of administration) of a centrally approved product is decided by a single authority (the European Commission). An application for a variation or line extension of a product approved nationally through a decentralized procedure or a mutual recognition procedure is decided by each of the 27 Member States, what increases the risk of delay in having the variation or line extension approved throughout Europe.
37. Under the European Commission's interpretation, the pediatric product should also be approved in the three additional EEA countries - see above.
38. The CMD(h) comprises one representative of each EU and EEA country. Pursuant to Article 27(1) of EC Directive 2001/83, its main task is to examine any question relating to marketing authorization of a medicinal product in two or more Member States through an MPR or DCP.
39. du Pont de Nemours & Co [2009] Ch.; See also J. Ball and E. Barnett, High Court upholds UK's strict approach on paediatric extension to SPCs, BSLR, 2009, Vol.10, Issue 2.
40. 1994 O.J. (L1) 3.
41. Directive 2001/20, 2001 O.J. (L121) 34-44 (EC) on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.
42. This is expressly confirmed by Article 16 of the SPC Regulation, which provides that the SPC extension may be revoked if granted contrary to the provisions of Article 36 of the Paediatric Regulation.
43. The circumstance that the trials for a new pediatric formulation or route of administration were not successful is not relevant for patients and healthcare professionals. Thus, such unsuccessful pediatric trials are logically not mentioned in Article 36 and their results need not be mentioned in the SmPC for the company to be eligible for the reward.
44. A MA is granted further to a MA application (or line extension), and a letter of approval is granted further to an application for a variation. To the extent that the Paediatric Regulation applies to MA applications and applications for a variation (new indication), both are relevant. However, for purposes of this article we will generally use the term "MA" unless the comment especially relates to a variation.
45. Article 10.1 of EC Directive 2001/83 and Article 14.11 of EC Regulation 726/2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.
46. Commission Guidance on elements required to support the significant clinical benefit in comparison to existing therapies of a new therapeutic indication in order to benefit from an extended (11 year) marketing protection period (Nov. 2007).
47. See footnote 7.
48. The European Commission accepts a self-certification from the applicant, but NPOs may be more demanding and ask, for example, for copies of the actual MAs.
49. Case C-181/95, Biegen Inc. v. Smithkline Beecham Biologicals SA, 1997 E.C.R. I-00357.
50. See footnote 40.
51. "[44] In that regard, it must be borne in mind that the purpose of the requirement imposed by Article 8(1)(b) of the Regulation to include a copy of the marketing authorization with the application for a supplementary protection certificate is to identify the product and verify that the time-limit for submitting an application and, where applicable, the duration of the supplementary protection are observed. It is therefore a formal requirement whose purpose is to demonstrate the existence of an authorization to place the product on the market as a medicinal product." [45] Where the basic patent and the marketing authorization are held by different persons and the patent holder is unable to provide the competent national authorities with a copy of that authorization, granted by the authorities of a Member State, in accordance with Article 8(1)(b) of the Regulation, the application for a certificate must not be refused on that ground alone. By simple cooperation, the national authority granting the certificate can obtain a copy of the marketing authorization from the national authority which issued it (see, to that effect, Case C-201/94 The Queen v Medicines Control Agency ex parte Smith and Nephew [1996] ECR I-5819, paragraph 28). If that were not the case, the entitlement to the certificate conferred by Article 6 of the Regulation on the basic patent holder would be rendered nugatory."
52. Following the European Commission's position, the UK Patents Court considered that the update of the SmPC is a separate substantive requirement. An MA with a compliance statement will prove both compliance with an agreed PlP and the update of the SmPC as the updated SmPC is attached to the MA. See also U. Gassner, Paediatric Extensions: the requirement of a compliance statement, 7 J1PL&P 457 (2009).
53. Article 23(2) of the Paediatric Regulation.
54. The EMEA is not the competent authority for granting Community MA but it is entrusted with the compliance check of the pediatric data, and the scientific assessment of all the data submitted by the company to support its regulatory application.
55. Article 23(1) of the Paediatric Regulation. The assessment report is prepared by the scientific committee of the regulatory authority that examines the data submitted by the applicant to prove the quality, safety, and efficacy of the product and concludes on such quality, safety, and efficacy (Article 24(4) of EC Directive 2001/83). The regulatory authority's decision is based on that report and, in practice, usually follows its conclusion. At the Community level, the assessment report is prepared by the Committee for Medicinal Products for Human Use (CHMP), one of the scientific committees of the EMEA (Articles 5 and 6 of EC Regulation 726/2004).
56. "If within the period laid down in Article 28(4), a Member State cannot approve the assessment report, the summary of product characteristics, the labelling and the package leaflet on the grounds of potential serious risk to public health, it shall give a detailed exposition of the reasons for its position to the reference Member State, to the other Member States concerned and to the applicant. The points of disagreement shall be forthwith referred to the coordination group." Article 29(1) of EC Directive 2001/83 is implemented by the Commission Guideline on the definition of a potential serious risk to public health in the context of Article 29(1) and (2) of EC Directive 2001/83. On 16 October 2008, the ECJ confirmed that CMS may refuse to recognize the documents prepared by the RMS only where there is a potential serious risk to public health (Case C-452/06, Synthon, 2008 O.J. (C313)4). The compliance statement does not relate to public health but to the paediatric reward, which is its very purpose.
57. In support of a restrictive interpretation see also A. Calles Sanchez, Implementing paediatric extensions to SPCs: marketing authorisation in "all Member States", 5 JIPL&P 305 (2009).
58. The term "Biogen case law" refers both to the ECJ decision and the Advocate General's opinion, Case C-181/95, Biogen Inc. v. Smithkline Beecham Biologicals SA, 1997 E.C.R. I-00357.
59. A variation to the MA of a medicinal product must be approved through the same procedure as the MA. Thus, a new indication to a medicinal product approved through an MRP must also be approved through an MRP. Variations are currently regulated by Regulation 1085/2003, 2003 O.J. (L159) 24-45 (EC) concerning the examination of variations to the terms of a marketing authorization for medicinal products for human use and veterinary medicinal products falling within the scope of Regulation 2309/93, 1993 O.J. (L214) 1-21 (EEC) (centrally approved medicinal products) and Regulation 1084/2003, 2003 O.J. (L159) 1-23 (EC) concerning the examination of variations to the terms of a marketing authorization for medicinal products for human use and veterinary medicinal products granted by a competent authority of a Member State (MRP or DCP medicinal products). As of 1 January 2010, variations will be regulated by Regulation 1234/2008, 2008 O.J. (L334) 7-24 (EC) concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products. The new regulation simplifies without however substantially modifying the variation procedures.
60. Article 28(5) of EC Directive 2001/83.
61. Article 29 of EC Directive 2001/83.
62. Article 32 of EC Directive 2001/83.
63. Articles 33 and 34 of EC Directive 2001/83.
64. Article 34(3) of EC Directive 2001/83.
65. CMD(h) Recommendations for implementing Commission decisions following an Article 29 application under the Paediatric Regulation (Feb. 2009).
66. For example, for an application for a Type II variation (new indication), the average period for issuing the actual letter of approval is 3 months in France, 2 to 3 months in the Netherlands, 1 to 3 months in Spain, and 18 months in Poland. Luxembourg waits for the Belgian approval, which itself takes 7 months on average.
67. Cases where compliance was found at the time of filing of the regulatory application but denied during the scientific assessment so that the pediatric product is approved and the pediatric data is not compliant.
68. Case C-189/01, Jippes et al., 2001 E.C.R. I-5689, para. 81.
69. du Pont de Nemours, Application No. 950009. The decision was opposed by a generic company, but the opposition was dismissed.
70. du Pont de Nemours & Co [2009], Appeal.
71. New Article 10(6) of the SPC Regulation.
72. 6 February 2009; Merck & Co.. Inc's application, Case 0/035/09; 9 April 2009, du Pont de Nemours application, Case 0/096/09, 9 April 2009.
73. See footnote 73.
74. See footnote 72.
75. E. Nettleton, Paediatric Extensions: More SPC Disharmony?, Patent World, Oct. 2009, Issue 216, p.23.
76. Other Member States may have adopted the same position, but it is difficult to determine as some NPOs do not systematically publish their decisions on their website.
77. Netherlands: 22 February 2009, Merck & Co., Inc., Application No. 300287; UK: 14 April 2008, Merck & Co., Inc., BL 0/108/08. The UK decision was largely commented: Katza, Negative Term Supplementary Protection Certificates granted by UK Intellectual Property Office, JIPL&P 542 (2008); Snodin/Miles, Making the Most of Paediatric SPC Extensions, RAJ Pharma 387 (2008).
78. Snodin/Miles, Making the Most of the Paediatric SPC Extensions, RAJ Pharma 459 (2007) and RAJ Pharma 1 (2008); U. Gassner, Supplementary Protection Certificate and Paediatric Market Exclusivity, 6 A&R (2008); H. Leighton, Practicalities of Paediatric Extensions to the Supplementary Protection Certificate, 64 Journal of Generic Medicines 94 (2008).
79. On this specific issue see ECJ, 3 Sept. 2009, Case C-482/07, AHP Manufacturing.
80. Article 4 of the SPC Regulation: "Within the limits of the protection conferred by the basic patent, the protection conferred by a certificate shall extend only to the product covered by the authorization to place the corresponding medicinal product on the market and for any use of the product as a medicinal product that has been authorized before the expiry of the certificate."
81. Article 8 (2) of the Orphan Regulation provides for a reduction of market exclusivity (see below). Article 8 (3) provides for certain exceptions to market exclusivity. An MA may be granted for the same therapeutic indication to a similar medicinal product if (i) the MAH for the original orphan medicinal product has given his consent; or (ii) the MAH for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product; or (iii) the second applicant can establish in the application that the second medicinal product, although similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior. Regulation 847/2000, 2000 O.J. (L22) 53-55 (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' defines the concepts of 'similar medicinal product' and 'clinical superiority'.
82. On 17 September 2008, the European Commission adopted a guideline that sets out the general principles and procedures for reviewing and reducing the period of market exclusivity (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, 2008 O.J. (C242) 8-11 (EC)).
83. 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, 2008 O.J. (C242) 8-11 (EC). "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." 84 If the applicant for a PUMA also developed other, non-paediatric indications, he may file another application for those indications but that application would not go through the centralised procedure. 85 Case C-452/06, Synthon, 2008 O.J. (C313) 4. The ECJ ruled that a CMS may be held liable for damages for not having recognised the MA granted by the RMS.