The background to the complaint

1. The complainant is a company holding marketing authorisations for a prolonged-release medicinal product containing opioids (the 'A product'), which is sold throughout the European Union and used to treat severe pain[1].

2. On 16 April 2007, the complainant wrote to the Commission's Directorate-General for Enterprise and Industry expressing concern in relation to a number of products placed on the European market as generic prolonged-release opioid (the 'B product'). The complainant explained that, in January 2007, the German regulatory authority granted marketing authorisations for the B product to five applicant companies. Germany acted as the 'reference Member State' under the 'decentralised procedure' for granting marketing authorisations for medicinal products[2], and the A product served as the reference product for the B product.

3. According to the complainant, in March 2007, four out of those five companies had already placed the B product on the German market. Furthermore, the procedure for placing the B product in other Member States' markets was underway.

4. The complainant informed the Commission that it had conducted tests on the B product and found that, when combined with alcohol, the B product released the active substance more rapidly than the reference A product. This, according to the complainant, compromised patient safety and constituted a serious risk to public health. The consumption of alcohol whilst being prescribed a generic prolonged-release opioid product could result in patients suffering significant side effects, such as somnolence and respiratory depression and, in the worst case scenario, even a fatal overdose.

5. The complainant alerted the German authorities, which acknowledged, in a letter to the above five authorised manufacturers, that there was a risk associated with the B product. They further proposed that a warning be inserted in the B product's Summary of Product Characteristics and Patient Information Leaflet (the 'summary and leaflet') highlighting the danger of taking the B product with alcohol.

6. However, in the complainant's view, this proposal was insufficient. According to the complainant, the United States Food and Drug Administration (the 'US FDA') had the same view. The US FDA considers that if a product shows vulnerability to alcohol, it should be reformulated so that it conforms with the reference product that is not vulnerable to alcohol.

7. In addition, according to the complainant, the German authorities misinterpreted the data relating to the percentage of alcohol required to cause the B product to release the opioid in an uncontrolled fashion. Their proposed warning implied that the risk to patient safety arose only in instances when the B product was taken together with alcohol. However, the tests conducted by the complainant did not support such a conclusion. It was impossible to predict when alcohol consumption would cause risks for a patient taking the B product.

8. In the complainant's view, the only reasonable approach would be to withdraw the B product from the EU market and to suspend the marketing authorisations until the product's safety was confirmed through its reformulation. Relatedly, according to the complainant, the German authorities failed to comply with the precautionary principle because there was already a product on the market that did not present the same potential danger to public health.

9. In addition to the above, in its correspondence of 16 April 2007, the complainant asked the Commission to explain whether, in light of Case C-74/03 Smithkline Beecham Plc v Laegemiddelstyrelsen (the 'Synthon Case')[3], the B product could be considered as a generic of the reference product A, in accordance with the definition of a generic product given by Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (the 'Medicinal Code')[4], as amended[5]. Similarly, the complainant wished to know whether the B product should have been allowed to use the 'abridged' decentralised procedure provided for in that code[6]. In the complainant's view, the B product did not fall within the Medicinal Code's definition of generic medicinal product and, consequently, the applicant companies could not have used the decentralised abridged procedure to request their marketing authorisations.

10. In light of the above, the complainant requested the Commission to ask Member States to withdraw the marketing authorisations for the B product and suspend their assessment of the applications for marketing authorisations for the B product that were still pending.

11. Finally, with its letter dated 16 April 2007, the complainant forwarded to the Commission (i) a study on "The Effects of Ethanol on the Release of Opioids from Oral Prolonged-release Preparations" from authors at "Napp Pharmaceuticals Research Limited, Science Park, Milton Road, Cambridge UK" and the "Academic Unit of Clinical Pharmacology, University of Sheffield, The Royal Hallamshire Hospital, Sheffield" (the 'Ethanol Paper'); (ii) the report of the US "FDA's ACPS meeting, October 2005 awareness topic: mitigating the risks of ethanol induced dose dumping from oral sustained/controlled release dosage forms"; (iii) the "advisory press release from health Canada: potentially fatal interaction between slow-release opioid painkillers and alcohol", dated 3 August 2005; (iv) the complainant's own "data reference RPA study report 2007 [on] the effects of ethanol on the in-vitro dissolution rate of [the B product]", dated 11 March 2007; and (v) a "comparison of % API released for [the B product] with [A product] at different alcohol concentrations".

12. On 23 and 24 April 2007, the Commission raised the concerns set out in the complainant's letter dated 16 April 2007 at a meeting of the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (the 'CMD(h)')[7]. Germany, which acted as the reference Member State for the B product, reported that it had performed a formal risk-assessment procedure and concluded that the in vitro tests provided by the complainant had no clinical relevance. Nonetheless, it stated that, as a precaution, it decided to include information on the simultaneous taking of ethanol and sustained release formulations containing opioids in the relevant sections of the B product's summary and leaflet. There, it was outlined that the product should not be taken together with alcohol.

13. Subsequently, on 8 May 2007, the Commission replied to the complainant's letter dated 16 April 2007, stating that it was reassured that the reference Member State was already taking risk-minimisation measures. Moreover, the Member States involved in the then ongoing further marketing authorisation procedures had also been alerted to the matter. They would consider it in the course of the procedure with a view to addressing any possible concerns. Consequently, in the Commission's view, the relevant national authorities were addressing the complainant's concerns and no action on the Commission's part was therefore necessary. The Commission would, nevertheless, continue to monitor the ongoing procedures.

14. On 23 May 2007, the complainant requested to have a meeting with the Commission in order to explain the data gathered. It understood that the Commission did not deny that there was a safety issue with the B product. However, despite this fact, the Commission still endorsed the position of the German authorities as adequate. The complainant did not agree that the national authorities had duly addressed its concerns, and thus argued that the Commission should take action at the EU level. According to the complainant, this matter involved 'Community interests'. The Commission should, therefore, use the procedure provided for in Article 31 of the Medicinal Code, and refer that matter to a proper scientific evaluation at the Committee for Medicinal Products for Human Use (the 'CHMP'), with a view to protecting patients' health in the whole of the EU[8]. Finally, in the complainant's opinion, the Commission had failed to address its query relating to the definition of 'generic medicinal product' and the appropriateness of using the abridged decentralised procedure.

15. On 21 June 2007, the Commission met the complainant and received some information from it.

16. On 4 July 2007, the Commission forwarded the information it received on 21 June 2007 to the CMD(h). The Commission requested the CMD(h) to raise the matter with the Member States and keep it informed of any developments.

17. Between 16 and 18 July 2007, the CMD(h) discussed the above information.

18. On 26 July 2007, the complainant forwarded to the Commission its summary of the meeting of 21 June 2007. In the summary, the complainant outlined that, during the meeting, it provided evidence that the B product "dose-dumped"[9] in the presence of alcohol. Thus, the safety profile of the B product was very different from that of the reference product A. The Commission did not dispute the complainant's conclusions. However, it was not prepared to initiate the procedure provided for in Article 31 of the Medicinal Code that involved a referral to the CHMP. It considered that the national regulatory agencies, which were aware of the issues relating to the B product, were competent to draw their own conclusions as to whether the B product should be authorised or not. In the Commission's view, it was the national authorities' responsibility to decide whether the quality, safety and efficacy of the B product had been confirmed.

19. In accordance with the complainant's recollection of its meeting with the Commission of 21 June 2007, as detailed in the summary that the complainant prepared of that same meeting, the Commission considered that applicants for marketing authorisations were not precluded from using the abridged procedure if the medicinal product did not fall within the definition of a generic medicinal product. The applicants would, however, have to ensure that they supplemented their regulatory dossier with additional scientific information, as provided for in Article 10(3) of the Medicinal Code[10]. Consequently, the complainant concluded in its summary that the Commission agreed with its opinion that, in cases where there is a difference between the safety profiles of the generic medicinal product and the reference medicinal product, the procedure provided for in Articles 10(1) and (2) of the Medicinal Code is not appropriate.

20. The complainant asked the Commission to confirm that its understanding of the Commission's position was correct, and also to inform it whether there were any further developments relating to the ongoing decentralised procedures relating to the B product.

21. On 19 September 2007, the CMD(h) concluded that there were no safety problems with the generic versions of the opioid as long as they were used in accordance with the product information. On the hypothesis that they were indeed used with concomitant alcohol intake, the CMD(h) considered it highly unlikely that there would be any additional safety risks. The assessment made by Germany, which acted as reference Member State, allowed the conclusion that there was no dose-dumping for the generic opioid products. In addition, the CMD(h) had doubts as to whether time-resistance to alcohol, which was a parameter used in the in vitro dissolution test, was of physiological relevance.

22. On 20 September 2007, the Commission replied to the complainant's summary of the 21 June 2007 meeting. It emphasised that the summary reflected the complainant's interpretation of the meeting. The Commission did not share some of the assumptions and pointed out that it did not take any position during the meeting as to the scientific assessment of the B product. Nevertheless, the Commission confirmed that the competent authorities to assess the applications were indeed the national authorities to whom those applications were addressed. However, on the basis of the information provided by the complainant, the Commission decided to monitor the situation.

23. In its reply, the Commission further stated that Article 10(1) of the Medicinal Code provided for the production of appropriate data to demonstrate bioequivalence between the generic medicinal product and the reference medicinal product[11]. However, where the legal definition of a generic medicinal product did not apply, or where it was not possible to demonstrate bioequivalence through bioavailability studies, or where there were changes to the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration in relation to the reference product, applicants should provide, in accordance with Article 10(3) of the Medicinal Code, results of appropriate pre-clinical tests or clinical trials[12].

24. The Commission finally informed the complainant that it had requested the CMD(h) to assess the information it provided, and that it was waiting for the CMD(h)'s reply.

25. On 24 September 2007, the complainant emphasised to the Commission that it was seeking its interpretation of Article 10, paragraphs (1), 2(b) and (3) of the Medicinal Code in light of the Synthon Case. In this respect, the complainant argued that generic medicinal products and reference medicinal products need only be the same in terms of their active substance. However, if the excipient composition or the differences in impurities lead to differences in the health and safety profile of the generic medicinal product when compared to that of the reference medicinal product, then such a medicinal product could not fall within the definition of generic medicinal product, provided for in Article 10(2)(b) Medicinal Code[13]. In the complainant's view, in line with the Synthon Case[14], a generic product that differs for identified reasons in terms of safety or efficacy from the reference product, that is, which is not essentially similar, would fall under the procedure provided for in Article 10(3) of the Medicinal Code[15].

26. With its letter dated 24 September 2007, the complainant also enclosed a presentation on the "Prevalence and Costs of Concomitant Use of Alcohol in Medicaid Patients Dispensed Opioid Analgesics for Chronic Pain [by authors from] Purdue Pharma, I.P., Stamford, CT [and] Thomson Medstat, Ann Arbor, MI" (the 'Alcohol Use in Patients Presentation') and requested the Commission to forward it to the CMD(h). It finally noted that Denmark had granted six new marketing authorisations to products similar to the B product, and asked the Commission about the latest developments at the CMD(h).

27. Later, on 3 October 2007, the complainant sent to the Commission a "Communication [on the] Influence of Opioid Use on Surgical and Long-term Outcome After Resection for Chronic Pancreatis [f]rom the Departments of Surgery, Gastroenterology, Radiology, and Anasthesiology, Royal Liverpool University Hospital, Liverpool, UK" (the 'Opioids Communication'). In the complainant's view, the Opioids Communication evidenced that patients taking opioids ignored warnings and consumed alcohol.

28. On 5 October 2007, the Commission informed the complainant about the CMD(h)'s conclusions of 19 September 2007. The Commission was reassured by these conclusions and considered that it did not need to intervene further. It also informed the complainant that, according to the CMD(h), the Member States had approved applications for marketing authorisations relating to other similar medicinal products. Finally, as regards Article 10 of the Medicinal Code, the Commission stated that paragraph (2)(b) of that Article provided for general rules as regards data requirements for generic medicinal products, and paragraph 3 of that Article provided for additional results of appropriate pre-clinical tests or clinical trials in specific cases.

29. On 11 October 2007, the complainant replied arguing that the CMD(h) had scientific misconceptions as regards the Ethanol Paper. According to the complainant, the CMD(h) also ignored the problem analysed in the Alcohol Use in Patients Presentation and in the Opioids Communication relating to alcohol intake in patients who are prescribed opioids. In the complainant's view, that problem could not be solved by warnings in the summary and leaflets. Relatedly, the complainant was surprised that the German authorities did not consider dose-dumping to be of physiological relevance. It emphasised that, in the past, the Commission had removed another medicinal product from the market due to regulatory authorities', including the German authorities', concerns relating to the effect of alcohol on the prolonged-release mechanism. In the complainant's view, the Commission should refer the matter to the European Medicines Agency (EMA). Finally, the complainant considered that the Commission had yet again failed to give its interpretation of Article 10 of the Medicinal Code. The complainant therefore reiterated its request for such an interpretation.

30. On 8 November 2007, the Commission forwarded the Opioids Communication to the German authorities and informed the complainant accordingly. The Commission also reiterated to the complainant that it was reassured by the CMD(h)'s response and that the matter should be dealt with by the relevant national authorities. In addition, it stated that the CMD(h)'s conclusion that there was no risk to public health was shared by the authors of the Ethanol Paper[16]. The Commission further informed the complainant that, for the ease of the regulators and companies concerned, it had published a notice to applicants for marketing authorisations with a view to addressing key issues of interpretation of the new legislation (the 'Notice to Applicants'): "Volume 2A 'Procedures for marketing authorisation / Chapter 1 'Marketing Authorisation'" of the Notice to Applicants provided for a clear outline of how the Commission interpreted the possible application and data requirements necessary for each of the procedures.

31. On 14 November 2007, the complainant stated that the Commission had also misunderstood the Ethanol Paper. In this regard, the complainant pointed out that the Ethanol Paper evidenced that the reference product A was not vulnerable to dose-dumping. It did not make any reference to the B product. Other data, presented to the Commission on a number of occasions, clearly showed that the B product was vulnerable to dose-dumping. The Commission referred to a statement made in the Ethanol Paper which related specifically to the complainant's A product. Such a statement could not, therefore, be taken out of context and viewed as a general statement on the safety of all prolonged-release opioid products. According to the complainant, the Ethanol Paper actually called for the testing of all prolonged-release opioid products to ensure the absence of dose-dumping in the presence of alcohol. Relatedly, the complainant disagreed with some of the CMD(h)'s conclusions relating to ingestion of alcohol by patients taking generic prolonged-release opioid products. It presented some new information relating to the gastric residence of A product when compared to that of the B product.

32. In its letter dated 14 November 2007, the complainant also concluded that the Commission shared its interpretation of Article 10 of the Medicinal Code, in light of the Synthon Case: a generic product that differs for identified reasons in terms of safety and/or efficacy from the reference product, that is, which is not essentially similar, should undergo the procedure provided for in Article 10(3) of the Medicinal Code. In this respect, the complainant emphasised that all applications for the B product were submitted under paragraphs (1) and (2) of Article 10 of the Medicinal Code. However, in light of the clear safety differences between the reference A product and the B product, which were evidenced further by the additional warnings in the B product's summary and leaflet, the Commission now needed to address an infringement of the Medicinal Code; in particular, the failure to follow correct procedures to obtain a marketing authorisation for a medicinal product.

33. Finally, with its letter dated 14 November 2007, the complainant forwarded to the Commission (i) an article on "Predictability of the Potential for Ethanol Released Dose Dumping in Oral Prolonged Release Opioid Formulations" of its own authorship; (ii) a paper on "Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging", from the University of Greifswald and the University Hospital Charité, Berlin, Germany; (iii) a paper on the "Impact of the intragastric location of extended release tablets on food interactions", from the University of Greifswald, the Physikalisch-Technische Bundesanstalt and the Universitätsmedizin Berlin, Germany, and AstraZeneca R and D Mölndal, Sweden; and (iv) extracts from the European Product Index website. The complainant had already brought all of the above to the attention of the relevant national authorities.

34. On 5 December 2007, the Commission replied expressing its regret that the complainant had "misunderstood" its reference to the Ethanol Paper. It also reiterated that any further scientific discussions should be carried out with the relevant competent national authorities. It finally referred to its previous letters dated 20 September, 5 October and 8 November 2007 regarding its interpretation of Article 10 of the Medicinal Code.

35. On 15 January 2008, the complainant reiterated that the Commission had misinterpreted the Ethanol Paper. Moreover, it failed to address the complainant's concerns expressed in its letters dated 24 September, 11 October and 14 November 2007. In this respect, the complainant emphasised that it had provided in vitro data evidencing that the B product's prolonged-release mechanism did not remain intact in the presence of ethanol. When extrapolated to in vivo situations, the data indicated that there was a potentially serious risk of dose-dumping. In the complainant's view, on the basis of the evidence received, the Commission should thus refer the matter to the CHMP. It should also take action to ensure the correct application of Community law, notably by dealing with the Member States' failure to follow correct procedures to obtain a marketing authorisation.

36. On the same date, the complainant wrote also to the then Commissioner for Enterprise and Industry and Vice-President of the Commission (the 'Commissioner'), requesting him to intervene. The complainant added that one national authority had in the meantime reversed its decision to grant substitution status to the B product on the basis that problems occurred if patients did not comply with the additional warnings relating to alcohol.

37. On 25 January 2008, the complainant sent to the Commission and the national authorities two expert opinions regarding public safety risks associated with alcohol-vulnerable prolonged-release opioids. In the complainant's view, the above expert opinions contradicted the CMD(h)'s conclusions.

38. On 11 February 2008, the Commissioner replied to the complainant's letter dated 15 January 2008, stating that he was determined to ensure the highest level of patient safety. The Commissioner informed the complainant that he had instructed his services to thoroughly re-examine the relevant issues, including whether there were any new scientific findings that had not been taken into account by the national experts in their meeting of July 2007.

39. On 19 March 2008, the Commission wrote to the complainant stating that it had always replied to its communications and given it the opportunity to explain and provide all data it considered necessary. The Commission emphasised in this regard that it was up to the CMD(h) to assess the complainant's data because it concerned medicinal products that had been authorised at the national level. The CMD(h) had given due consideration to the complainant's information on the safety of the B product. Relatedly, the national authorities had further evaluated the latest scientific elements provided by the complainant. Therefore, the Commission did not need to trigger the Community procedure in this case. Nonetheless, it would continue closely to follow developments regarding this matter. Finally, according to the Commission, there was no evidence of any infringement of the Community legal framework in the procedure for granting the marketing authorisations for the B product.

40. On 7 May 2008, the complainant sent to the Commission (i) a new expert opinion, which it had also forwarded to the national authorities; and (ii) a response from the US FDA to two petitions, in which it set out its position in relation to prolonged-release opioids which were vulnerable to alcohol. According to the complainant, the above documents supported its position concerning the safety and marketing of the B product.

41. On 21 May 2008, the Commission forwarded the above documents to the CMD(h) to be considered in the framework of its ongoing assessment of the remaining documentation received from the complainant.

42. In June 2008, the CMD(h) discussed the additional information provided by the complainant in a meeting.

43. On 11 July 2008, the CMD(h) reported to the Commission that Germany, which acted as the reference Member State for the B product, and the UK, which was one of the Member States concerned by the application for marketing authorisation of the B product, had prepared detailed assessment reports on the additional documentation[17]. Germany concluded that the clinical relevance of the complainant's data was marginal. Therefore, the CMD(h) agreed that its original decision should remain unchanged. Furthermore, in the leaflet for both the reference product and the generic medicinal products, it was clearly indicated that the product should not be taken with alcohol. Relatedly, the UK had discussed the possible clinical significance of a "worst case scenario" if the patients disregarded the information provided in the package leaflet. It also discussed whether the warnings in the leaflet were sufficient to prevent patients from taking alcohol concomitantly. The CMD(h) further considered that it was unclear how it was possible to predict an in vivo interaction based on static in vitro data.

44. Notwithstanding its above considerations, the CMD(h) took note of the US FDA's approach to the requirements of an in vitro dissolution test. Subsequently, it decided to ask the CHMP 'Quality Working Party' (the 'CHMP QWP') to advise it on the possible need for routine in vitro dissolution testing to investigate the possibility of an alcohol interaction for all modified-release dosage forms of oral opioid products. The CMD(h) sought advice as to what should be considered "relevant" in vitro studies and how it should interpret the results of the in vivo clinical situations. The CMD(h) further considered that there could also be the need to involve the CHMP 'Efficacy Working Party' (the 'CHMP EWP'). Finally, it had also decided to contact a number of patient groups and discuss whether they considered warnings in the leaflet adequate to prevent patients from consuming alcohol concomitantly with opioids and/or had suggestions to improve the text.

45. On 31 July 2008, the complainant turned to the Ombudsman.

The subject matter of the inquiry

46. In its original complaint, the complainant alleged that the Commission acted unlawfully by not referring the issue of the potential serious risk to public health to the CHMP, and that it failed to provide reasons for this failure.

47. The complainant also alleged that the Commission acted unlawfully by not pursuing the Member States for a procedural violation of Community law, that is, using a wrong procedure in authorising the B product, and that it failed to provide reasons for this failure.

48. The complainant claimed that the Commission should address and remedy the above two instances of maladministration.

49. After the Ombudsman opened his inquiry into the above allegations and claims, the complainant and the Commission continued to exchange bilateral correspondence on the subject-matter of the complaint, which they also copied to the Ombudsman.

50. The Ombudsman finds it useful to emphasise in this respect that, as correctly pointed out by the Commission, conducting discussions in parallel with the Ombudsman's inquiry would result in an unnecessarily long inquiry and make it impossible for the Ombudsman to decide on the complaint until all relevant facts had been duly discussed by the parties and brought to his attention.

51. In light of the factual developments reported in the above-mentioned correspondence and, notably of the fact that, on 18 September 2009, the Commission used the procedure provided for in Article 31 of the Medicinal Code to refer the matter to the CHMP, the Ombudsman considers that the complainant's first allegation and the related claim as originally formulated have become devoid of purpose.

52. In this respect, however, the Ombudsman notes that, in its correspondence with the Commission subsequent to the referral the complainant formulated a new allegation that the Commission had failed to act in due time and that the scope of its referral was too broad. The Commission outlined its position on this new allegation in its subsequent replies, which were also copied to the Ombudsman.

53. Therefore, in light of the above developments, the Ombudsman deals with the following allegations and claims in the present decision:

Allegations:

(1) The complainant alleges that the Commission (i) failed to refer the issue of the potential serious risk to public health of the B product to the CHMP in a timely way and (ii) wrongly extended the scope of its referral to matters other than those relating to the B product.

(2) The complainant also alleges that the Commission acted unlawfully by not pursuing the Member States for a procedural violation of Union law, that is, for using the wrong procedure in authorising the B product.

Claim:

The complainant claims that the Commission should pursue the Member States for a procedural violation of the Community law; that is, using the wrong procedure in authorising the B product.

54. Finally, the Ombudsman points out that the present decision will not deal with any of the matters referred to by the parties which are not directly related to the above allegations and claim. Should the complainant have any grievances against the Commission in respect of any such other matters, it could submit a new complaint to the Ombudsman, after making the necessary prior administrative approaches to the Commission in this regard[18].

The inquiry

55. On 15 October 2008, the Ombudsman forwarded the complaint to the President of the European Commission.

56. On 11 February 2009, the Ombudsman received the Commission's opinion, which he forwarded to the complainant with an invitation to make observations. On 31 March and 7 May 2009, the complainant sent its observations.

57. On 29 June 2009, the Ombudsman forwarded the complainant's observations to the Commission, asking it to provide additional comments on the following questions:

"(1) Has the Commission carried out any assessment of the information and the scientific papers which [the complainant] brought to its attention by letters of 11 October 2007, 14 November 2007, 25 January 2008 and 7 May 2008? If so, with what conclusions? Or has the Commission merely relied on the fact that [the complainant], or the Commission itself, sent the above scientific papers to the competent national authorities?

(2) Having regard to the above information and scientific papers, as well as to the information contained in the related correspondence to the Ombudsman and the Commission dated 7 May 2009, is the Commission still of the opinion that the measures adopted by the CMD(h) are sufficient to address the safety issue raised by [the complainant]? In the absence of in vivo data, and considering the risk that has been highlighted by the in vitro data, does the Commission still consider that no referral to the CHMP is necessary? Could the Commission explain the reasons for its opinion?

(3) In light of the same information, is the Commission still of the opinion that there is no evidence of a procedural violation of Community law? Could the Commission explain the reasons for its opinion?"

58. The Commission replied on 8 October 2009. The Ombudsman forwarded the Commission's reply to the complainant for its observations.

59. On 23 October and 16 December 2009, the complainant sent its observations.

The Ombudsman's analysis and conclusions

Preliminary remarks

60. The Treaty on the Functioning of the European Union (TFEU) empowers the Ombudsman to receive complaints concerning instances of maladministration in the activities of the Union institutions, bodies, offices or agencies with the exception of the Court of Justice of the European Union acting in its judicial role[19].

61. The Ombudsman has no powers to deal with complaints against the authorities of Member States, even if they involve an alleged violation of EU law. Consequently, the Ombudsman’s inquiry in the present case only concerns the possibility of maladministration by the Commission.

62. The Ombudsman recalls that ombudsmen in the Member States are competent to deal with complaints concerning alleged violations of EU law by the authorities they supervise.

A. Allegation that the referral to the CHMP was too late and too broad in scope

Arguments presented to the Ombudsman

[20]

63. The complainant alleged that the Commission (i) failed to refer the issue of the potential serious risk to public health of the B product to the CHMP in a timely way and (ii) wrongly extended the scope of its referral to matters other than those relating to the B product.

64. The complainant argued that it had provided the Commission with expert opinions supporting the view that opioid patients who consumed alcohol could be exposed to a serious risk of dose-dumping. If the Member States had taken due note of the above evidence, and in the absence of relevant in vivo data, they would not have concluded that the B product was safe. Consequently, the consensus reached at the CMD(h) that the warnings were sufficient was essentially groundless.

65. Relatedly, according to the complainant, at least one Member State (the Czech Republic) raised concerns regarding alcohol vulnerability. Some other Member States also clearly had difficulty accepting Germany's assessment. Consequently, the Member States failed properly to deal with the safety issue raised by the complainant and the Commission was thus faced with an identified 'Community interest' which could not be rectified at the national level. The Commission was thus obliged to trigger the referral provided for in Article 31 of the Medicinal Code.

66. With its observations, the complainant attached a new Expert Declaration, dated 16 December 2008, which, in its view, attested that the generic applicants should have been required to perform in vivo studies in order to determine the effect of alcohol on the controlled release of opioids in the body[21].

67. In the meantime, the complainant also sent to the Commission a number of new documents directly, notably (i) the "Need for in vitro Dissolution Studies with Alcohol for Modified Release Oral Products Including Opioid Drug Products"; and (ii) "Questions & Answers: Positions on specific questions addressed to the [CHMP] EWP therapeutic subgroup on Pharmacolinetics" (the 'Q&A'), dated 22 January 2009, both of which are published on EMA's website; (iii) a publication on "Ethanol-Drug Absorption Interaction: Potential for a Significant Effect on the Plasma Pharmacokinetics of Ethanol Vulnerable Formulations"[22]; and (iv) a study report on the "Use of opioid analgesics in patients with and without alcohol related diagnoses and the incidence of opioid intoxication", from the Bremen Institute for Prevention Research and Social Medicine[23].

68. The complainant further argued that the CMD(h) did not have the means to carry out scientific assessments. The CMD(h) was, in the complainant's view, rather a forum where representatives of the Member States agreed on practical guidance in order to assist applicants in the context of certain procedures for the grant of marketing authorisations. Whilst the CMD(h) could resolve a disagreement relating to a specific product based on the information put before it, it was not the task of its members, albeit scientists, to resolve scientific issues which required broader analysis. The CMD(h)'s own Rules of Procedure provided that scientific matters should be referred to EMA[24].

69. In reply, the Commission pointed out that, in light of the fact that the applicant for the B product had sought the marketing authorisation under the mutual recognition/decentralised procedure, the body that had primary responsibility for issues connected with that marketing authorisation was the CMD(h). The members of the CMD(h) act on behalf of the relevant national authorities[25], which are responsible for granting most of the marketing authorisations for medicinal products in the EU.

70. The complainant was, according to the Commission, wrong to state that the CMD(h) could not make scientific assessments. The Commission referred in this respect to the CMD(h) Rules of Procedure and emphasised that the complainant made reference to an article of those rules that dealt with requests for advice from companies or Member States[26]. The complainant did not make any such request for scientific advice to the CMD(h).

71. The Commission also explained that, in accordance with the Medicinal Code, the CMD(h) solved cases with diverging opinions among the Member States in the context of the granting, suspension, withdrawal, revocation or variation of marketing authorisations[27]. The CMD(h)'s main role was not to produce guidance, assist applicants or give advice, but rather to consider points of disagreement raised by Member States and resolve issues to avoid referrals to the CHMP[28]. The complainant raised a matter that concerned a marketing authorisation, which thus fell under the CMD(h)'s core task in the context of the mutual recognition/decentralised procedure. Decisions relating to the marketing authorisation of the B product, including those potentially required on grounds of public health, could only be made by competent Member State authorities[29].

72. According to the Commission, the CMD(h) consulted the CHMP QWP on matters relating to tests necessary to investigate the possibility of alcohol interaction for 'modified release dosage form oral opioid products' in the context of the CMD(h)'s assessment of the risk of dose-dumping of opioids in the presence of alcohol. On 22 January 2009, the CHMP QWP replied in relation to the specific case of the B product, taking the view that appropriate warnings in the product literature were sufficient[30]. Notwithstanding this fact, the CHMP QWP also recommended that the CHMP EWP be consulted on the clinical relevance of physiochemical incompatibility with co-administered alcohol. The latter delivered its opinion, covering a large range of products, including the B product, on 23 July 2009.

73. The complainant noted that, according to the CHMP QWP's opinion, warnings in the literature of a medicinal product that indicate vulnerability to alcohol through in vitro testing could be sufficient in some circumstances. However, they would not be sufficient where there were serious concerns with respect to efficacy and safety.

74. Relatedly, according to the complainant, the CHMP EWP, which was the independent scientific body at the EU level with competence on clinical issues, considered the influence of alcohol and the risk for unexpected release caused by alcohol ingestion important for both modified and generic release formulations. Therefore, according to the CHMP EWP, warnings were not an adequate means of addressing a potentially clinically important formulation interaction with alcohol.

75. In reply to the Ombudsman's request for further information, the Commission explained that, under the pharmaceutical acquis, the network of national and European bodies are responsible for authorising medicinal products. They were also responsible for the activities relating to the surveillance of adverse reactions and quality and/or safety concerns which could result in suspension or revocation of marketing authorisations.

76. The Commission thus emphasised that, in accordance with the legislation in force, it has no tasks relating to the performance of scientific assessments on medicinal products. Such assessments fall under the competence of EMA and the Member States' network of medicines agencies. The legislator, acting in the interest of public health, excluded possible undue political and economic influence by separating scientific assessment tasks from the Commission.

77. According to the Commission, its role is thus exclusively regulatory. This role differs greatly depending on whether a medicinal product is authorised centrally or nationally. The 'centrally authorised medicinal products' are authorised by the Commission, following a scientific evaluation by the CHMP. For such products, the Commission is also responsible for the regulatory follow-up, notably through the inclusion of warnings, or the suspension and even withdrawal of central marketing authorisations on the basis of safety and quality concerns, following scientific advice from the CHMP. In case of the 'nationally authorised medicinal products', such as in the case at hand pertaining to the B product, the Member State authorities are responsible for issuing the marketing authorisations and conducting all post-marketing surveillance activities, such as detecting potential safety issues and ensuring the necessary follow-up through scientific assessments, inspections and/or regulatory actions on the marketing authorisation.

78. Notwithstanding the above facts, the Commission also pointed out that it has the power to act with regard to nationally authorised medicinal products in a limited number of cases. It may refer a matter relating to such products to the CHMP with a view to adopting a Commission decision binding on the Member States. However, the 'interests of the Community', provided for in Article 31 of the Medicinal Code, do not concern every case in which the safety of nationally authorised medicinal products is disputed. The Medicinal Code provides for the necessary tools and obligations for such concerns to be addressed by the Member States. It is not because a company highlights a potential serious risk to public health that the Commission has to refer the matter to the CHMP. Moreover, the Community interest referral is not intended to provide companies with an opportunity to overrule the scientific assessment made by the competent national authorities.

79. If the Commission starts a Community interest referral, it deprives Member States of their competence to deal with their national medicinal product. Indeed, after the matter is referred to the CHMP, the Commission may issue a decision that will override previous national decisions on the same matter. In order to be able to launch the referral provided for in Article 31 of the Medicinal Code, it is necessary that the Member States first fail adequately to deal with the matter in question or that the Community action is considered a better way to address the issue, in strict respect of the principle of subsidiarity. Typical cases where the Commission has launched a Community interest referral have thus been those where Member States' scientific assessments provided for different conclusions.

80. Relatedly, in the case of centrally authorised medicinal products, the Commission, acting within the powers conferred to it by the relevant EU legislation and assisted by the CHMP with regard to the scientific evaluation, is the competent authority to analyse the data submitted to it[31]. In case of a nationally authorised medicinal product, such as the B product, the Commission is not competent to analyse the data. This falls under the responsibility of the relevant national authorities.

81. Therefore, although it carefully analysed all information the complainant had brought to its attention, the Commission did not make any scientific assessments, nor did it evaluate the data and the studies provided in order to see whether they supported the complainant's positions vis-à-vis the B product. The Commission rather ascertained whether the issue brought up by the complainant was a "specific case where the interests of the Community were involved", in accordance with Article 31 of the Medicinal Code and in light of the fact that the B product was a 'nationally authorised medicinal product'. In doing so, the Commission first identified the safety concern in question, and, second, assessed whether that concern was being dealt with adequately by the Member States.

82. In this respect, the Commission stated that it was initially satisfied that the Member States had adequately dealt with the situation by conducting scientific assessments and reaching a unanimous conclusion providing for a safety warning concerning the intake of alcohol with all products containing opioids. Consequently, the Commission concluded that the conditions for launching a Community referral were not fulfilled.

83. However, according to the Commission, the CMD(h) subsequently decided to consult the CHMP. The CHMP EWP issued an opinion that concerned a much larger range of products than the B product. It found that warnings were not sufficient to address potential safety concerns in some cases[32]. Consequently, the Commission decided, on 18 September 2009, that is, after the Ombudsman's request for further information, to launch a referral under Article 31 of the Medicinal Code.

84. This referral concerned the interaction with alcohol of modified-release oral opioid products at "level III of the WHO" scale for the management of pain (intense sustained pain resistant to previous medications). The Commission informed the complainant that it would take a decision, on the basis of the CHMP's subsequent opinion on whether additional measures were needed in respect of the opioid medicinal products existing on the market.

85. The Commission also rejected the complainant's allegation that it should have referred the specific case of the B product to the CHMP a long time ago. It argued in this respect that, until the CHMP EWP issued its opinion, both the CMD(h) and the CHMP QWP unanimously agreed on the measures already taken in connection with the B product. Consequently, it was not justified to trigger a referral, given that all the Community bodies that examined the issue were in agreement as to the measures taken in connection with the B product. In addition, the Court of Justice of the European Union has ruled that recourse to the referral procedure entailed a transfer of competence from the Member States to the Commission, which therefore has to be interpreted strictly, limiting such a referral to the cases expressly foreseen in the legislation[33].

86. The complainant expressed surprise that, in spite of the CHMP EWP's statement that warnings were an inadequate safeguard as regards the risk posed by alcohol-vulnerable opioids available on the EU market, such as the B product, the Commission found it appropriate to trigger a referral which covered a much broader range of issues and products. According to the complainant, the Commission's referral even covered products which were not vulnerable to alcohol, such as the A product, and issues which, although important, were not as urgent as those relating to the B product, such as labelling. Thus, in the complainant's view, the referral triggered by the Commission could have the effect of delaying any conclusion being reached on the B product and thus prolonging the risk associated to that product for EU patients.

87. Thus, in its observations on the Commission's reply to the Ombudsman's request for further information, the complainant suggested that the Commission may have been prompted to trigger the referral because the CHMP EWP's opinion on the clinical relevance of physicochemical incompatibility with co-administered alcohol was inconvenient to it. Moreover, triggering a referral only now, and on a broader range of products and issues than those relating to a medicinal product which was on the market and which, in the opinion of the CHMP EWP, posed a risk to patients which had not been adequately addressed, was not the measure sought by the complainant, but rather a delaying tactic. It thus did not, in the complainant's view remedy what the complainant characterised as "the Commission's maladministration".

88. Finally, the Commission's references to the case-law of the Court of Justice of the European Union[34], according to which the recourse to the referral procedure entailed a transfer of competence from the Member States to the Commission, which therefore had to be interpreted strictly and limited to the cases expressly foreseen in the legislation, were, in the complainant's view, not justified. That case-law was decided on the basis of Article 31 of the Medicinal Code "in its previous incarnation"[35], which provided the following: "[t]he Member States or the Commission or the applicant or holder of the marketing authorisation may, in specific cases where the interests of the Community are involved, refer the matter to the [CHMP]..." At present, Article 31 of the Medicinal Code states that: "[t]he Member States or the Commission or the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Community are involved, refer the matter to the [CHMP]..." In the complainant's view, changes to the pharmaceutical legislation that were introduced in 2004 clearly make the referral procedure obligatory in specific cases where the interests of the Community are involved. This was a specific case where the interests of the Community were undeniably involved, because the B Product posed a potential serious risk to public health. Consequently, the Commission was obliged to trigger an Article 31 referral in relation to the specific case of the B product when it became apparent that the Member States were not adequately addressing the issue at stake.

The Ombudsman's assessment

The legal framework

89. The TFEU, in force since 1 December 2009, provides that common safety concerns in public health matters are subject to a shared competence between the Union and the Member States[36]. The Union shall have competence to carry out actions to support, coordinate or supplement the actions of the Member States in, notably, the protection and improvement of human health[37]. Union action, which shall complement national policies, shall be directed towards improving public health. It shall "respect the responsibilities of the Member States for the definition of their health policy and for the organisation and delivery of health services and medical care." The responsibilities of the Member States shall include the management of health services and medical care and the allocation of the resources assigned to them[38].

90. According to Article 35 of the Charter of Fundamental Rights of the European Union, "[e]veryone has the right of access to preventive health care and the right to benefit from medical treatment under the conditions established by national laws and practices. A high level of human health protection shall be ensured in the definition and implementation of all the Union's policies and activities."[39]

91. In this context, the Ombudsman notes that, according to the Medicinal Code, the essential aim of any rules governing the production, distribution and use of medicinal products must be to safeguard public health. This is to be attained by means which do not hinder the development of the pharmaceutical industry or trade in medicinal products within the Community. However, disparities between certain national provisions may hinder trade in medicinal products and directly affect the functioning of the internal market. Such hindrances must therefore be removed accordingly. Thus, a set of rules was laid down on the control of medicinal products, accompanied by duties incumbent upon the Member States' competent authorities ensuring compliance with legal requirements[40].

92. The Medicinal Code represents an important step towards achieving the free movement of medicinal products[41]. It provides for a procedure whereby a marketing authorisation for a medicinal product granted by a competent authority in one Member State is recognised by the competent authorities of another Member State unless there are serious grounds that the authorisation of the medicinal product concerned may present a risk to public health. In the event of a disagreement between Member States about the quality, the safety or the efficacy of a medicinal product, a scientific evaluation of the matter is undertaken according to a Community standard. This leads to a single decision being taken in the area of disagreement, which is binding on the Member States concerned[42].

93. In order better to protect health and avoid any duplication of effort during the examination of application for a marketing authorisation for medicinal products, Member States systematically prepare assessment reports in respect of each medicinal product authorised by them and exchange the reports upon request. Ultimately, they are able to suspend the examination of an application which is under active consideration in another Member State with a view to recognising the decision reached by the latter Member State[43]. No medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State in accordance with the Medicinal Code[44].

94. With a view to granting marketing authorisation for a medicinal product in more than one Member State, an applicant shall submit an application based on an identical dossier in those Member States. It shall request one Member State to act as a 'reference Member State' and to prepare an assessment report on the medicinal product. If the medicinal product has already received a marketing authorisation at the time of application, the 'concerned Member States' shall recognise the marketing authorisation granted by the reference Member State. To this end, the marketing authorisation holder shall request the reference Member State either to prepare an assessment report on the medicinal product or, if necessary, to update any existing assessment report. The reference Member State shall prepare or update the assessment report and send it together with the approved summary of product characteristics, labelling and package leaflet to the concerned Member States and to the applicant[45].

95. If a Member State cannot approve the assessment report, the summary of product characteristics, the labelling and the package leaflet because of a potentially serious risk to public health, it shall provide in detail the reasons for its position to the reference Member State, to the other Member States concerned and to the applicant.

96. The above points of disagreement are then referred to a coordination group which examines questions relating to the marketing authorisation of a medicinal product in two or more Member States. This coordination group is composed of one representative per Member State, which is appointed for a renewable period of three years and has its secretariat at EMA[46]. Within the coordination group, all the above Member States shall use their best endeavours to reach an agreement on the action to be taken[47]. If two or more applications have been made for marketing authorisation for a particular medicinal product, and if Member States have adopted diverging decisions concerning the authorisation of the medicinal product or its suspension or revocation, a Member State, the Commission, the applicant or the marketing authorisation holder may refer the matter to the CHMP[48].

97. Relatedly, according to Article 31(1) of the Medicinal Code, the Member States or the Commission, the applicant or the marketing authorisation holder shall, in specific cases where the interests of the EU are involved, refer the matter to the CHMP before any decision is reached (i) on a request for a marketing authorisation; (ii) concerning the suspension or revocation of an authorisation, (iii) in relation to any other variation to the terms of a marketing authorisation which appears necessary, in particular to take account of the information collected in accordance with the provisions of the Medicinal Code relating to pharmacovigilance[49].

98. The CHMP shall then consider the matter concerned and issue a reasoned opinion within a certain deadline. EMA shall inform the applicant or the marketing authorisation holder where the CHMP is of the opinion that (i) the application does not satisfy the criteria for authorisation; (ii) the summary of the product characteristics proposed by the applicant or the marketing authorisation holder should be amended; (iii) the authorisation should be granted subject to certain conditions, in view of conditions considered essential for the safe and effective use of the medicinal product including pharmacovigilance; or (iv) a marketing authorisation should be suspended, varied or revoked. The applicant or the marketing authorisation holder may request a re-examination of the opinion.

99. EMA forwards the final opinion of the CHMP to the Member States, to the Commission and to the applicant or the marketing authorisation holder, together with a report describing the assessment of the medicinal product and stating the reasons for its conclusions. The opinion may be in favour of granting or maintaining an authorisation to place the medicinal product concerned on the market[50].

100. After receiving the above opinion, the Commission prepares a draft decision on the application taking into account EU law. Where, exceptionally, the draft decision is not in accordance with EMA's opinion, the Commission shall provide a detailed explanation on the reasons behind the differences. The draft decision shall be forwarded to the Member States and the applicant or the marketing authorisation holder[51].

101. The Commission shall take a final decision, which is addressed to all Member States and which is sent to the marketing authorisation holder or applicant for information. The concerned Member States and the reference Member State shall either grant or revoke the marketing authorisation, or vary its terms as necessary to comply with the decision[52].

The assessment of the allegation

102. Having regard to the above legal framework, the Ombudsman understands the facts of the complaint as follows: the applicants for marketing authorisation of the generic B product decided to submit their applications in Germany. Consequently, acting as the reference Member State, Germany carried out its assessment and granted the requested marketing authorisation. Expectedly, under the mutual recognition procedure, this assessment would be recognised by all other concerned Member States where the B product was to be marketed.

103. However, the complainant, who holds the marketing authorisation of the product which served as a reference for the generic B product, and is therefore its direct competitor, was able to provide in vitro tests attesting that the B product, in contrast to the reference product, was vulnerable to alcohol. After the Commission and the national authorities were alerted to this fact, Germany proposed for warnings to be included in the B product's summary and leaflet drawing attention to the dangers of taking it with alcohol. The complainant found this measure insufficient and considered that the Commission should intervene. In support of its position, it provided the Commission with a number of scientific publications evidencing that patients taking strong opioids would disregard such a warning and consume alcohol. However, the Commission decided to intervene only when the CHMP EWP issued an opinion stating that warnings may not be sufficient to deal with concerns relating to opioids' vulnerability to alcohol.

104. It is therefore necessary to assess whether the Commission should indeed have intervened earlier, that is, in direct reply to the complainant's concerns, or whether it was correct to leave the decision concerning the measures to adopt with regard to the B product to the Member States.

105. The B product applicants sought and obtained marketing authorisation from the German authorities. It follows that the B product is, as the Commission pointed out, a 'nationally authorised medicinal product'. The Ombudsman thus understands that the Commission had no role to play in the authorisation process. In these circumstances, it is reasonable to assume that it would be for the relevant national authorities, and not for the Commission, to conduct any activities after that authorisation was granted, and notably to assess any concerns that could be raised with respect to the safety and/or efficacy of the medicinal product in question. Applied to the case at hand, it was appropriate for the complainant's concerns to be addressed to the German authorities, as they indeed were in the present case.

106. In addition to the complainant's own initiative to inform the German authorities directly about its findings, which resulted in Germany advising the applicant companies to include a warning on the B product summary and leaflet, the Commission duly submitted all of the complainant's concerns to Germany in the context of the CMD(h). The German and the other national authorities were thus able to assess (i) the various scientific studies enclosed with the complainant's correspondence of 16 April 2007 and, notably, the Ethanol Paper; (ii) the information submitted by the complainant during the meeting with the Commission of 21 June 2007; (iii) the Opioids Communication, submitted by the complainant to the Commission on 3 October 2007; (iv) the article and the papers referred to in the complainant's correspondence of 14 November 2007 and submitted to the national authorities directly by the complainant; (v) the two expert opinions the complainant submitted on 25 January 2008; and (vi) the expert opinion and the US FDA's response to two citizens petitions, submitted by the complainant on 7 May 2008.

107. Relatedly, the CMD(h), that is, the representatives of the Member States, gathered in the coordination group to examine questions relating to marketing authorisations of medicinal products in two or more Member States[53], assessed the evidence submitted by the complainant on 23 and 24 April 2007 and between 16 and 18 July 2007. Thus, it is undisputed that both Germany, the reference Member State and, therefore, the first and foremost addressee of the complainant's concerns, as well as all other Member States where the B product marketing authorisations were still pending, that is, the concerned Member States, were duly informed about the scientific data provided by the complainant and could take any action that they deemed appropriate. In this respect, the Ombudsman notes that, in addition to meeting the complainant on 21 June 2007, the Commission informed the complainant about the results of the CMD(h)'s above assessments on 8 May and 5 October 2007.

108. At first, the Member States agreed unanimously that including warnings on the B product's summary and leaflet was a measure appropriate to deal with the safety concerns raised by the complainant. Later, however, following its latest assessment at the meeting of June 2008, on 11 July 2008 the CMD(h) decided to consult the CHMP QWP and EWP on matters relating to alcohol-interaction testing for opioid products. Additionally, the CMD(h) decided to consult a patients' group on the adequateness of the proposed warning. The Commission informed the complainant about the above on 22 August 2008. In these circumstances, the Ombudsman takes the view that the Commission was entitled to consider that it should abstain from itself taking any action at that stage, given that the CMD(h) appeared to have taken account of the complainant's remarks regarding the adequacy of in vitro testing and the warning, and sought the advice of the CHMP.

109. The Ombudsman notes the CMD(h)'s references to the opinion expressed by the UK and the complainant's references to the Czech Republic[54]. Although it appears that, at some point, the Member States would have adopted different approaches to the matters referred to them by the complainant, they were still able to deal with them by acting in accordance with the rules provided for in the Medicinal Code. Thus, the Ombudsman sees no reason why the Commission, and not the Member States, should have been obliged to intervene in a procedure relating to a 'nationally authorised medicinal product' by making a referral to the CHMP itself, at that stage.

110. Subsequently, on 9 July and 12 August 2009, the Commission informed the complainant about the CHMP QWP and EWP's replies to the CMD(h)'s consultation. Whilst the CHMP QWP considered that warnings were sufficient, unless serious concerns were raised with respect to efficacy and safety, the CHMP EWP took the view that warnings against alcohol were not an appropriate means of addressing a potentially clinically important formulation when it interacted with alcohol. In light of the fact that the latter opinion affected, according to the Commission, a much larger range of products than the B product, the Commission decided, on 18 September 2009, after the Ombudsman's request for further information from it, to launch a referral to the CHMP under Article 31 of the Medicinal Code concerning the interaction with alcohol of modified release oral opioid products and inform the complainant accordingly on 7 October 2009.

111. The complainant considers that the Commission's referral is unduly delayed. However, as explained above, the Ombudsman takes the view that the Commission was not required to deal with the issues brought up by the complainant in the context of a procedure relating to a 'nationally authorised medicinal product', which had already been dealt with by the Member States. Relatedly, the fact that the complainant considers that Article 31 of the Medicinal Code provides, in its current wording, for an obligation for the Commission to refer to the CHMP in specific cases where the interests of the Community are involved, does not preclude that a similar obligation may also exist for the Member States[55]. In the Ombudsman's view, the Commission was entitled to consider that, in accordance with the principle of subsidiarity, it should only make a referral under Article 31 of the Medicinal Code if the Member States were unable to reach a consensus. Relatedly, the Ombudsman finds it further reasonable that the Commission intervened only after the CHMP EWP had expressed doubts as to the sufficiency of warnings accompanying strong opioid products[56]. Consequently, the Ombudsman does not share the complainant's view that, in summary, the Commission's referral came too late.

112. The complainant also takes the view that the scope of the Commission's referral to CHMP under Article 31 of the Medicinal Code constitutes evidence of delaying tactics in removing the B product from the EU market. However, the Ombudsman notes that the CHMP EWP's opinion, delivered in reply to the CMD(h)'s consultation on the "Potential for Alcohol (Ethanol) Induced Dose Dumping of Oral Opioid Modified Release Products" covered not only the B product, but also a much larger range of products. The Commission's referral thus follows EWP's advice covering a large range of products. The Ombudsman considers it reasonable that, in light of such an advice, the Commission made a referral that also covered the same range of products. The Ombudsman, therefore, does not share the complainant's view in this regard either.

113. In light of all the above, the Ombudsman considers that the Commission adequately performed its duties throughout the different stages of the procedure relating to a 'nationally authorised medicinal product'. It did this, first, by submitting the scientific information it received from the complainant to the Member States and, later, by proceeding to a referral under Article 31 of the Medicinal Code only after all competent scientific authorities had been consulted. One of them had issued an opinion that concerned a larger number of medicinal products and expressed doubts about the adequacy of the measures taken to address a potentially clinically dangerous interaction of those products with alcohol. Consequently, the Ombudsman concludes that no maladministration by the Commission can be found as regards the complainant's first allegation.

B. Allegation of unlawfulness for not pursuing Member States and the corresponding claim

Arguments presented to the Ombudsman

114. The complainant alleged that the Commission acted unlawfully by not pursuing the Member States for a procedural violation of Community law, that is, for using the wrong procedure to authorise the B product.

115. In support of this allegation, the complainant argued that the Commission failed properly to address its requests for an interpretation of Article 10(1), (2) and (3) of the Medicinal Code in light of the Synthon Case[57].

116. The complainant claimed that the Commission should address and remedy the above instance of maladministration by pursuing the Member states in question for an infringement of Union law.

117. In its opinion, the Commission took the view that the B product had been correctly authorised under Article 10 of the Medicinal Code. In this respect, it emphasised that paragraphs 1 and 3 of Article 10 of the Medicinal Code did not constitute different procedural routes for marketing authorisation, but rather a single procedural route. Paragraph 3 provided for specific data requirements, by stipulating that, where certain differences between the reference and the generic product were detected, the results of appropriate pre-clinical tests or clinical trials must be provided.

118. According to the Commission, given that the different dissolution profiles were not known at the time, the initial applications submitted for the B product contained the data required for generic products pursuant to Article 10(2)(b). This data demonstrated that the B product had the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product A. It also showed that the B product was bioequivalent to A.

119. The Commission then went on to emphasise that, as soon as the complainant provided data showing the difference in the dissolution profile, the national authorities requested the marketing authorisation holders and applicants of the generic products to provide their own results of in vitro studies to comply with the data requirements of Article 10(3) of the Medicinal Code, that is, to substantiate differences between the reference and generic products. Since these results confirmed the data provided by the complainant, the additional safety warning was included for the already authorised products, as well as for the generic products which were subsequently authorised. The Commission had already relied on the data requirement contained in Article 10(3) of the Medicinal Code when it first contacted the CMD(h) to request the holders of the marketing authorisation for the B product to generate data on alcohol vulnerability. By requesting advice from the CHMP QWP, the Member States took steps which could eventually lead to producers of such generic products having to routinely supplement the data package under Article 10(3).

120. Consequently, according to the Commission, Article 10 of the Medicinal Code explicitly authorises a medicinal product that does not fulfil the definition of 'generic', or which is not bioequivalent, or which presents differences in its safety or efficacy profile with the reference product. The Synthon Case did not affect this interpretation. In fact, that case dealt with an issue which was not addressed in the legislation existing at the time, and which is now clarified in Article 10(2)(b) of the Medicinal Code. It held that the definition of a generic product does not exclude a product which contains the same active substance as the reference product combined with a different salt.

121. The Commission's interpretation of the data requirements under Article 10 of the Medicinal Code were duly conveyed to the complainant in the meeting of 21 June and in the letters dated 20 September, 5 October and 8 November 2007.

122. After the Ombudsman opened his inquiry, the complainant and the Commission exchanged new arguments directly and put the Ombudsman in copy.

123. The complainant emphasised that it did not claim that, in cases where the definition of a generic product in Article 10(2)(b) of the Medicinal Code is not met, an authorisation under Article 10 of that code is never possible. The complainant agreed with the Commission that, in such circumstances, the additional data requirements of Article 10(3) of the Medicinal Code must be complied with. However, it disagreed that those requirements had been met in the present case. In its view, it would have only been so if there had been appropriate in vivo data demonstrating that the B product did not pose a risk of dose-dumping in patients. In the absence of any such in vivo data, the complainant maintained that the requirements of Article 10(3) of the Medicinal Code had not been satisfied and that the Commission, as Guardian of the Treaty, was under an obligation to pursue Member States for a procedural violation of the Community legal framework.

124. According to the complainant, the US FDA required in vivo data for all controlled-release opioid formulations which have shown vulnerability to alcohol in vitro. Since 2005, the US FDA required in vitro ethanol dissolution data for all prolonged-release products. Where the in vitro data demonstrates that the product is vulnerable to ethanol and/or the formulation suggests that in vivo dose-dumping is possible, the US FDA requires the applicant to submit robust in vivo evidence in order to ensure that the product is clinically safe.

125. In addition, according to the complainant, in light of the CHMP EWP's recommendations, it appeared that the CHMP was moving towards the position that a product cannot be considered a generic if, unlike the innovator product, it is vulnerable to alcohol. Accordingly, in the absence of in vivo data showing that the B product did not pose a clinically relevant risk of dose-dumping in patients consuming alcohol, the Commission was obliged to pursue the Member States for a procedural violation of Community law.

126. In reply to the Ombudsman's request for further information, the Commission stated that the Member States acted in accordance with the legislation by requesting additional data from the marketing holders and applicants of the B products to substantiate differences between the reference and the generic products. The Commission noted that the complainant disagreed with the scientific evaluation of the national competent authority as regards the type of data requested. However, according to the Commission, Article 10 of the Medicinal Code left it up to the competent authorities to decide on the type of data to be submitted in such situations. The divergence of opinions as regards a scientific evaluation which was carried out correctly within the applicable legal framework did not amount to a procedural violation by the Member States concerned and thus did not constitute a reason for the Commission to bring an action against the Member States.

127. In its direct contacts with the complainant, the Commission explained further that the CHMP QWP did not recommend carrying out in vivo studies unless serious concerns were raised with respect to efficacy and safety. In the context of the specific evaluation of the question from the CMD(h), the CHMP QWP did not consider that this was necessary in the case of opioid products. Relatedly, the CHMP EWP "[did] not believe that in vivo studies would be a reliable way of investigating the clinical relevance". It was, in the CHMP EWP's view, "preferable to rely on the in vitro dissolution data unless the sensitivity of an in vivo study could be robustly demonstrated."

128. In its observations on the Commission's reply, the complainant took the view that in vitro data was insufficient in light of the risk posed by the B product. Unless reformulation was required for any product showing vulnerability to alcohol in vitro, in vivo data was essential in order to establish the clinical relevance of the risk. Although Article 10(3) did not specify the kind of data required, the purpose of the additional data was to point out the differences between the reference product and the generic product. In the present case, the in vitro data relating to the B product highlighted the risk, but did not provide support for the marketing authorisation. It should have been clear to the Commission that the alcohol vulnerability of the B product could only be disregarded if the risk was shown to be of no clinical relevance. This could only be established by in vivo data.

129. The complainant observed further that, according to the CHMP EWP, an in vivo study might be an insufficient measure to assess the risk because it would be impossible to control all factors that could contribute to an adverse outcome. The CHMP EWP thus advocated a reformulation of the product on the basis of the in vitro data, unless the sensitivity of an in vivo study could be robustly demonstrated. In the complainant's view, it was therefore clear from the CHMP EWP's opinion that a product cannot be authorised as a generic where it has a different safety profile from the reference product for patients who consume alcohol. As an absolute minimum, the regulatory authorities should have required sufficiently accurate in vivo testing for the B product. The Commission therefore acted unlawfully in not pursuing Member States for a procedural violation of the Community legal framework.

The Ombudsman's assessment

The legal framework

130. The Medicinal Code provides that, in order to obtain an authorisation to place a medicinal product on the market, an application must be made to the competent authority of the Member State concerned. Such an authorisation may only be granted to an applicant established in the EU.

131. The application has to be accompanied by specific information and documents relating to the applicant and the medicinal product, notably the results of pharmaceutical (physico-chemical, biological or microbiological) tests, pre-clinical (toxicological and pharmacological) tests, and clinical trials[58].

132. However, according to Article 10(1) of the Medicinal Code, an applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if it can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised for not less than eight years in a Member State or in the Community.

133. Article 10(2)(b) of the Medicinal Code defines 'generic medicinal product' as a medicinal product which has the same qualitative and quantitative composition of active substances and the same pharmaceutical form as the reference medicinal product[59], and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. 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 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 are not required from the applicant if it can demonstrate that the generic medicinal product meets the relevant criteria defined in the appropriate detailed guidelines.

134. Finally, according to Article 10(3) of the Medicinal Code, in cases where the medicinal product does not fall within the above definition of a generic medicinal product, where bioequivalence cannot be demonstrated through bioavailability studies, or where changes are made in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration vis-à-vis the reference medicinal product, applicants must provide the results of the appropriate pre-clinical tests or clinical trials.

The assessment of the allegation and claim

135. At the outset, the Ombudsman notes that, ultimately, the complainant agrees that applicants for marketing authorisation of the B product could have obtained that authorisation under the 'abridged procedure' provided for in Article 10(1) of the Medicinal Code. It nonetheless contests that, after providing suitable evidence that the B product could not have been considered a generic of its reference product because it reacted to alcohol differently, the Member States should have requested applicants to provide evidence that the B product was safe. Since in vitro data showed that the B product was vulnerable to alcohol, the above could only be achieved by appropriate in vivo data. By not requesting such data, but nevertheless granting the B product manufacturer the marketing authorisation, Member States infringed the Medicinal Code. This, according to the complainant, should have been duly followed-up by the Commission by opening an infringement procedure against Germany, which was the reference Member State that first authorised the marketing in the EU of the B product as a generic of the complainant's product.

136. The Ombudsman notes that Article 10(3) of the Medicinal Code provides for applicants to submit "results of the appropriate pre-clinical tests or clinical trials"[60]. However, the Medicinal Code does not state whether the pre-clinical tests or clinical trials should be conducted in vitro or rather in vivo.

137. In the present case, the reference Member State requested the applicant for the B product to submit in vitro tests which, in summary, confirmed the safety issue brought up by the complainant. Given that the Member States considered the in vitro data, and notably the data provided to them by the complainant, to be of marginal relevance, the Ombudsman understands that, ultimately, the Member States did not have any serious concerns with respect to the efficacy and safety of the B product. They thus considered a safety warning advising against the consumption of the product with alcohol to be sufficient. This was later accepted by the other Member States in the context of the CMD(h), until they decided to consult the CHMP's working parties QWP and EWP.

138. In this respect, the Ombudsman notes that, after having been consulted, the CHMP QWP held that in vivo studies were not necessary, unless there were serious concerns with respect to efficacy and safety of the generic. The CHMP EWP found that it was preferable to rely on in vitro dissolution data unless the sensitivity of an in vivo data study could be robustly demonstrated[61].

139. The Ombudsman therefore notes that the scientific assessment of the various experts involved, and the opinions expressed by the various assessment bodies consulted, were not in agreement as regards the need to conduct in vivo in addition to, or rather than, in vitro tests. The Ombudsman further recalls that the B product was a 'nationally authorised medicinal product' and that all actions relating to its marketing authorisation and/or subsequent activities were under the Member States' responsibility. In light of the CMD(h)'s actions adopted in the context of the marketing authorisation procedure of the B product, and the legal framework applicable to the case at hand, the Ombudsman does not consider that the scientific evidence available to the Commission clearly indicated that the Member States should require in vivo tests of the B product. Thus, the Ombudsman finds no maladministration on the part of the Commission regarding the complainant's second allegation and the related claim.

C. Conclusion

On the basis of his inquiry into this complaint, the Ombudsman closes it with the following conclusion:

There has been no maladministration on the part of the Commission.

The complainant and the President of the Commission will be informed of this decision.

 

P. Nikiforos Diamandouros

Done in Strasbourg on 10 December 2011

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[1] The company was represented by a law firm. The term “complainant” in the present decision refers to both the company and the law firm.

[2] Paragraph 12 of the Preamble to the Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (as amended, OJ 2001 L 311, p. 67) provides that "a marketing authorization for a medicinal product granted by a competent authority in one Member State [the 'reference Member State'] ought to be recognized by the competent authorities of the other Member States [the 'concerned Member States'] unless there are serious grounds for supposing that the authorization of the medicinal product concerned may present a risk to public health. In the event of a disagreement between Member States about the quality, the safety or the efficacy of a medicinal product, a scientific evaluation of the matter should be undertaken according to a Community standard, leading to a single decision on the area of disagreement binding on the Member States concerned. [T]his decision should be adopted by a rapid procedure ensuring close cooperation between the Commission and the Member States."

This Paragraph also refers to the so-called "centralized Community procedure" for obtaining marketing authorisations for medicinal products, "established by 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 [OJ 1993 L 214, as amended by Commission Regulation (EC) No 649/98, OJ 1998 L 88, p. 7]".

[3] [2005] ECR I-595.

[4] Article 10(2)(b) of the Medicinal Code provides that "'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. 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."

[5] OJ 2001 L 311, p. 67. The Ombudsman notes that neither the complainant nor the Commission provided him with a copy of the amended Medicinal Code. For the present decision, the Ombudsman therefore consulted the "consolidated Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use as amended by Directive 2002/98/EC [of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood components (OJ 2003 L 33, p. 40)], Directive 2004/24/EC [of the European Parliament and the Council of 31 March 2004 amending the Medicinal Code as regards herbal medicinal products (OJ 2004 L 136, p. 85)] and Directive 2004/27/EC [of the European Parliament and the Council of 31 March 2004 (OJ 2004 L 136, p. 34)]", available on the EUR-LEX website (www.eur-lex.europa.eu) through a link on the website of the European Medicines Agency (www.ema.europa.eu). The Medicinal Code mentioned throughout the decision is therefore the amended version of that code.

[6] Article 10(1) of the Medicinal Code provides that "... the applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised ... in a Member State or in the Community."

[7] Article 27 of the Medicinal Code provides for "1. A coordination group ... for the examination of any question relating to marketing authorisation of a medicinal product in two or more Member States ... The [European Medicines] Agency shall provide the secretariat of this coordination group.

2. The coordination group shall be composed of one representative per Member State ... Members of the coordination group may arrange to be accompanied by experts.

3. The coordination group shall draw up its own Rules of Procedure ..."

[8] Article 31(1) of the Medicinal Code provides that: "[t]he Member States or the Commission or the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Community are involved, refer the matter to the [CHMP] before any decision is reached on a request for a marketing authorisation or on the suspension or revocation of an authorisation, or on any other variation to the terms of a marketing authorisation which appears necessary, in particular to take account of the information collected in accordance with [the provisions of the Medicinal Code relating to pharmacovigilance].

The Member State concerned or the Commission shall clearly identify the question which is referred to the Committee for consideration and shall inform the applicant or the marketing authorisation holder.

The Member States and the applicant or the marketing authorisation holder shall supply the Committee with all available information relating to the matter in question."

[9] The Ombudsman understands this term to refer to the rapid and unintended release of a drug which has been administered in a form that is intended to ensure its gradual release.

[10] Article 10(3) of the Medicinal Code provides that: "[i]n cases where the medicinal product does not fall within the definition of a generic medicinal product ... or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be provided."

[11] See footnote 6 above.

[12] See footnote 10 above.

[13] See footnote 4 above.

[14] According to the complainant, the two products dealt with in the Synthon Case were considered essentially the same because it was not necessary "that there [was] an exact molecular match between the active ingredients ... A difference such as that at issue ... cannot normally prevent two medicinal products from being regarded as essentially similar. That cannot be the case if ... that difference must be regarded as significant as regards safety or efficacy of the product for which the [marketing authorisation] is sought."

[15] See footnote 10 above.

[16] The Commission cited the Ethanol Paper as to provide for the following statement: "results have shown that the prolonged release mechanisms of the products remain intact under the testing conditions. When extrapolated to the in vivo situation, the data indicate that there is no risk of a potentially dangerous dose-dumping."

[17] Article 28 of the Medicinal Code provides that "1. With a view to the granting of a marketing authorisation for a medicinal product in more than one Member State, an applicant shall submit an application based on an identical dossier in these Member States. ... The applicant shall request one Member State to act as ‘reference Member State’ and to prepare an assessment report on the medicinal product ... 2. Where the medicinal product has already received a marketing authorisation at the time of application, the concerned Member States shall recognise the marketing authorisation granted by the reference Member State ..."

[18] In accordance with Article 2(4) of the Ombudsman's Statute.

[19] Article 228 TFEU.

[20] These arguments include those submitted with the initial complaint and the Commission's opinion, exchanged directly by the parties and forwarded to the Ombudsman, in the complainant's observations on the Commission's opinion, in the Commission's reply to the Ombudsman's request for further information and the complainant's observations on that reply, when relevant in view of the developments of the case.

[21] The Ombudsman forwarded this document to the Commission with his request for further information.

[22] According to the complainant, the publication contained the following statement: "[i]t is clear that ethanol sensitive formulations with significant in vitro dose dumping such as this one discussed here [the B product], will most likely lead to in vivo dose dumping [i.e., increased maximal plasma exposure (Cmax) and shorter time to Tmax] at higher ethanol concentrations in patients to a varying degree."

[23] According to the complainant, the study report revealed that the overall prevalence of alcohol-related disorders in German patients with high potency opioids was 5.6 %, and that male patients aged 40-60 years showed a prevalence of approximately 15%. This was, in the complainant's view, particularly alarming in light of the fact that a substantial number of patients with an alcohol disorder could be exposed to opioid formulations which were vulnerable to alcohol, such as the B product, and were unlikely to be deterred from drinking alcohol by a warning.

[24] The CMD(h) Rules of Procedure are available on the Heads of Medicines Agencies' website (www.hma.eu). Article 10 of the CMD(h) Rules of Procedure provides that: "[r]equests for advice submitted by companies or by one or more EEA Member State shall be dealt with in accordance with a defined procedure to be adopted by CMD(h) including the criteria for acceptance of such a request. Advice on scientific matters should be referred to the EMEA to be dealt with as a scientific advice."

[25] Article 1(2) of the CMD(h) Rules of Procedure states that "[the CMD(h)] members should be from the national competent authorities and have adequate regulatory and/or scientific expertise. The also should have sufficient delegated authority to express final positions and confirm their regulatory authority's intention to implement the final outcome ..."

[26] See footnote 24 above.

[27] In this respect, the Commission referred to Articles 27(1), 29(1) and (3), and 30(2) of the Medicinal Code.

[28] The section on 'Agreements' of the CMD(h) Rules of Procedure provides, in its Article 8, that

"1. Each member shall have one vote.

2. Whenever possible, agreements on the list of products for harmonisation, guidelines, SOPs, recommendations, procedural or regulatory practices or position statements of the CMD(h) shall be adopted by consensus ...

3. The agreement adopted shall, where necessary, be concluded in a formal binding decision by the regulatory authorities of the representatives of the CMD(h) ...

4. Any divergent positions shall be mentioned in the agreements of the CMD(h) upon request of those members concerned. They shall state clearly the reasons on which they are based ..."

Relatedly, Article 9 of the CMD(h) Rules of Procedure provides that "[a]greements are to be reached by consensus among all EEA Member States concerned by the procedure. In the absence of consensus of the EEA Member States concerned, the [EMA] shall be immediately informed with a view to the application of the procedure laid down under Articles 32, 33 and 34 [of the Medicinal Code, relating to CHMP's assessments and the Commission's taking of relevant decisions]."

[29] In this regard, the Commission referred to the section of the Medicinal Code relating to 'Supervision and sanctions':

"[Article 111] 1. The competent authority of the Member State concerned shall ensure, by means of repeated inspections, and if necessary unannounced inspections, and, where appropriate ... to carry out tests on samples, that the legal requirements governing medicinal products are complied with ... Such inspections shall be carried out by officials representing the competent authority ...

[Article 116] The competent authorities shall suspend, revoke, withdraw or vary a marketing authorisation if the view is taken that the product is harmful under normal conditions of use, or that it lacks therapeutic efficacy, or that the risk-benefit balance is not positive under the normal conditions of use, or that its qualitative and quantitative composition is not as declared. Therapeutic efficacy is lacking when it is concluded that therapeutic results cannot be obtained from the medicinal product. An authorisation shall also be suspended, revoked, withdrawn or varied where the particulars supporting the application ... are incorrect or have not been amended ..., or where the controls ... have not been carried out.

[Article 117] 1. Without prejudice to the measures provided for in Article 116, Member States shall take all appropriate steps to ensure that the supply of the medicinal product is prohibited and the medicinal product withdrawn from the market, if the view is taken that:

(a) the medicinal product is harmful under normal conditions of use; or

(b) it lacks therapeutic efficacy; or

(c) the risk-benefit balance is not favourable under the authorised conditions of use; or

(d) its qualitative and quantitative composition is not as declared; or

(e) the controls on the medicinal product and/or on the ingredients and the controls at an intermediate stage of the manufacturing process have not been carried out or if some other requirement or obligation relating to the grant of the manufacturing authorisation has not been fulfilled ..."

[30] According to the Commission, the CHMP QWP's letter dated 22 January 2009 provided as follows: "QWP supports the steps taken with the specific opioid [and x] products: where incompatibility with alcohol is evident, it is sufficient to address safety or other concerns by the inclusion of appropriate warnings in the product literature."

[31] See judgment of the Court of First Instance (Fifth Chamber) of 18 December 2003 in Case T-326/99 Olivieri v Commission and EMEA, paragraph 93, [2003] ECR II-6053: "[t]he applicant for marketing authorisation and, as such, addressee of the contested decision, Dr Olivieri cannot claim entitlement to challenge, in an action for annulment, the scientific evaluation made by the CPMP and confirmed by the Commission ... Moreover, the Commission was required, in the interest of public health, to take into consideration and carefully evaluate the scientific data and the opinions which she had sent to it ... Dr Olivieri's participation in the assessment procedure is therefore confined solely to the production of relevant information relating to deferiprone and does not extend to the scientific assessment of that data for the purpose of authorising the marketing of that product. That task falls exclusively to the Commission under the procedures established by Regulation No 2309/93."

[32] "The SPCs of some strong opioid products, but by no means all, contraindicate concomitant alcohol consumption because of the pharmacodynamic interaction (CNS effects). However EWP does not consider that contraindicating alcohol is an appropriate means of addressing a potentially clinically important formulation interaction with alcohol. A proportion of patients taking strong opioids for severe pain will inevitably consume alcohol regardless of wording in the SPC and PIL. Indeed palliative care physicians may consider it appropriate for their patients to be allowed alcohol in moderation provided due care is taken. Furthermore it is likely that even if patients read the PIL and package warnings for a medicine when they are first prescribed it they might be less likely to do so for repeat prescriptions. A product specific warning might therefore be missed if the product in question has been generically substituted."

[33] Joined cases T-74/00 et al., Artegodan GmbH and others v Commission [2002] ECR II-4945 and Case C-39/03 P Commission v Artegodan GmbH and others [2003] ECR I-7885.

[34] See footnote 33 above.

[35] Article 12 of the 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 (OJ 1975 L 147, p. 13).

[36] Article 4(2)(k) TFEU. According to the Treaty Establishing the European Community (TEC), in force at the time of the facts at the origin of the present complaint, the activities of the Communities included a contribution to the attainment of a high level of health protection (Article 3(1)(p) of the TEC). For the latest consolidation version of the TEC, see OJ 2006 C 321 E, p. 37.

[37] Article 6(a) TFEU. Article 137(1)(a) TEC provided that the Community shall support and complement the activities of the Member States in the improvement of the working environment to protect workers' health and safety.

[38] Article 168(1) and (7) TFEU. Articles 152(1), (2) and (5) TEC provided that a high level of human health protection shall be ensured in the definition and implementation of all Community policies and activities. Community action, which shall complement national policies, shall be directed towards improving public health. The Community shall complement the Member States' action in reducing drug-related health damage, including information and prevention. It encourages cooperation between the Member States in these areas, who coordinate among themselves their policies and programmes. The Commission may, in close contact with the Member States, take any useful initiative to promote such coordination. Community action in the field of public health shall fully respect the responsibilities of the Member States for the organisation and delivery of health services and medical care.

[39] OJ 2010 C 83, p. 389.

[40] Paragraphs 2 to 6 of the Preamble of the Medicinal Code.

[41] Paragraph 14 of the Preamble of the Medicinal Code.

[42] Paragraph 12 of the Preamble of the Medicinal Code. This Paragraph also refers to the so-called "centralized Community procedure" for obtaining marketing authorisations for medicinal products, "established by 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 [OJ 1993 L 214, p. 1, as amended by Commission Regulation (EC) No 649/98, OJ 1998 L 88, p. 7]".

[43] Paragraph 15 of the Preamble of the Medicinal Code.

[44] Article 6(1) of the Medicinal Code.

[45] Article 28(1) and (2) of the Medicinal Code. Provisions on labelling and the package leaflet may be found in Articles 54 and the following of the Medicinal Code.

[46] Article 27(1) of the Medicinal Code.

[47] Article 29 of the Medicinal Code.

[48] Article 30(1) of the Medicinal Code.

[49] The provision of Article 31(1) of the Medicinal Code is further clarified in the Notice to Applicants available on the website of the European Medicines Agency (www.ema.europa.eu), Volume 2A 'Procedures for Marketing Authorisation', Chapter 3 Community Referral Procedures', Section 4.1 'Article 31 of [the Medicinal Code] ("Community interest referral") / Basic principles' in the following terms: "[t]his referral is to be started in specific cases where the interests of the Community are involved. The expression "interests of the Community" refers particularly to the interests of public health related to medicinal products on the market of the Community in the light of quality, safety and efficacy data and to the free movement of products within the Community."

[50] Article 32 of the Medicinal Code.

[51] Article 33 of the Medicinal Code.

[52] Article 34 of the Medicinal Code.

[53] Article 27(1) of the Medicinal Code.

[54] Relatedly, the Ombudsman's notes further the complainant's reference to an unidentified national authority in its letter to the Commissioner dated 15 January 2008.

[55] "The Member States or the Commission or the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Community are involved, refer the matter to the [CHMP] ... before any decision is reached on a request for a marketing authorisation or on the suspension or revocation of an authorisation, or on any other variation to the terms of a marketing authorisation which appears necessary ..."

[56] See footnote 32 above.

[57] Case C-74/03 Smithkline Beecham [2005] ECR I-595.

[58] Article 8 of the Medicinal Code.

[59] The meaning of the "qualitative and quantitative composition" is set out in the Notice to Applicants available on the website of the European Medicines Agency (www.ema.europa.eu), Volume 2A 'Procedures for Marketing Authorisation', Chapter I 'Marketing Authorisation', Section 5.3.2 'Applications according to Article 10 of [the Medicinal Code] / "Same qualitative and quantitative composition"' in the following terms: "[t]his requirement that the generic and reference products have the same qualitative and quantitative composition extends only to the active substance(s) and not to the other ingredients of the product. However, differences in excipient composition or differences in impurities must not lead to significant differences as regards safety and efficacy. The competent authorities will evaluate these differences in the light of all scientific knowledge at their disposal. See also ruling of the European Court of Justice in case C-74/03, Smithkline Beecham, judgment of 20 January 2005."

[60] "In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided in paragraph 2(b) or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be provided."

[61] Also according to the complainant, the CHMP EWP's opinion provided for the following statement: "[i]f the generic shows significantly greater susceptibility [to alcohol] than the brand leader this would normally be considered an important quality issue that would necessitate reformulation of the product."