OPINION OF ADVOCATE GENERAL

MENGOZZI

delivered on 4 October 2018 ( 1 )

Case C‑680/16 P

Dr. August Wolff GmbH & Co. KG Arzneimittel,

Remedia d.o.o.

v

European Commission

(Appeal — Directive 2001/83/EC — Medicinal products for human use — Commission decision ordering the Member States to revoke or vary national marketing authorisations for medicinal products with 0.01% estradiol by weight for topical use — Conditions for referring a matter to the Committee for Medicinal Products for Human Use — Objective impartiality — Right to be heard — Principle of proportionality — Principle of equal treatment)

Table of contents

I. Legal framework II. Background to the dispute III. Procedure before the General Court and the judgment under appeal IV. Procedure before the Court and forms of order sought V. Legal assessment A. The first ground of appeal, alleging infringement of Articles 31 and 32 of the HUM Code 1. The first part, alleging misinterpretation of Article 31 of the HUM Code (a) Summary of the arguments of the parties (b) Assessment 2. The second part, alleging infringement of the requirement for neutrality laid down in Article 32(2) of the HUM Code and the principle of a diligent and impartial examination laid down in Article 41(1) of the Charter (a) Summary of the arguments of the parties (b) Assessment 3. The third part, alleging infringement of Article 32(3) of the HUM Code and the right to be heard (a) Summary of the arguments of the parties (b) Assessment 4. Conclusion on the first ground of appeal B. The second ground of appeal, alleging infringement of Article 116(1) and Article 126(1) of the HUM Code 1. The first part, alleging infringement of the principles of a balanced burden of demonstration and proof since the existence of a risk was based on the absence of post-authorisation studies (a) Summary of the arguments of the parties (b) Assessment 2. The second part, alleging a lack of a comprehensible link between the medical or scientific findings and the conclusions of the CHMP (a) Summary of the arguments of the parties (b) Assessment 3. The third part, alleging an incorrect risk assessment because the pharmacovigilance data was not taken into account (a) Summary of the arguments of the parties (b) Assessment 4. The fourth part, alleging misrepresentation of the available pharmacovigilance data and inaccuracy as regards the content of the scientific guidelines in the final opinion of the CHMP (a) Summary of the arguments of the parties (b) Assessment 5. Conclusion on the second ground of appeal C. The third plea, alleging infringement of the principles of proportionality and equal treatment 1. The first part, alleging infringement of the principle of proportionality (a) Summary of the arguments of the parties (b) Assessment 2. The second part, alleging infringement of the principle of equal treatment (a) Summary of the arguments of the parties (b) Assessment 3. Conclusion on the third ground of appeal VI. The action before the General Court VII. Costs VIII. Conclusion

1. By their appeal, Dr. August Wolff GmbH & Co. KG Arzneimittel (‘August Wolff’ or ‘the first appellant’) and Remedia d.o.o. (‘Remedia’) ask the Court to set aside the judgment of the General Court of 20 October 2016, August Wolff and Remedia v Commission (T‑672/14, not published, ‘the judgment under appeal’, EU:T:2016:623).

2. By judgment under appeal, the General Court dismissed the action brought by those undertakings seeking annulment of Commission Implementing Decision C(2014) 6030 final of 19 August 2014 concerning the marketing authorisations for high concentration of estradiol containing human medicinal products for topical use in the framework of Article 31 of Directive 2001/83/EC of the European Parliament and of the Council (‘the implementing decision’). On the basis of an opinion of the Committee for Medicinal Products for Human Use (‘the CHMP’), that implementing decision had imposed on the renewal of the marketing authorisation (‘MA’) for the medicinal product concerned, namely Linoladiol N, a condition restricting the period of use to four weeks, with the concomitant exclusion of repeated use.

3. The present appeal gives the Court the opportunity to rule for the first time on Article 31(1) of 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 ( 2 ) (‘the Community code relating to medicinal products for human use’ or ‘the HUM Code’) and in particular on the conditions governing referral by the competent national authorities to the CHMP under that procedure. Moreover, the Court is called upon to rule for the first time on Article 32(3) of the HUM Code, by specifying the scope of the right to be heard conferred on the AM applicant or holder under that provision, and on whether the appointment as chief rapporteur to the CHMP of a member of the national authority which has made a referral to the CHMP, under the procedure laid down by Article 31 of the HUM Code, is compatible with the principle of impartiality enshrined in Article 41 of the Charter of Fundamental Rights of the European Union (‘the Charter’).

I. Legal framework

4. Under Article 31 of the HUM Code: ‘1. The Member States, the Commission, the applicant or the marketing authorisation holder shall, in specific cases where the interests of the Union are involved, refer the matter to the Committee [for Medicinal Products for Human Use] for application of the procedure laid down in Articles 32, 33 and 34 before any decision is reached on an application for a marketing authorisation or on the suspension or revocation of a marketing authorisation, or on any other variation of the marketing authorisation which appears necessary. Where the referral results from the evaluation of data relating to pharmacovigilance of an authorised medicinal product, the matter shall be referred to the Pharmacovigilance Risk Assessment Committee and Article 107j(2) may be applied. The Pharmacovigilance Risk Assessment Committee shall issue a recommendation according to the procedure laid down in Article 32. The final recommendation shall be forwarded to the Committee for Medicinal Products for Human Use or to the coordination group, as appropriate, and the procedure laid down in Article 107k shall apply. …’

5. Article 32 of the HUM Code provides: ‘1. When reference is made to the procedure laid down in this Article, the Committee shall consider the matter concerned and shall issue a reasoned opinion within 60 days of the date on which the matter was referred to it. However, in cases submitted to the Committee in accordance with Articles 30 and 31, this period may be extended by the Committee for a further period of up to 90 days, taking into account the views of the applicants or the marketing authorisation holders concerned. In an emergency, and on a proposal from its Chairman, the Committee may agree to a shorter deadline. 2. In order to consider the matter, the Committee shall appoint one of its members to act as rapporteur. The Committee may also appoint individual experts to advise it on specific questions. When appointing experts, the Committee shall define their tasks and specify the time-limit for the completion of these tasks. 3. Before issuing its opinion, the Committee shall provide the applicant or the marketing authorisation holder with an opportunity to present written or oral explanations within a time limit which it shall specify. The opinion of the Committee shall be accompanied by a draft summary of product characteristics for the product and a draft text of the labelling and package leaflet. If necessary, the Committee may call upon any other person to provide information relating to the matter before it. The Committee may suspend the time-limits referred to in paragraph 1 in order to allow the applicant or the marketing authorisation holder to prepare explanations. 4. The [European Medicines] Agency shall forthwith inform the applicant or the marketing authorisation holder where the opinion of the Committee is that: (a) the application does not satisfy the criteria for authorisation; or (b) the summary of the product characteristics proposed by the applicant or the marketing authorisation holder in accordance with Article 11 should be amended; or (c) 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 (d) a marketing authorisation should be suspended, varied or revoked. Within 15 days after receipt of the opinion, the applicant or the marketing authorisation holder may notify the Agency in writing of his intention to request a re-examination of the opinion. In that case, he shall forward to the Agency the detailed grounds for the request within 60 days after receipt of the opinion. Within 60 days following receipt of the grounds for the request, the Committee shall re-examine its opinion in accordance with the fourth subparagraph of Article 62(1) of Regulation [EC] No 726/2004. ( 3 ) The reasons for the conclusion reached shall be annexed to the assessment report referred to in paragraph 5 of this Article. 5. Within 15 days after its adoption, the Agency shall forward the final opinion of the Committee 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. In the event of an opinion in favour of granting or maintaining an authorisation to place the medicinal product concerned on the market, the following documents shall be annexed to the opinion: (a) a draft summary of the product characteristics, as referred to in Article 11; (b) any conditions affecting the authorisation within the meaning of paragraph 4(c); (c) details of any recommended conditions or restrictions with regard to the safe and effective use of the medicinal product; (d) the proposed text of the labelling and leaflet.’

6. Under Article 33 of the HUM Code: ‘Within 15 days of the receipt of the opinion, the Commission shall prepare a draft of the decision to be taken in respect of the application, taking into account Community law. In the event of a draft decision which envisages the granting of marketing authorisation, the documents referred to in Article 32(5), second subparagraph shall be annexed. Where, exceptionally, the draft decision is not in accordance with the opinion of the Agency, the Commission shall also annex a detailed explanation of the reasons for the differences. The draft decision shall be forwarded to the Member States and the applicant or the marketing authorisation holder.’

7. Article 34 of the HUM Code reads as follows: ‘1. The Commission shall take a final decision in accordance with, and within 15 days after the end of, the procedure referred to in Article 121(3). …’

8. The first subparagraph of Article 116 of the HUM Code provides: ‘The competent authorities shall suspend, revoke or vary a marketing authorisation if the view is taken that the medicinal product is harmful or that it lacks therapeutic efficacy, or that the risk-benefit balance is not favourable, or that its qualitative and quantitative composition is not as declared. Therapeutic efficacy shall be considered to be lacking when it is concluded that therapeutic results cannot be obtained from the medicinal product.’

9. Under Article 126 of the HUM Code: ‘An authorisation to market a medicinal product shall not be refused, suspended or revoked except on the grounds set out in this Directive. No decision concerning suspension of manufacture or of importation of medicinal products coming from third countries, prohibition of supply or withdrawal from the market of a medicinal product may be taken except on the grounds set out in Articles 117 and 118.’

II. Background to the dispute

10. It is clear from paragraphs 1 to 12 of the judgment under appeal that August Wolff holds MAs in several Member States, including the Federal Republic of Germany, for the medicinal product Linoladiol N or Gel Linoladiol N 0.1 mg/g or Linoladiol N 0.1 mg/g vaginal cream (‘Linoladiol N’). Remedia holds the MA for Linoladiol N in Croatia.

11. Linoladiol N is a cream intended for treating menopausal women with vaginal and vulvar atrophy. It contains the hormone estradiol as its active substance in a concentration of 100 micrograms per gram.

12. That medicinal product was first authorised in Germany in 1978. On 26 September 2005, the competent German authority, namely the Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical Devices, Germany, ‘the BfArM’), refused to renew the authorisation. Consequently, the first appellant initially lodged an appeal against that decision with the Verwaltungsgericht Köln (Administrative Court, Cologne, Germany), which dismissed its appeal by judgment of 27 October 2009. It then brought an appeal before the Oberverwaltungsgericht für das Land Nordrhein-Westfalen (Higher Administrative Court for the Land of North Rhine-Westphalia, Germany). By judgment of 13 March 2013, that court annulled the decision of 26 September 2005 and ordered the BfArM to reconsider the application for renewal of the authorisation of Linoladiol N, in the light of its legal opinion. By decision of 11 July 2013, that authority accordingly granted the renewed authorisation for Linoladiol N for certain presentations of the product.

13. While the above judicial proceedings were still pending, the German authorities made a referral concerning Linoladiol N to the CHMP of the European Medicines Agency on 24 May 2012, pursuant to Article 31(1) of the HUM Code.

14. Following the procedure laid down in Article 32(2) of the HUM Code, the CHMP appointed as rapporteur Ms Martina Weise, its member of German nationality, who was employed by the BfArM.

15. On 19 December 2013, the CHMP issued a provisional opinion, the re-examination of which was requested by the first appellant. On 25 April 2014, the CHMP issued its final opinion. On 19 August 2014, the European Commission adopted the implementing decision.

16. In accordance with the measures proposed in the final opinion of the CHMP, that decision provides, in Annex IV thereto, that the summary of product characteristics and package leaflets of medicinal products such as Linoladiol N must specify a maximum treatment duration of four weeks without repetition.

III. Procedure before the General Court and the judgment under appeal

17. On 19 September 2014, the appellants brought their action for partial annulment of the decision at issue.

18. By separate document, lodged at the Registry of the General Court on 30 September 2014, the appellants made an application for interim measures, in which they submitted that the President of the General Court should suspend the operation of the decision at issue. By order of 15 December 2014, the President of the General Court dismissed that application and reserved the costs.

19. Having rejected the pleas raised by the appellants, the General Court dismissed the action in its entirety and ordered them to pay the costs.

IV. Procedure before the Court and forms of order sought

20. By application lodged at the Registry of Court of Justice on 23 December 2016, the appellants brought the present appeal.

21. The appellants claim that the Court should set aside the judgment under appeal and annul the decision at issue. In the alternative, they claim that the case should be referred back to the General Court. Finally, they claim that the Commission should be ordered to pay the costs.

22. The Commission contends that the Court should dismiss the appeal and order the appellants to pay the costs.

V. Legal assessment

23. In support of their appeal, the appellants raise three grounds of appeal, alleging, respectively, infringement of Articles 31 and 32 of the HUM Code, infringement of Article 116 of that code, read in conjunction with Article 126 thereof, and infringement of general principles of EU law, such as the principle of proportionality and the principle of equal treatment.

A. The first ground of appeal, alleging infringement of Articles 31 and 32 of the HUM Code

24. This ground of appeal is composed of three parts. First, the appellants complain that the General Court misinterpreted Article 31 of the HUM Code by failing, in the judgment under appeal, to take into account that under that provision the opening of the procedure laid down therein is subject to specific conditions. Secondly, the appellants submit that the General Court infringed Article 32(2) of the HUM Code by disregarding the requirement for neutrality enshrined in that provision and the principle of a diligent and impartial examination laid down in Article 41(1) of the Charter. Thirdly, they complain that the General Court infringed Article 32(3) of the HUM Code and the right to be heard.

1. The first part, alleging misinterpretation of Article 31 of the HUM Code

(a) Summary of the arguments of the parties

25. This first part of the first ground of appeal is directed against paragraphs 29, 37, 38, 44 to 49, 59, 61, 63, 65 and 67 of the judgment under appeal, in that the General Court overlooked that Article 31 of the HUM Code makes the opening of the ad hoc procedure provided for therein subject to a temporal condition and the condition that ‘interests of the Union’ are involved.

26. The appellants consider that, according to the General Court’s interpretation of Article 31(1) of the HUM Code, the only condition for opening that procedure is that the medicinal product under examination is authorised in several Member States. Consequently, a competent national authority could at any time request the examination of a medicinal product by the CHMP under the procedure laid down in Article 31 of the HUM Code, without the adoption of a decision on the authorisation of the medicinal product concerned at national level precluding that procedure from being initiated.

27. In the appellants’ view, that argument contradicts, first of all, the wording of Article 31(1) of the HUM Code. The word ‘before’, which appears in that provision, clearly indicates that the Member States cannot make a referral to the Committee at all times. On the contrary, they may make a referral to it only prior to the adoption of a national decision.

28. In the present case, the appellants claim that the Federal Republic of Germany initiated the procedure laid down in Article 31 of the HUM Code on 31 May 2012, that is to say well after the date on which the German authorities gave a decision on the authorisation of Linoladiol N (26 September 2005). In so far as the General Court held that the relevant national decision was that by which the German authorities granted the authorisation renewal for Linoladiol N dated 11 July 2013, it does not correctly distinguish between the decision-making power of the administration and court proceedings.

29. Moreover, the appellants consider that the General Court should not, when defining the purpose of Article 31(1) of the HUM Code, have relied on a guide drawn up by the respondent in order to assess the legality of acts adopted by the respondent itself, without disregarding the principle of the separation of powers.

30. Furthermore, the appellants take the view that the Federal Republic of Germany committed an abuse of rights by initiating the procedure laid down in Article 31 of the HUM Code solely in order to avoid being the losing party in the action brought by the appellants before the German courts against the decision of 26 September 2005, which is the date on which the German authorities gave a decision on the MA for Linoladiol N refusing to renew that MA.

31. Finally, the appellants consider that, by leading to divergent assessments in the various Member States, the initiation of the procedure at issue following the adoption of a conflicting decision by a national authority would undermine the objective of the HUM Code, which is to prevent hindrances to trade in medicinal products on the market.

32. The appellants also submit that the General Court also incorrectly assessed the condition that the procedure laid down in Article 31 the HUM Code may be initiated ‘in specific cases where the interests of the Union are involved’. Where a medicinal product has already been authorised, such an interest exists where current knowledge concerning its efficacy and safety justify referral to the CHMP. In that regard, the fact that the studies considered by the CHMP in that context dated from 2004 shows that there were no new data which could justify initiation of the procedure under Article 31 of the HUM Code.

33. The Commission considers that the General Court correctly interpreted Article 31(1) of the HUM Code. Having held that it is not certain, in the light of the wording of that provision, that the adoption at national level of an act concerning the MA, including an act which had been challenged before national courts, would deprive national bodies of the option of consulting the CHMP, the General Court based its interpretation on the context of that article and the objectives pursued by the rules of which it is part. In the Commission’s view, it thus correctly reached the conclusion that the abovementioned objectives support a broad interpretation of the conditions for initiating the procedure under Article 31(1) of the HUM Code and that every Member State has an interest in opening that procedure so long as it may still act in respect of an MA.

34. Moreover, that institution considers that the General Court cannot be criticised for having relied, when defining the objective of that provision, inter alia on a guide drawn up by the Commission as a non-legally binding document.

35. As regards the condition concerning the existence of ‘interests of the Union’, the Commission contends that that condition refers to the need to evaluate a medicinal product, or its active substance, at an EU level and that that need is clearly evident in the event of authorisation of the same active substance in several Member States, as is the case here. In that context, the question of whether or not the relevant data are new is irrelevant to the assessment of that condition.

(b) Assessment

36. It should be recalled that Article 31 of the HUM Code states that the procedure which is laid down therein may be initiated, first, where there are ‘interests of the Union’ and, secondly, before the Member State has reached any decision on the MA application.

37. The appellants claim that the two conditions were assessed incorrectly in the judgment under appeal.

38. I shall begin by examining the appellants’ complaint concerning the condition relating to ‘interests of the Union’.

39. In paragraphs 59 to 66 of the judgment under appeal, after observing that the concept of ‘interests of the Union’ is not defined in the HUM Code, the General Court held that it must be interpreted in such a way as to ensure a balance between the overriding objectives of that code, namely the objective of protecting public health in the European Union and the objective of ensuring the free movement of medicinal products on the EU market. Consequently, it makes provision for the concerted cooperation of the Member States which have granted MAs for medicinal products containing the same active substance with a view to protecting public health in the European Union. That concept plays its full role, in the General Court’s view, as soon as MAs for the same medicinal product have been granted in several Member States and as uncertainties concerning the active substance have been raised, which is true of the present case.

40. In that context, the fact that the BfArM, when making the referral to the CHMP, did not demonstrate that such uncertainties were based on the suspicion of a ‘serious and new’ risk is irrelevant, in the General Court’s view, since that concept is not applicable in the procedure under Article 31 of the HUM Code.

41. That interpretation appears to me to be free of any error of law.

42. The concept of ‘interests of the Union’ is not defined anywhere in the HUM Code. As the General Court noted in paragraph 59 of the judgment under appeal, apart from in Article 31, it is referred to only in recital 57 the HUM Code, where it is stated that that concept entails ensuring that the pharmacovigilance systems for medicinal products authorised by any of the procedures are consistent. However, it does not appear to me that that element could assist in determining its scope.

43. The content of that concept must, therefore, be established by striking a balance between the competing objectives of the HUM Code, namely safeguarding public health and the free movement of medicinal products. Thus, it must allow each Member State the option of raising any uncertainty concerning the active substance of a medicinal product which already holds an MA in other Member States, while ensuring that the final decision on the suspension or revocation of those MAs should be made at EU level.

44. A reading of Chapter III of the guidance published by the Commission in ‘The rules governing medicinal products in the European Community’, Volume II: ‘Notice to applicants for [MAs] for medicinal products for human use in the Member States of the European Community’ (‘the Notice to Applicants’ or ‘the guide’) does not, in my view, justify a different interpretation. In accordance with the Notice to Applicants, the concept of ‘interests of the Union’‘refers particularly to the interests of public health related to medicinal products in the Union in the light of quality, safety and efficacy data, and to the free movement of products within the Union’.

45. It therefore appears to me that, while the final decision regarding the suspension or revocation of MAs must be adopted at EU level, it falls within the competence of each Member State to determine the level of protection of health that would justify a referral to the CHMP.

46. That is why I consider that the appellants’ first complaint, that the General Court interpreted the concept of ‘interests of the Union’ incorrectly because it did not hold that referral to the CHMP is justified only in the presence of ‘new data’ raising doubts concerning the efficacy or safety of the medicinal product in question, cannot be upheld, since it would restrict the Member States’ discretion in choosing the appropriate level of health protection.

47. Contrary to the appellants’ submission, it clearly follows from the second subparagraph of Article 31(1) of the HUM Code (‘Where the referral results from the evaluation of data relating to pharmacovigilance of an authorised medicinal product ...’) that the existence of new pharmacovigilance data is not one of the grounds for a referral to the CHMP. ( 4 )

48. I therefore consider that the General Court did not err in law when it held that the Commission did not infringe Article 31(1) of the HUM Code by accepting from the BfArM a referral to the CHMP which was not justified on the basis of new data.

49. I shall now examine the complaint concerning the alleged misinterpretation by the General Court of the condition that a referral may be made to the CHMP by the competent national authority only before a decision is taken on the MA application.

50. Before beginning my analysis, I think it would be helpful briefly to summarise the passage of the judgment under appeal against which that complaint is directed, which begins at paragraph 28 and ends at paragraph 49 of that judgment.

51. First of all, the General Court held that, since the wording of Article 31(1) of the HUM Code did not provide a definite answer as to whether the adoption of any decision concerning an MA prevents the procedure laid down in that article from being initiated, it was necessary to interpret that provision in the light of the objectives pursued by the HUM Code.

52. In that regard, the General Court observed that the purpose of the HUM Code is, first, to eliminate hindrances to the trade in medicinal products between Member States by avoiding divergent scientific assessments of comparable medicinal products and, secondly, to contribute to the protection of health by ensuring high standards of quality and safety. It then recalled that the procedure referred to in Article 31 of that code has the function of coordinating and guiding in a common direction the actions taken by the competent authorities. Consequently, the purpose of that article, in the view of the General Court, supports a flexible interpretation of the conditions for referral laid down therein.

53. According to the General Court, the same broad approach is suggested by the fact that the procedure under Article 31 of the HUM Code culminates in a Commission decision which is binding on Member States, whereas such a decision did not have binding effect before the adoption of Directive 2004/27/EC. ( 5 )

54. Another element in support of the abovementioned interpretation can, in the General Court’s view, be deduced from a reading of Chapter I of the Notice to Applicants, which shows that Member States have the right to initiate the procedure under Article 31 of the HUM Code provided that they may still act in relation to an MA.

55. On the basis of those considerations, the General Court concluded that, by adopting the implementing decision at the end of the procedure arising from the referral to the CHMP by a national authority, where that procedure was conducted in parallel with national judicial proceedings brought against the initial decision of that authority concerning a national MA, the Commission had not infringed Article 31(1) of the HUM Code.

56. For my part, like the appellants, I consider that conclusion to be incorrect.

57. First of all, I am persuaded that the wording of Article 31(1) of the HUM Code makes it possible to resolve that issue with certainty, as the appellants have, in essence, stated. The word ‘before’ in the wording of that article refers unambiguously to the temporal succession of the steps taken by the various participants in the procedure before the CHMP. A fundamental principle follows therefrom, namely that the procedure before the CHMP must precede the adoption of the national decision. This means that the ‘decision’ to which Article 31(1) of the HUM Code refers is the decision taken by the competent administrative authorities and not also that of judicial authorities. ( 6 ) In conclusion, if the EU legislature had intended to leave the competent national authorities free to refer a matter to the CHMP at any time where the interests of the Union were involved, it would, in my view, have worded that provision differently.

58. I find it surprising, therefore, that the General Court was so quick to conclude that the text of Article 31(1) of the HUM Code does not provide any clarification on the issue forming the subject matter of this complaint.

59. Moreover, the teleological interpretation of that provision provided by the General Court does not seem to me to be capable of calling into question the restrictive conclusion which follows from a reading of its wording.

60. In that regard, I do not deny that the General Court correctly identified the objective of the procedure laid down in Article 31(1) of the HUM Code, namely that of avoiding divergent assessments in the various Member States and the resulting hindrances to trade by means of coordinating and guiding in a common direction the exercise of national competences. Nevertheless, I do not concur with the General Court’s conclusion that that element supports a broad interpretation of the condition for referral to the CHMP in question.

61. In order to explain the reason for my disagreement, I would recall that the procedure under Article 31(1) of the HUM Code, which is in Chapter IV of the HUM Code, concerning mutual recognition and decentralised procedures, is only one of the procedures for referral of a matter to the CHMP, together with Articles 29 and 30 of that code.

62. As regards Article 30 of the HUM Code, in particular, it applies where Member States have adopted conflicting decisions concerning the MA for a single medicinal product, or the suspension or revocation of that MA. Its purpose is therefore to remedy a hindrance to the trade in medicinal products which has already arisen at the time of adoption of those decisions.

63. Given that it is reasonable to assume the scopes of two different provisions of the same Code do not overlap, I tend to believe that the function of Article 31 of the HUM Code is complementary to that of Article 30 of that code. Therefore, it seems to me that the latter must be understood as seeking to prevent hindrances to trade in medicinal products.

64. In that context, it may certainly be assumed, in the light of economic reality, that, after an administrative decision refusing the MA, such as that adopted in the present case by the BfArM on 26 September 2005, a hindrance to trade has already arisen. Therefore, initiation of the procedure laid down in Article 31(1) of the HUM Code after such a decision had been adopted, well before a national judicial authority had ruled on an action brought against that decision, would clearly run counter to the purposes of that procedure.

65. In my view, the Commission, in those circumstances, should therefore not have accepted the referral to the CHMP from the BfArM in the present case.

66. The second argument on which the General Court bases the rejection of that part of the plea, namely the binding nature of the decision which the Commission adopts at the end of the procedure under examination, does not appear to me to be capable of calling such a conclusion into question.

67. In the light of those considerations, the appellants’ complaint must be upheld.

68. Given that the teleological interpretation does not support that adopted by the General Court, the guide drawn up by the Commission in no way alters the interpretation of Article 31(1) of the HUM Code which I propose that the Court adopt, since that guide is clearly not binding on the Court.

69. Finally, as regards the complaint that the Federal Republic of Germany committed an abuse of rights by initiating the procedure under Article 31 of the HUM Code to prevent the BfArM from being the losing party in the appeal proceedings pending before the German administrative courts, I am of the opinion that the General Court did not err in finding that the appellants had provided only ‘allegations and suppositions’, such as the circumstance that the BfArM had attempted, before the Oberverwaltungsgericht für das Land Nordrhein-Westfalen (Higher Administrative Court for the Land of North Rhine-Westphalia), to obtain a stay of proceedings before that court. With regard to that circumstance, the fact that the BfArM expressly declared in its pleading that the stay of proceedings was requested pending the outcome of the proceedings before the CHMP does not, however, seem to me sufficient to establish the abusive nature of the steps taken by the BfArM. I therefore consider that that complaint must also be rejected.

70. In the light of the foregoing, the first part of the first ground of appeal must, in my view, be upheld in so far as the General Court should have found that the Commission had infringed Article 31(1) of the HUM Code by accepting, in the present case, the referral to the CHMP, despite the fact that it occurred after the adoption of the initial decision of the German administrative authorities.

2. The second part, alleging infringement of the requirement for neutrality laid down in Article 32(2) of the HUM Code and the principle of a diligent and impartial examination laid down in Article 41(1) of the Charter

(a) Summary of the arguments of the parties

71. The appellants consider that, in paragraphs 94 to 104 of the judgment under appeal, the General Court held that application of the principle of impartiality must be subject to excessively strict conditions.

72. For there to be an infringement of that principle, it is not necessary, in their view, for it to be established that there actually was a partial act, but suffices that external circumstances raise a reasonable ‘suspicion’ that the facts were not examined neutrally and objectively. Thus, objective impartiality is particularly precarious in the case of conflicts of interest arising from institutional links, with the typical case being where functions overlap. In the appellants’ view, Ms Weise’s dual capacity as an employee of the competent national authority, on the one hand, and as the chief rapporteur to the CHMP, on the other hand, therefore renders impossible any objective and impartial decision. Where there is suspicion as to the partiality of one of the persons responsible for the decision of the CHMP, objective impartiality is not ensured, in the appellants’ view, by the fact that the CHMP adopted that decision in committee or that the decision was adopted unanimously.

73. As regards subjective impartiality, the appellants claim that, contrary to the General Court’s finding, the fact that Ms Weise, in her capacity as rapporteur of the CHMP, recommended that the MA for Linoladiol N be revoked, in accordance with the previous decision of her employer, the BfArM, is evidence of the partiality with which Ms Weise carried out a very unfavourable evaluation of Linoladiol N. The partiality of that evaluation is also demonstrated, according to the appellants, by the fact that, in its final opinion, the CHMP adopted a more nuanced approach, in that it proposed only a simple variation of the MA for Linoladiol N.

74. The Commission challenges the argument that the appointment of the German member of the CHMP as rapporteur in a procedure initiated by the Federal Republic of Germany before the CHMP raises the suspicion, in the light of objective circumstances, that the facts had not been assessed neutrally and objectively. In that regard, the General Court has already held that, in the absence of other elements, that fact is irrelevant. Moreover, in the Commission’s view, the appellants disregard the fact that the General Court correctly assumed that Article 61(6) of Regulation No 726/2004, which expressly prohibits Member States ‘from giving committee members and experts any instruction which is incompatible with their own individual tasks or with the tasks and responsibilities of the Agency’, is already capable of ensuring a neutral and objective examination. In any event, the Commission points out that Ms Weise was only one of the four rapporteurs responsible for assessing Linoladiol N during the procedure before the CHMP.

(b) Assessment

75. It is appropriate at the outset to dispel any possible misunderstanding concerning the subject matter of this part of the first ground of appeal by carefully delimiting its scope.

76. First, this part is in no way based, as the Commission submits in its response, on the fact that the CHMP appointed as chief rapporteur a member with the same nationality as that of the authority which initiated the procedure under Article 31 of the HUM Code.

77. Secondly, despite its title, this part does not concern infringement of Article 32(2) of the HUM Code. On the contrary, the appellants acknowledge that that article imposes no restrictions on the CHMP’s discretion when appointing one of its members as a rapporteur. ( 7 )

78. As is clear merely from a reading of the arguments submitted by the appellants, they allege infringement only of Article 41(1) of the Charter, enshrining the ‘right to good administration’, in so far as it lays down the requirement that the institutions, bodies, offices and agencies of the European Union handle the affairs of all persons impartially. ( 8 )

79. First of all, it is appropriate to define the scope of the requirement of impartiality, as interpreted in the relevant case-law.

80. That requirement has already been interpreted by the Court in the context of assessing an alleged infringement of the right to a fair trial under Article 6 of the European Convention for the Protection of Human Rights and Fundamental Freedoms, signed in Rome on 4 November 1950 (‘the ECHR’). ( 9 ) In that context, the Court held that the requirement of impartiality of courts comprises two components which are, first, subjective impartiality, by virtue of which no member of the court concerned may show bias or personal prejudice, and, second, objective impartiality, under which there must be sufficient guarantees to exclude any legitimate doubt as to possible bias on the part of the court concerned. ( 10 )

81. Next, in its judgment of 11 July 2013, Ziegler v Commission (C‑439/11 P, EU:C:2013:513, paragraph 154), the Court acknowledged that the abovementioned interpretation had to be applied, by analogy, to the requirement of impartiality of the institutions, bodies, offices and agencies of the European Union, as is clear from Article 41 of the Charter.

82. Accordingly, when assessing the administrative action of the European Union, subjective impartiality must be examined in the light of the personal convictions and behaviour of the relevant member of that institution, body, office or agency. Given that it is presumed until proven otherwise, ( 11 ) subjective impartiality is difficult to challenge.

83. However, I am not convinced by the appellants’ allegations that Ms Weise acted partially when she proposed, in line with the earlier decision of her employer, that the MA for Linoladiol N be revoked. In that regard, the General Court did not, in my view, err in finding, in paragraph 97 of the judgment under appeal, that that position taken by Ms Weise amounts to the exercise of the functions assigned to a rapporteur of the CHMP. Moreover, the General Court was also right, in my view, to hold in paragraph 98 of the judgment under appeal that the appellants have not demonstrated that the absence of Ms Weise from the second hearing before the CHMP would have led to the conclusion that the MA for Linoladiol N should be maintained. Contrary to the appellants’ submission, no evidence to that effect is provided in paragraphs 37 to 42 of the application or at any other point in that document.

84. In any event, the appellants’ complaints in the appeal concern in particular the objective component of the requirement of impartiality which flows from Article 41 of the Charter.

85. In that connection, I would point out that the examination of objective impartiality requires an assessment of whether, irrespective of the personal conduct of the relevant member of the EU administration, there are ascertainable facts which may raise doubts as to his impartiality on the part of the person concerned, appearances possibly also being of importance. ( 12 ) In that regard, the case-law of the European Court of Human Rights has stated that the decisive factor is whether the apprehensions of the person concerned can be regarded as justified in objective terms. ( 13 )

86. If objective impartiality is so understood, there is no doubt, in my view, that it would be likely to be undermined in the event of a conflict of interest resulting from an overlap of functions, as the appellants submit in their appeal.

87. However, a mere overlap of functions is insufficient, in itself, to justify in objective terms the apprehensions of the person concerned regarding the existence of possible bias and thus to justify the finding of an infringement of objective impartiality.

88. That may be easily deduced from the judgment of the General Court of 5 July 2016, Commission v Hristov (T‑26/15 P, EU:T:2016:390). By upholding the appeal, the General Court effectively held that the Civil Service Tribunal’s finding in the judgment of 13 November 2014, Hristov v Commission and EMA (F‑2/12, EU:F:2014:245), according to which the fact that a member of the Management Board of the European Medicines Agency (the body taking the decision) also sat on the pre-selection panel of that agency (the body making the proposal) might have justified a legitimate doubt as to the impartiality of that panel, was legally incorrect because the Civil Service Tribunal had not established that the seats of the members in question on the Management Board of the European Medicines Agency had any ‘practical meaning’ with regard to their role on the pre-selection panel. ( 14 )

89. I take the view that the case-law has established the criteria for determining the circumstances in which the ‘double-hatted’ capacity of a member of an EU body has that ‘practical meaning’ with regard to his role within it.

90. In that regard, I refer in particular to the judgment of 20 December 2017, Spain v Council (C‑521/15, EU:C:2017:982). In that case, the Kingdom of Spain complained that the Commission had, inter alia, infringed objective impartiality by entrusting the conduct of an investigation procedure seeking to verify the accuracy of deficit data provided by that Member State to a team largely composed of members of Eurostat’s staff who had previously taken part in the visits to Spain which led the Commission to take the view that there were serious indications of facts justifying the initiation of such a procedure. ( 15 )

91. That plea was rejected by the Court on the basis of the following findings. First, in addition to falling within separate legal frameworks, the visits in question, on the one hand, and the investigation procedure, on the other, had different purposes. ( 16 ) While the purpose of the visits that Eurostat may carry out in the Member States is to allow the Commission services to assess the quality of the government debt and deficit data reported by the Member States, the purpose of the investigation procedure is to enable the Commission to conduct all investigations necessary to establish the existence of misrepresentations of those data, made either intentionally or by serious negligence, where it finds that there are serious indications of the existence of facts liable to constitute such a misrepresentation. Secondly, in the light of those separate legal frameworks and different purposes, even though the data which were the subject of those visits and the investigation procedure may have partially coincided, the assessments which Eurostat and the Commission were respectively called upon to make in respect of those data were, on the other hand, necessarily different. ( 17 ) Thirdly, it is to the Commission, and therefore to the Commissioners acting as a collegiate body, that the relevant rules ( 18 ) reserve the power to decide to initiate the investigation procedure, responsibility for conducting the investigation and the power to submit to the Council the recommendations and proposals that are necessary at the conclusion of the investigation, but those rules do not entrust Eurostat’s staff with any responsibility of their own. ( 19 )

92. In my view, it is appropriate at this stage to apply the criteria set out above to the present case. This will make it possible to establish whether the appointment of Ms Weise as chief rapporteur of the CHMP, in the context of the procedure relating to the application to renew the MA for Linoladiol N, was such as to give rise to objectively justified concerns on the part of the appellants as regards possible bias on the part of Ms Weise, since she is an employee of the BfArM, that is to say the national authority which made the referral to the CHMP, that authority had already adopted a negative decision in respect of that renewal and the BfArM was also the defendant in a dispute before the national administrative courts on the validity of its refusal decision.

93. It is therefore necessary to establish (i) whether the procedure governing the exercise of the function of the BfArM has the same purpose as that which governs the exercise of the function of the CHMP, ( 20 ) (ii) whether the assessments which the BfArM and the CHMP are respectively required to carry out are of the same nature and (iii) whether Ms Weise was entrusted with a ‘responsibility of her own’ in the context of the procedure before the CHMP. As regards the latter, I consider that it may be inferred from the previously discussed judgment that such responsibility of one’s own exists in the present case if Ms Weise’s role was regarded as decisive for the conduct or the outcome of that procedure. ( 21 )

94. In the first place, it seems to me to be certain that the procedure governing the exercise of the function of the BfArM must be regarded as having the same purpose as that governing the exercise of the function of the CHMP. In both cases, the purpose of the procedure is to provide the body concerned with the opportunity to conduct any medical or scientific assessments of the quality, safety and efficacy of medicinal products which are necessary for the adoption of a decision on the granting of an MA.

95. In the second place, in the light of the fact that the purpose of those procedures is identical, the evaluations of the quality, safety and efficacy of medicinal products conducted by the BfArM, on the one hand, and by the CHMP, on the other, are necessarily of the same nature. ( 22 )

96. In the third place, it cannot be denied, in my view, that the CHMP entrusted Ms Weise with a responsibility of her own in the context of the procedure for the renewal of the MA for Linoladiol N. Given that the chief rapporteur’s role consists, in accordance with Article 62(1) of Regulation No 726/2004, in the ‘coordination of the evaluation’ of the medicinal product under review, such a role necessarily gave Ms Weise the possibility of exercising considerable influence on the conduct of that procedure. ( 23 )

97. In those circumstances, it is obvious that the fact that she was accompanied, in the performance of her task, by a second rapporteur, namely the Dutch member of the CHMP, is not capable of calling into question the conclusion that Ms Weise had the possibility of exercising considerable influence on the conduct of the procedure. Contrary to the Commission’s claim in its response, nor is the fact that two other members of the CHMP, namely the Spanish and Austrian members, joined the first two, respectively as chief rapporteur and second rapporteur, at the review stage. That is not likely to counter the influence that Ms Weise was able to exercise, since the review has a substantially narrower scope than that of the first stage of the procedure, since ‘[it] may deal only with the points of the opinion initially identified by the applicant’, in accordance with the fourth subparagraph of Article 62(1) of Regulation No 726/2004.

98. Since the three criteria which flow from the case-law have been fulfilled, I take the view that the appointment of Ms Weise as chief rapporteur of the CHMP in the context of the procedure relating to the application to renew the MA for Linoladiol N constitutes an infringement of the objective component of the requirement of impartiality arising from Article 41 of the Charter, as interpreted by the case-law of the Court.

99. In the light of those considerations, I consider that the General Court erred in law in finding that Article 41 of the Charter had been complied with by the CHMP in the present case.

100. In my view, the second part of the first ground of appeal must therefore be upheld.

3. The third part, alleging infringement of Article 32(3) of the HUM Code and the right to be heard

(a) Summary of the arguments of the parties

101. According to the appellants, it is clear from paragraphs 106 to 112 of the judgment under appeal that the General Court disregarded the complaint relating to infringement of the right to be heard in so far as it did not acknowledge that that right necessarily includes the opportunity to comment on all the facts relevant to the decision, such as the fundamental restriction associated with the renewal of the MA for Linoladiol N (the prohibition on the repeated use of that medicinal product).

102. The infringement of the right to be heard also had an impact on the Commission’s final decision. Indeed, had the first appellant had the opportunity to express its view during the procedure before the CHMP, that body would have been obliged to assess the complaints put forward, in particular, in the third ground of appeal (infringement of the principles of proportionality and equal treatment).

103. The Commission denies that the first appellant, in the procedure before the CHMP, was not given the opportunity to be heard in relation to the proposed measure prohibiting the repeated use of Linoladiol N.

104. Moreover, it considers that the appellants have not adduced any evidence that the General Court erred in law in its interpretation, in paragraph 110 of the judgment under appeal, that the right to be heard, for the purposes of Article 32(3) of the HUM Code, obliges the CHMP only to offer the persons concerned the opportunity to provide explanations within a time limit which it is to specify. There is no doubt, in the Commission’s view, that that right was respected.

(b) Assessment

105. I would recall that Article 32(3) of the HUM Code provides that ‘before issuing its opinion, the [CHMP] shall provide the applicant or the marketing authorisation holder with an opportunity to present written or oral explanations within a time limit which it shall specify’.

106. In the judgment under appeal, the question of whether that article was infringed by the CHMP in the context of the procedure before it was answered in the negative. In its assessment, the General Court considered, in paragraph 109 of the judgment under appeal, that the first appellant had on several occasions had the opportunity to provide explanations both orally (hearings on 19 March, 18 November and 16 December 2013) and in writing (questionnaires received on 20 November 2012 and 22 February, 25 March, 20 September and 18 November 2013).

107. As regards the alleged irregularities under which the hearing of 18 November 2013 took place and the appellants’ impression that the intention of the CHMP was solely to adapt the information sheet for Linoladiol N in the light of the information sheet on which the Croatian authorisation was based, the General Court reiterated that the right to be heard requires the CHMP only to offer the persons concerned the opportunity to present explanations within a time limit specified by that body, which it did in the present case (paragraph 110 of the judgment under appeal). The CHMP was therefore not obliged, according to the General Court, to guarantee that it would be bound by a particular information sheet without amending it.

108. In that context, the General Court held, in paragraphs 111 and 112 of the judgment under appeal, that the appellants’ complaints concerning the CHMP’s conduct at the hearing of 13 December 2013 and the time limit for the reply to the fifth questionnaire constituted mere ‘factual irregularities’ and, as such, were not capable of giving rise to an infringement of Article 32(3) of the HUM Code. ( 24 )

109. At the outset, I would point out that I am in no way seeking to call into question the General Court’s finding that the CHMP has complied with its procedural obligations under the provision in question. However, I would recall that, as the appellants claim, the part of the plea under examination by the General Court also covered the material scope of the right to be heard as provided for in Article 32(3) of the HUM Code.

110. That is clear from a reading of the written pleadings submitted by the appellants at first instance.

111. In the application at first instance, that part of the plea included, in addition to the abovementioned complaints of a procedural nature, ( 25 ) a third substantive complaint under the heading ‘The first applicant was not heard with regard to the restriction of the period of use of Linoladiol N to four weeks with a concomitant exclusion of repeated use’.

112. The independence of that complaint from the first two is confirmed by the reply lodged at first instance, and in particular by a reading of paragraph 41, according to which ‘contrary to the view taken by the defendant, the objective of a hearing is not limited to providing a formal opportunity to make oral submissions on the scientific conclusions of the CHMP, as the hearing should also provide the opportunity to take a position on the legal consequences of those conclusions’, in conjunction with paragraph 42, in which the content of the complaint is set out in detail: ‘... the Commission cannot take into account arguments on which the persons concerned have not had the opportunity to state their views. In that regard, it should be accepted that the defendant acknowledges that the CHMP did not inform the first applicant of the proposed restriction of the use of the medicinal product Linoladiol N to a single use in the lifetime of a patient.’

113. In conclusion, the part of the ground of appeal in question, far from being limited to the rejection by the General Court of the infringement of the CHMP’s procedural obligations, also includes the complaint that the General Court failed to rule on the infringement of the first appellant’s right to be heard by the CHMP concerning the condition for the renewal of the MA for Linoladiol N, namely the restriction of the duration of use to four weeks with the concomitant exclusion of repeated use.

114. The question arises as to whether the General Court examined the complaint in question in the judgment under appeal.

115. Doubts may legitimately be raised in this regard. At first sight, paragraphs 109 to 112 of the judgment under appeal do not seem to contain an explicit answer from the General Court as to whether the fact that the first appellant was not heard on the restriction attached to the renewal of the MA for Linoladiol N constituted an infringement of the right to be heard.

116. However, I would point out that, according to settled case-law, the General Court’s reasoning may also be implicit, on condition that it enables the applicants to understand the grounds of the General Court’s judgment and provides the Court of Justice with sufficient evidence to exercise its powers of review. ( 26 )

117. In that regard, it must be ascertained whether the penultimate sentence of paragraph 110 of the judgment under appeal, read in the context of that paragraph, fulfils those conditions and whether it is, therefore, capable of fulfilling the General Court’s obligation to state reasons.

118. In paragraph 110 of the judgment under appeal, after pointing out that, when assessing the alleged irregularities under which the hearing of 18 November 2013 took place, ( 27 ) the right to be heard, for the purposes of Article 32(3) of the HUM Code, obliges the CHMP only to provide the persons concerned with an opportunity to present explanations within a time limit which it is to specify, the General Court held that ‘the CHMP was not, therefore, obliged to guarantee that it would adhere exclusively to a particular information sheet and that that information sheet could not be amended’. ( 28 )

119. That sentence could be understood, by means of an interpretative effort, as meaning that the CHMP was not obliged, when adopting its opinion, to adhere to the information sheet on which the appellants were able to state a position, namely that on which the Croatian authorisation was based, and was thus entitled to include the variation introducing the condition restricting the duration of use to four weeks with concomitant exclusion of repeated use without first giving the appellants the opportunity to express their view on that subject.

120. Therefore, the inclusion of the condition attached to the renewal of the MA for Linoladiol N, which was implemented in the present case by means of the amendment of the information sheet for the medicinal product, is not covered, in the General Court’s view, by the first appellant’s right to be heard under Article 32(3) the HUM Code.

121. That is the reading of paragraph 110 of the judgment under appeal on which the remainder of my reasoning is based.

122. However, before beginning the analysis, I cannot refrain from putting forward a general criticism of the General Court’s response to the complaint in question. Indeed, even if it is possible to conclude that that sentence of paragraph 110 of the judgment under appeal constitutes an ‘implied statement of reasons’ for the purposes of the case-law, it is regrettable that the General Court fulfilled its obligation by means of reasoning which is so concise and cryptic.

123. However, having concluded that there was no infringement of the obligation to state reasons, I shall now turn to the substance, and in particular the question whether the General Court correctly held that the range of explanations which the appellants were invited by the CHMP to provide should have extended to their position on the condition attached to the renewal of the MA for Linoladiol N.

124. In that regard, I would observe first of all that, given that Article 32(3) of the HUM Code has never been interpreted by the Court until now, the material scope of the right to be heard under the provision in question must be inferred from the case-law which has defined the scope of the right to be heard as a general principle of EU law.

125. The right to be heard is a general principle of EU law, enshrined in Article 41(2)(a) of the Charter. That provision defines it as ‘the right of every person to be heard, before any individual measure which would affect him or her adversely is taken’.

126. In that regard, the Court has stated repeatedly that persons having the right to be heard must be afforded the opportunity to make known their views on the truth and relevance of the facts and circumstances alleged as well as on the evidence used in support of those allegations. ( 29 ) That scope is further clarified by a series of judgments in which the Court held that the right to be heard extends to all the matters of fact and of law which form the basis for the decision-making act but not the final position which the administration intends to adopt. ( 30 )

127. In my view, it is on the basis of that case-law that it is necessary to assess whether the General Court’s conclusion can be supported.

128. In the present case, it is therefore necessary to determine whether the condition attached to the renewal of the MA for Linoladiol N must be classified as a matter of fact forming the basis of the implementing decision adopted by the Commission following the opinion of the CHMP, or whether it is, conversely, an element of the decision itself, on the basis that it is the result of an assessment of the facts.

129. To that end, it appears to me to be essential to establish whether the infringement of the right to be heard alleged by the appellants is directed against the abovementioned condition as such or against the scientific finding underpinning that condition, according to which the endometrial safety of oestrogens administered vaginally over the long-term or repeatedly cannot be guaranteed in the case of treatment extended beyond four weeks. ( 31 ) The condition as such is, in my view, part of the final position which the Commission intends to adopt following the assessment of the facts, ( 32 ) while the scientific finding underpinning it is one of the facts on which that position is based.

130. However, it seems to me to follow unambiguously from the appeal that the appellants complain that the CHMP did not hear the first appellant on the condition as such. They argue that the first appellant’s right to be heard covered ‘the question of what measure is necessary, in the authority’s view, in order to take into account the outcome of the analysis’. ( 33 )

131. That condition is thus part of the final position of the Commission and is therefore not covered by the first appellant’s right to be heard.

132. In those circumstances, the third part of the first ground of appeal must, in my view, be rejected.

4. Conclusion on the first ground of appeal

133. In the light of the foregoing, I propose that the Court uphold the first and the second part of the first ground of appeal and, consequently, declare it to be well founded.

B. The second ground of appeal, alleging infringement of Article 116(1) and Article 126(1) of the HUM Code

134. By the second ground of appeal, the appellants claim that, in paragraphs 121 to 199 of the judgment under appeal, the General Court, in assessing the various parts of the second plea raised at first instance, did not fully grasp the intention underlying the complaints raised and lost sight of the substance of the appellants’ arguments.

135. That ground of appeal is composed of four parts. First, the appellants consider that the General Court infringed the principle of a balanced burden of demonstration and proof in that its interpretation is tantamount to imposing on the MA holder the obligation to prove the safety of the medicinal product in question even after obtaining the MA. Secondly, they complain that the General Court erred in stating that the CHMP established in its opinion a comprehensible link between the medical or scientific findings and the conclusions. Thirdly, they claim that the General Court disregarded the fact that the pharmacovigilance data play a vital role in the assessment of the risks posed by marketed medicinal products. Fourthly, they allege that the General Court incorrectly assessed the appellants’ criticisms that the CHMP’s scientific conclusions were inaccurate owing to the misrepresentation of the available pharmacovigilance data concerning the safety of Linoladiol N and that it failed to address the appellants’ claims concerning the misrepresentation of the content of guidelines in relation to the topical use of oestrogens.

1. The first part, alleging infringement of the principles of a balanced burden of demonstration and proof since the existence of a risk was based on the absence of post-authorisation studies

(a) Summary of the arguments of the parties

136. The appellants consider that, in finding that the lack of studies capable of dispelling the doubts of the CHMP as to the existence of risks linked to the use of Linoladiol N was sufficient to justify a variation of the MA for the latter, the General Court infringed the principles of a balanced burden of demonstration and proof. It thus created a de facto obligation on the part of the authorisation holder to prove the safety of the medicinal product, by means of studies, even after obtaining the MA.

137. In that regard, a reading of the relevant provisions of the pharmacovigilance system provided for in Title IX of the HUM Code confirms, according to the appellants, that the holder of an MA is not required to conduct post-authorisation safety studies. As a result, the absence of such studies cannot be invoked against that holder.

138. The appellants also submit that the General Court’s findings cannot be founded on the arguments that it puts forward on the precautionary principle in paragraphs 137 to 140 of the judgment under appeal, since it did not take into account the fact that the risk assessment cannot be based on purely hypothetical considerations. However, the CHMP’s assumptions, set out by the General Court in paragraph 143 of the judgment under appeal, that the known risks resulting from the use of hormone replacement therapy could also exist for Linoladiol N, should be classified, in the appellants’ view, as hypothetical considerations of that nature.

139. According to the appellants, the only exception to the principle that the risk assessment cannot be based on hypothetical considerations is not applicable in the present case. According to the case-law, it occurs only where it proves to be impossible to determine with certainty the existence or extent of the alleged risk because of the insufficiency, inconclusiveness or imprecision of the results of studies conducted, but serious doubts are raised as to the safety of the medicinal product and it is therefore likely that real harm to public health exists. However, the pharmacovigilance system laid down for medicinal products makes it possible, in the present case, to determine with certainty the existence or extent of the risks associated with the use of Linoladiol N. Furthermore, in its judgment of9 September 2003, Monsanto Agricoltura Italia and Others (C‑236/01, EU:C:2003:431), the Court held that protective measures could not be based on a purely hypothetical risk assessment, except in the case of novel foods. A medicinal product such as Linoladiol N, which has been present on the market for 45 years, is not a novel product, however.

140. According to the Commission, the General Court responded correctly to the only two questions of law relating to the allocation of the burden of proof. First, in paragraph 135 of the judgment under appeal, it took the view that it was for the Commission to prove a deterioration of the risk-benefit balance of Linoladiol N. Secondly, in paragraphs 137 to 140 and 174 of that judgment, it held that the precautionary principle justifies the adoption of a restrictive measure where it proves to be impossible to determine with certainty the existence or the extent of the alleged risk. However, according to the Commission, the appellants in no way contested the merits of the assessment of those questions of law. On the contrary, they merely criticised the General Court for the findings made in paragraphs 142, 143 and 171 to 173 of the judgment under appeal, and for the conclusion reached in paragraph 179 of that judgment, namely that the Commission had discharged its burden of proof. Their arguments are therefore directed exclusively at the General Court’s examination of the evidence. This part of the second ground of appeal is, therefore, inadmissible at the appeal stage.

(b) Assessment

141. At the outset, it would appear useful to recall briefly the General Court’s reasoning in paragraphs 135 to 144 of the judgment under appeal.

142. First of all, the General Court noted that, as regards the revocation, suspension or variation of an MA under Article 116 the HUM Code, the burden of proving the efficacy and safety of a medicinal product lies with the competent authority, namely the Commission.

143. With regard to the standard of proof incumbent on the Commission, the General Court recalled that, where there is uncertainty as to the existence or extent of risks to human health, the precautionary principle allows, with a view to ensuring that public health requirements take precedence over economic interests, the adoption of protective measures without having to wait until the reality and seriousness of the risk becomes fully apparent, where new data give rise to serious doubts as to either the safety or the efficacy of the medicinal product concerned, leading to an unfavourable assessment of the risk-benefit balance for that medicinal product. In that context, the General Court stated that, according to the case-law of the Court, the Commission may confine itself to providing ‘solid and persuasive evidence on the basis of which, while not dispelling scientific uncertainty, there can be reasonable doubt as to the safety or efficacy of the medicinal product’. ( 34 ) In that regard, the General Court noted that the CHMP had considered that the known risks arising from the use of systemic products containing oestrogens for hormone replacement therapy could also exist for Linoladiol N. Considering that that was ‘solid and persuasive evidence’, the General Court held that the Commission had thus discharged its burden of proof.

144. As regards the admissibility of this part of the ground of appeal, which is disputed by the Commission, I shall merely observe that the alleged infringement of a balanced burden of proof is a question of law subject to review by the Court of Justice on appeal. ( 35 ) The present part of the ground of appeal must therefore be regarded as admissible.

145. As to the substance, however, I do not find the appellants’ argument convincing.

146. As the General Court recalls in paragraph 135 of the judgment under appeal, the general principle governing the allocation of the burden of proof in the context of Article 116 of the HUM Code provides that it is for the Commission to establish whether the conditions for revoking, suspending or varying the MA have been satisfied. However, the holder of the MA for a medicinal product is not required, during the period of validity of that MA, to adduce evidence of the effectiveness or safety of the medicinal product concerned.

147. Where there is scientific uncertainty as to the existence or extent of risks to human health, the case-law applied by the General Court shows that the Commission may adopt a protective measure (revocation, suspension or variation of the MA) without waiting for the risks in question to materialise, by applying the precautionary principle, but only with a view to substantiating its reasonable doubts as to the safety or efficacy of the medicinal product concerned with solid and persuasive evidence.

148. In the present case, the General Court found that the CHMP’s observations that the known risks arising from the use of hormone replacement therapy could also exist for Linoladiol N provided such ‘solid and persuasive evidence’.

149. I have no doubt whatsoever that that assessment by the General Court, which is based on the case-law of the Court, does not give rise to a reversal of the burden of proof obliging the holder of the MA to prove the safety of the medicinal product by means of post-authorisation studies, as the appellants claim. On the contrary, even though the standard of proof which the Commission must satisfy is lower in this case, that institution is still required to establish the facts justifying its position that a protective measure is necessary because of the deterioration of the risk-benefit balance of Linoladiol N.

150. Moreover, the General Court has already explicitly ruled, in a recent judgment, that ‘taking measures under Article 116 of the HUM Code in cases of scientific uncertainty or reasonable doubts as to the efficacy or safety of a medicinal product cannot be treated as equivalent to a reversal of the burden of proof’. ( 36 )

151. In view of the situation of scientific uncertainty as to the existence or extent of the risk to health which could justify the adoption of a protective measure by the Commission in application of the precautionary principle, I do not concur with the appellants’ argument that the General Court erred in its interpretation of the case-law by disregarding the possibility that that situation could not arise when applying the HUM Code, owing to the pharmacovigilance system established as part of the latter.

152. In that regard, I note that the EU judicature has already applied the precautionary principle in the context of the HUM Code, having identified such a situation of scientific uncertainty, in the judgment of 11 December 2014, PP Nature-Balance Lizenz v Commission (T‑189/13, not published, EU:T:2014:1056, paragraph 37 et seq.). Indeed, it appears to me that the Court should concur with that position of the General Court, given the importance of the precautionary principle for ensuring, in the pharmaceutical field, that requirements linked to the protection of public health take precedence over economic interests.

153. Finally, as regards the appellants’ statement that scientific uncertainty could exist only for new products and thus not for Linoladiol N, which has been present on the market for decades, I consider that such a conclusion cannot be drawn from the judgment of 9 September 2003, Monsanto Agricoltura Italia and Others (C‑236/01, EU:C:2003:431) for two main reasons. First, that judgment was delivered in a different field from that at issue in the present case. Secondly, while it is true that, in that judgment, the Court ruled that protective measures (provisional restriction or suspension of marketing) could be validly based on the presence of potential risks in the case of novel foods, that judgment seems to me by no means to exclude the possibility that such reasoning may also be considered sufficient in the case of foods already present on the market. In that situation, the Court was simply called on to interpret certain provisions of the regulation on novel foods and novel food ingredients. ( 37 )

154. In the light of the foregoing considerations, the first part of the second ground of appeal must, in my view, be rejected.

2. The second part, alleging a lack of a comprehensible link between the medical or scientific findings and the conclusions of the CHMP

(a) Summary of the arguments of the parties

155. In the light of paragraphs 149 to 164 and 188 to 197 of the judgment under appeal, the appellants claim that the General Court disregarded the fact that the CHMP had still not explained why it had rejected the conclusions contained in the reports or studies relied on by the appellants. Moreover, the General Court’s considerations are often contradictory, incomplete or incorrect.

156. In the first place, the appellants claim that, even though the General Court referred, in paragraph 147 of the judgment under appeal, to their arguments concerning the difficulty of applying to a local treatment a risk assessment based on systemic exposure and concerning the fact that the frequency of use of Linoladiol N is lower than that of systemic hormone replacement therapy, it is clear from a reading of the CHMP’s conclusions, cited in paragraphs 151 to 158 of that judgment, that the CHMP did not take those arguments into account in its assessment.

157. In the second place, the appellants submit that the General Court reaches an incomprehensible and contradictory conclusion in paragraph 160 of the judgment under appeal, in response to the appellants’ argument that, having regard to the baseline post-menopausal values, the CHMP’s use of thresholds lower than those used by the scientific literature was not capable of undermining the coherence and logic of the CHMP’s scientific opinion. The increase beyond the baseline post-menopausal values was, in the CHMP’s view, an essential element of the risk assessment.

158. In the third place, in paragraph 161 of the judgment under appeal, the General Court did not respond, in the appellants’ view, to their argument that the CHMP did not take sufficient account, in its report, of the fact that the increase in blood-estradiol levels arising from the use of Linoladiol N was only transitory and the blood-estradiol levels did not exceed the limits of the baseline post-menopausal values during a dosage cycle with Linoladiol N.

159. In the fourth place, the appellants complain that, in the context of the assessment set out at paragraph 162 of the judgment under appeal, the General Court did not examine their argument that the fact that the maintenance dose of Linoladiol N is higher compared with other preparations intended for topical vaginal treatment with estradiol does not lead to an increased risk.

160. In the fifth place, the appellants submit that the General Court should have examined a comparative table, submitted by the appellants at the hearing before that court, which extended the comparison made by the CHMP in its final evaluation report between Linoladiol N and products with a lower dosage for systemic hormone replacement therapy. According to the appellants, that table demonstrates that the estradiol levels resulting from several applications with Linoladiol N and the systemic hormone replacement therapy product ‘Estreva’ are not similar, and that in the case of Linoladiol N those values are not much higher than a medicinal product containing a lower dosage. The General Court’s conclusion that exposure to estradiol with Linoladiol N was comparable, rather, to that of systemic hormone replacement therapy therefore lacks any basis in logic.

161. Finally, the appellants claim that the General Court did not respond to their argument that a medicinal product for vaginal application entails a lower risk of venous thromboembolism than hormone replacement therapy administered orally.

162. The Commission replies that, by the complaints raised in this part of the ground of appeal, the appellants merely assert that the CHMP’s final opinion is inconclusive. None of the complaints indicate a procedural irregularity or an infringement of EU law. This part of the ground of appeal is therefore inadmissible.

163. In particular, with regard to the comparative table submitted by the appellants at the hearing before the General Court, the Commission submits that the General Court did not err in rejecting that evidence, given that it was submitted for the first time at the hearing, without any justification, in breach of Article 85(3) of the Rules of Procedure of the General Court. Moreover, the table at issue is, in the Commission’s view, merely evidence, the assessment of which falls to the General Court. In any event, even in the event that the Court does not agree on this point, the Commission takes the view that the General Court could not have been led to conclude that the logical basis of the statement of reasons for the final opinion of the CHMP would have been removed, since the CHMP had at its disposal other comparisons which it examined in accordance with its obligations, as shown by paragraphs 155, 156 and 158 of the judgment under appeal. In any event, the medicinal product Estreva, cited in the comparative table, cannot, according to the Commission, be compared with Linoladiol N. It is used for hormone replacement therapy, while Linoladiol N is used only as a local hormone replacement.

(b) Assessment

164. First of all, it should be recalled that, as regards the opinion of the CHMP, the General Court’s review is limited to the proper functioning of the CHMP and the internal coherence and the statement of reasons for its opinion. As regards the last aspect, it is clear from the case-law of the General Court that it is empowered only to examine whether the opinion contains a statement of reasons from which it is possible to ascertain the considerations on which the opinion is based, and whether it establishes a comprehensible link between the medical or scientific findings and its conclusions. ( 38 ) Since this case simply involves applying in the field of science the settled case-law that complex assessments of the Commission are subject only to a limited judicial review, as the Commission enjoys a wide measure of discretion, ( 39 ) I invite the Court, above all, to confirm the validity of the General Court’s case-law.

165. Applied in the present case, the case-law of the General Court means, in my view, that the evidence which must be adduced by the appellants cannot be limited to the fact that the General Court did not find that one of the elements considered by the CHMP in its medical or scientific assessment was incorrect. They are also obliged to demonstrate that that element is so fundamental that an error in relation to it is such as to eliminate the logical link between the medical or scientific findings and the conclusions of the CHMP.

166. It is in the light of those principles that I shall examine the admissibility, disputed by the Commission, and, where appropriate, the merits of each of the complaints raised by the appellants.

167. As regards the difficulty of applying to a local treatment, such as Linoladiol N, a risk assessment based on systemic exposure, I consider that this complaint is amenable to review by the Court in the context of the appeal.

168. An error concerning the possibility of comparing the results of the risk assessment of Linoladiol N and systemic hormone replacement therapy is, as the appellants appear to submit, capable of eliminating the ‘comprehensible link’ between the key scientific finding of the CHMP (blood-estradiol levels after administration of Linoladiol N are similar to those reached during systemic hormone replacement therapy) and the conclusions in its final opinion (Linoladiol N poses the same risks as products intended for systemic hormone replacement therapy and a restrictive measure relating to its use is therefore necessary). The complaint at issue is therefore, in my view, admissible.

169. As regards the substance, however, I consider that no such infringement was committed by the General Court. It seems to me that paragraphs 151 to 158 of the judgment under appeal, in which the General Court summarises the CHMP’s conclusions, set out the reasons why the CHMP had considered that the results of the risk assessment for hormone replacement therapies may be applied to a local treatment, such as Linoladiol N.

170. It is clear from that summary that (i) the CHMP had submitted a comparison of Linoladiol with other medicinal products for topical use, based on pharmacokinetic data, from which it was apparent that the level of estradiol after the administration of Linoladiol N was significantly higher than that observed following administration of other estradiol-based products with a lower dosage and (ii) the level of estradiol after administration of Linoladiol N was as high as in the case of temporary hormone replacement therapy.

171. It is on the basis of those factors that the General Court was in a position to conclude, in paragraph 158 of the judgment under appeal, that ‘while maintaining the distinction between topical treatment and hormone replacement therapy, the CHMP has established a comprehensible link between the medical and scientific findings concerning the characteristics of Linoladiol N and the conclusions of the final opinion of 25 April 2014’.

172. In the light of those considerations, the first complaint must, in my view, be rejected.

173. Secondly, as regards the use of thresholds relating to post-menopausal baseline values of estradiol below those used in the scientific literature, ( 40 ) the General Court held, in paragraph 160 of the judgment under appeal, that, even if the appellants had adduced evidence substantiating that claim, ‘[they] do not demonstrate to the requisite legal standard that that isolated element of the CHMP’s reasoning should lead to a diametrically opposed conclusion and that it would undermine the coherence and consistency of the scientific opinion’.

174. In essence, the General Court held that it had not been proven that the element in question was so fundamental that an error in relation to it was such as to eliminate the logical link between the medical or scientific findings and the conclusions of the CHMP.

175. I would point out from the outset that I am not convinced by the present complaint.

176. I do not deny that the thresholds for the baseline post-menopausal values appear prima facie to be a necessary element for assessing whether the systemic effects which ultimately lead to exposure to risks similar to those associated with hormone replacement therapy could occur after administration of an estradiol-based product. Moreover, that follows from the citation of the scientific conclusions of the CHMP in paragraph 151 of the judgment under appeal, according to which ‘systemic effects can be expected given that estradiol levels increase beyond post-menopausal levels’. However, in my view, it could be considered that that causal link referred to the relationship between systemic effects and the increase in estradiol levels beyond the thresholds for baseline post-menopausal values which were used by the CHMP. In other words, if, owing to the use of the thresholds identified by the appellants, which are higher than those used by the CHMP, the increase in estradiol levels did not result in those thresholds being exceeded, it cannot in principle be excluded that systemic effects are also apparent.

177. The above consideration is, in my view, capable of supporting the General Court’s finding that the appellants have not established to the requisite legal standard in their application the reason why the fact that the baseline post-menopausal values were not correct was in itself capable of undermining the conclusions reached by the CHMP.

178. Thus, even though I am aware that rejection of the present complaint would ideally have called for more in-depth reasoning on the part of the General Court, I consider that an examination of the answer which emerges from paragraph 160 of the judgment under appeal must lead to the conclusion that the General Court did not fail to fulfil its obligation to state reasons.

179. In the light of the foregoing, the present complaint must, in my view, be rejected.

180. Thirdly, as regards the absence of a response from the General Court to the argument that the CHMP did not take sufficient account of the fact that the rise in blood-estradiol levels resulting from the use of Linoladiol N was only transitory, it seems to me that the appellants do not succeed in demonstrating that the General Court did not take that element into account in its assessment.

181. In paragraph 161 of the judgment under appeal, the General Court noted that the CHMP had indicated, on the basis of two scientific studies (SCO 5109 and SCO 5174), that blood-estradiol levels in the case of a twice-weekly administration of Linoladiol N corresponded to those during a hormone replacement therapy and that those high levels had still not returned to their original value after thirty-six hours.

182. Thus, the General Court does not therefore appear to have overlooked the fact that the rise in blood-estradiol levels resulting from the use of Linoladiol N was transitory and that concentrations of estradiol could return to their initial value after more than thirty-six hours.

183. However, even if is only implicit in paragraph 161 of the judgment under appeal that the General Court actually took that element into account, this does not in any way constitute a failure to state reasons, as the appellants, in essence, submit. In that regard, it is sufficient to recall the case-law, which I have already mentioned in point 116 of this Opinion, according to which the General Court is not required to provide an account that follows exhaustively and one by one all the arguments put forward by the parties to the dispute; the reasoning may therefore be implicit on the condition that it enables the persons concerned to know why the General Court did not uphold their arguments and provides the Court of Justice with sufficient information to exercise its powers of review, which seems to me clearly to be the case here.

184. In any event, the present complaint is not such as to prove that the element concerned, namely the temporary nature of the increase in blood-estradiol levels, was capable of eliminating the comprehensible link between the medical or scientific findings and the conclusions of the CHMP.

185. In those circumstances, the present complaint must, in my view, be rejected.

186. Fourthly, as regards the alleged absence, in the judgment under appeal, of an examination of the appellants’ argument that the fact that the maintenance dose of Linoladiol N was higher than that of other estradiol-based preparations did not entail an increased risk, it is sufficient to observe that there is no doubt that such an assessment falls within the wide measure of discretion which the Commission enjoys in an area such as this, which requires it to undertake complex medical or scientific evaluations, and is therefore not subject to judicial review by the General Court, except in cases of obvious error, misuse of powers or where the Commission has clearly exceeded the bounds of its discretion, which is not alleged in the present case. The appellants cannot therefore complain that the General Court failed to rule on that point.

187. Fifthly, as to the failure to examine the comparative table, I would begin by noting, like the Commission in its response, that that table was presented for the first time at the hearing before the General Court and that its minutes do not mention any justification provided by the appellants for such a delay, in breach of Article 85(3) of the Rules of Procedure of the General Court. Since no justification was actually provided, the failure to examine that table in the judgment under appeal can be explained by the fact that the General Court rightly declared it to be inadmissible by implication.

188. In any event, I agree with the position taken in that regard by the Commission in its response in that, even if it had been deemed admissible and examined as to its substance, the comparative table at issue would be irrelevant because it could not have led the General Court to conclude that the comprehensible link between the medical or scientific findings and the conclusions of the CHMP was thereby eliminated.

189. First of all, the probative value of that table is clearly reduced by the fact that it provides a comparison of Linoladiol N with only one other medicinal product, namely Estreva.

190. Moreover, the comparison of Linoladiol N and Estreva does not appear to me to be compatible with the logic underlying the CHMP’s reasoning in its final opinion, as summarised by the General Court in paragraphs 151 to 158 of the judgment under appeal.

191. As the General Court held in paragraph 158 of that judgment, the conclusion that Linoladiol N temporarily led to estradiol levels comparable to those resulting from the use of hormone replacement therapy was reached by the CHMP ‘while maintaining the distinction between topical treatment and [hormone replacement therapy]’, that is to say by comparing Linoladiol N only with other topical treatments. Estreva, which is used for hormone replacement therapy and consequently has a different method of administration, cannot therefore be compared with Linoladiol N.

192. Thus, in the event that the Court declares the complaint in question admissible, I think that it should be rejected on the substance.

193. I therefore propose that the second part of the second ground of appeal be rejected in its entirety.

3. The third part, alleging an incorrect risk assessment because the pharmacovigilance data was not taken into account

(a) Summary of the arguments of the parties

194. The appellants consider that the General Court overlooked, in its argument in paragraphs 170 to 172 of the judgment under appeal and in its finding in paragraph 176 of that judgment, that the pharmacovigilance data, according to the philosophy of the HUM Code, play a crucial role in the assessment of the actual risks posed by marketed medicines.

195. As regards paragraph 171 of the judgment under appeal, the appellants observe that it is contradictory to consider the low number or even absence of safety alerts linked to the use of Linoladiol N as evidence of the existence of a risk, as the General Court did. In the light of the considerations in paragraph 172 of the judgment under appeal concerning the lack of interest for spontaneous reports, the appellants submit that the General Court failed to address their argument that there is no scientific proof that there has been ‘under-reporting’ in relation to older medicinal products. In that regard, the General Court did not respond, in the appellants’ view, to the argument that, since Linoladiol N is a medicinal product available exclusively on prescription from a gynaecologist who monitors its long-term use, it is scarcely credible that no gynaecologist would have reported any risks associated with such use if they had actually arisen. Finally, the appellants complain that the General Court did not respond to their claim that, even with a 90% rate of under-reporting, the supposed risks from the use of Linoladiol N would in any event have materialised if they had actually existed.

196. The Commission contends that the appellants’ arguments are not directed against a legal assessment by the General Court, but an assessment of the CHMP.

197. In particular, regarding the lack of a response to the argument that Linoladiol N is a medicinal product available only on prescription, the long-term use of which is monitored by a gynaecologist, the Commission submits that it was not substantiated by evidence offered in support and, in any event, was referred to only at the hearing at first instance without any justification for that delay, in breach of Article 85(3) of the Rules of Procedure of the General Court.

(b) Assessment

198. By their first complaint, the appellants allege that the General Court did not acknowledge the crucial role played by the pharmacovigilance data in the re-evaluation of the risk-benefit balance of the medicinal products, in that it found that the CHMP had inferred evidence of risks associated with the use of Linoladiol N from the low number or even absence of safety alerts concerning such risks, which is inherently contradictory. In doing so, the appellants criticise the General Court, in essence, for not having held that the CHMP’s error in that regard had the effect of eliminating the comprehensible link between the medical and scientific findings, and the conclusions of the CHMP.

199. I take the view that the General Court was right to hold that the appellants’ criticisms, repeated against the findings of the General Court in their appeal, were based on an incorrect reading of the opinion of the CHMP.

200. In its scientific conclusions, the CHMP did not consider, as the appellants submit, that the small amount of pharmacovigilance data available (11 cases in total, including only one concerning Linoladiol N) was proof of the risks associated with the use of Linoladiol N. On the contrary, it held that, particularly where a ‘substantial under-reporting of adverse effects’ must be assumed for an old medicinal product such as Linoladiol N, it was impossible to draw any conclusions on the safety of that medicinal product from the pharmacovigilance data.

201. In the light of that scientific uncertainty, as the General Court explained in paragraphs 174 to 176 of the judgment under appeal, the CHMP provided solid and persuasive evidence, in accordance with the case-law on the application of the precautionary principle, establishing reasonable doubt as to the safety or efficacy of Linoladiol N.

202. The CHMP therefore inferred evidence of risks associated with the use of Linoladiol N not from the low number of safety alerts concerning those risks, but from the doubts that it had reasonably set out as regards the safety and efficacy of Linoladiol N, as the General Court rightly noted.

203. Therefore, in view of the fact that the General Court correctly demonstrated the presence of a comprehensible link between the medical or scientific findings and the conclusions of the CHMP on the presence of risks, I consider that the complaint at issue must be rejected.

204. As to the lack of response, in paragraph 172 of the judgment under appeal, to the argument that there is no scientific evidence of under-reporting in relation to older medicinal products, it is sufficient to note that such an assessment falls within the wide measure of discretion which the Commission enjoys in that area, which requires it to undertake complex medical or scientific assessments, and is subject to only limited review by the General