Judgment;Abstract — ECLI:EU:T:2019:892
Date: 2019-12-19
Language of the case: English
Court formation: Sixth Chamber
Subject matter: Public health
Procedure: Action for annulment - unfounded
Origin: United Kingdom

summary of product characteristics, but also of more involved accompanying medical measures such as the use of genotyping and ECG monitoring. In addition to all the measures proposed, the applicant also asserted that consideration should be given to the use of iloperidone as a second line treatment. – The complaint that the evaluation of the RMMs is vitiated by a breach of the obligation to state reasons and manifest errors of assessment 122 The applicant submits that the evaluation of the RMMs it submitted in support of its MA application is vitiated by a failure to state reasons and is, in any event, manifestly incorrect. According to the applicant, the CHMP did not provide, in its assessment report, plausible reasons why the RMMs proposed, which included the possibility of limiting the MA to second line treatment (that is to say for cases where other products are not effective or are not tolerated by the patient), were not considered to be sufficient to manage the safety risks presented by iloperidone. 123 The applicant points out that, in order to manage the risks of QT interval prolongation, it submitted four types of RMM frequently used on the EU market, in particular for products intended for the treatment of schizophrenia. First, it claims that it has, as is common practice, included in the summary of product characteristics and in the patient information leaflet strict warnings and specific precautions for use stating that the product could prolong the QT interval and have adverse effects, also mentioning that sudden deaths have been reported. Second, it states that, in accordance with current practice and in line with the CHMP recommendations on that point, it has included precautions, or even contra-indications, to prevent the administration of iloperidone to higher risk patients, that is to say, patients inherently at risk of experiencing the adverse effects theoretically associated with QT interval prolongation. Third, it suggested, also in line with the CHMP recommendations, that the summary of product characteristics include a statement that genotyping should be performed for all patients prior to the initiation of treatment in order to identify patients with a certain genotype for whom iloperidone should be contra-indicated. Fourth, it agreed and proposed to limit initiation of iloperidone treatment to settings in which a cardiologist is available and to require that ECG monitoring be performed before and during iloperidone treatment. 124 The applicant maintains that the combination of those four RMMs and the proposal to limit the use of iloperidone to ‘second line’ treatment, which, as suggested by the scientific advisory group convened in May 2017, it submitted in the context of its re-examination request by means of an elaborate treatment algorithm, ought to have led the CHMP to conclude that the risks presented were managed adequately, which it failed to do. The CHMP’s conclusions allegedly establish no comprehensible link between the scientific findings, and are therefore vitiated by a failure to state reasons and manifest errors of assessment, in particular as regards the examination of genotyping measures and the use of ECG, and also as regards the proposal for second line use. 125 In the present case, it should be recalled that the CHMP took the view that the RMMs proposed were not sufficient to manage adequately the risk detected, namely the substantial arrhythmogenic potential of iloperidone. 126 The CHMP opinion, set out in Annex I to the contested decision, provides the following summary: ‘In consideration of the complex causal chain linking the exposure to [i]loperidone to events such as [t]orsades de [p]ointes, including unknown and stochastic elements and elements subject to an unpredictable variability, it is considered that the [RMMs] proposed would not adequately address in clinical practice the risk identified. For example, the proposal to perform ECGs at the estimated Tmax could miss the actual Tmax due to intrinsic or extrinsic factors, leading to an underestimation of QTcF prolongation. In addition, whether the correct implementation of the complete set of measures would be feasible in all clinical settings is questionable due to practical reasons (for example, the availability of suitably trained cardiologists), as also mentioned by the experts in the ad-hoc meeting.’ 127 The CHMP assessment report explains the reasons why the RMMs proposed were deemed to be insufficient. 128 It is apparent, in particular, that, at the stage of the first examination of the MA application at issue in the present case, the CHMP stated as follows: ‘Considering all available non-clinical and clinical data (including the thorough QTc study, the overall clinical program[me] and the cases of cardiac-related/sudden unexplained death in clinical trials and post-marketing), iloperidone has a substantial and exposure-dependent arrhythmogenic potential. The fact that the metabolism of [i]loperidone relies heavily on CYP3A4 and CYP2D6 increases the risks of drug-drug interactions and makes the medicine metabolism highly sensitive to genetic polymorphisms. [RMMs] such as CYP2D6 genotyping or extensive ECG monitoring are not considered sufficient to minimise this risk.’ 129 It is also apparent from the CHMP assessment report that the CHMP, at the stage of re-examination of the MA application, maintained its conclusion that the RMMs proposed were not sufficient for the following reasons: ‘It is acknowledged that for a niche product intended for use in a small number of patients the proposed [RMMs] would seem to be feasible in some clinical settings in the EU but probably not all. However, the ability of the proposed measures to appropriately address the risks is questioned in presence of known and unknown sources of variability. Some examples of this can be provided, but a comprehensive list cannot by definition be formulated: – While the recommendation would be to perform the ECG at Tmax, this could be missed due to intrinsic or extrinsic factors. – The increase in exposure with non-contradicted inhibitors of [i]loperidone’s metabolism might be subject to a significant variability in [the] presence of a small safety margin. Similarly, the proposal to lower the threshold for contraindicating [iloperidone] based on QT at baseline cannot be accepted due to the within-subject variability of this measurement in the population concerned.’ 130 In the section entitled ‘Conclusion and Updated Risk Benefit Assessment’, in paragraph 5 of the CHMP assessment report, the CHMP concluded that: ‘Considering all available non-clinical and clinical data (including the thorough QTc study, the overall clinical program[me] and the cases of cardiac-related/sudden unexplained death in clinical trials and post-marketing), [i]loperidone has a substantial and exposure-dependent arrhythmogenic potential. It is not considered that the [RMMs] proposed would appropriately address the risk identified in this specific case. Hence, the safety of [i]loperidone has not been sufficiently demonstrated.’ 131 It must be noted that, first, the CHMP opinion and assessment report on which the contested decision is based are not vitiated by an inadequate statement of reasons regarding the RMMs and that, second, the CHMP, in its assessment report, expressed, as required by the case-law, a set of plausible reasons in support of its conclusion that the RMMs proposed were not capable of countering the potentially adverse effects of iloperidone. 132 In the first place, as regards the first two categories of RMMs proposed, so called ‘routine’ measures, being the information and warnings contained in the summary of product characteristics and patient information leaflet, as the Commission stated in its defence, it is apparent from that information taken as a whole that, in view of the severity of the risk identified, the appropriateness of ‘simple’ RMMs, such as warnings in the summary of product characteristics and the patient information leaflet was excluded. 133 In the second place, with regard to the RMM consisting of the use of genotyping, it appears that, in essence, the CHMP considered it to be insufficient for two main reasons. 134 First, the CHMP concluded that genotyping could control only partially the risks created by exposure to iloperidone. As the Commission explained in its written pleadings, since it is accepted that the arrhythmogenic potential of that substance increases with exposure, it has become clear that, the higher the level of that substance in the blood, the greater the patient’s exposure to a risk of a potentially fatal cardiac arrhythmia. Conversely, the faster iloperidone is metabolised, the lower the risk. It is apparent from the data made available to the CHMP that iloperidone is mainly metabolised by two enzymes, namely cytochrome P450 3A 4 (CYP3A4) and cytochrome P450 2D 6 (CYP2D6), which can be inhibited by the consumption of medicinal products. In such a case, genotyping does not allow a sufficiently reliable identification to be made of patients for whom iloperidone consumption generates significant risks. 135 That analysis is clearly set out by the CHMP in its assessment report in the following terms: ‘The increases of Cmax up to 2.3 fold observed with metabolic inhibition are not insignificant and importantly this is a mean value; it does not describe the extent to which some individuals might show a much greater increase in iloperidone Cmax in the presence of strong CYP3A4 and CYP2D6 inhibitors. This will depend on the activity of the minor metabolic pathways for iloperidone, which could very well be highly variable. In the context of the risk assessment for drug induced [torsades de pointes] the population mean effect is less relevant than the worst case scenario. No data are available to establish the likely effect on drug levels in patients with low activity of the minor metabolic pathways for [i]loperidone exposed to mild CYP3A4 and CYP2D6 inhibitors.’ 136 Second, even if exposure to iloperidone could be satisfactorily controlled by the use of genotyping, it is apparent from the CHMP assessment report that the view was taken that, although there was at first sight a clear link between QT interval prolongation (and therefore arrhythmogenic potential) and that exposure, such exposure was not the only factor linked to the use of iloperidone capable of resulting in effects such as torsades de pointes which can be fatal for the patient. In other words, the view was taken that controlling exposure to iloperidone, in particular by means of genotyping, would not mitigate adequately the risks associated with consumption of that medicinal product. 137 The CHMP therefore explained in the assessment report that: ‘The experts reflected that the causal chain linking the exposure to [i]loperidone to events such as [t]orsade[s] de [p]ointes is complex and includes some unknown or stochastic elements which by definition would be of very difficult control in any risk minimisation plan to be implemented in the clinical setting.’ 138 In the third place, as regards the evaluation of the RMM consisting of the use of ECG, the conclusions reached with regard to the use of genotyping apply mutatis mutandis. 139 Indeed, the use of that RMM at ‘Tmax’, which consists of an estimate of the time elapsed until the maximum plasma concentration is reached, was regarded as not sufficiently effective given a number of intrinsic (related to the individual patient) and extrinsic (related to the availability in the clinical settings concerned of a cardiologist to monitor patients with schizophrenia) factors. 140 As regards the use of ECG at baseline, that is to say the stage when prescribing iloperidone is envisaged, the CHMP noted that it does not necessarily provide reliable information on the patient’s QT interval. The CHMP assessment report therefore states that ‘the proposal to lower the threshold for contraindicating [iloperidone] based on QT at baseline cannot be accepted due to the within-subject variability of this measurement in the population concerned’. 141 In other words, according to the CHMP, since the values obtained by means of ECG vary widely from one individual to another and are therefore unpredictable, the use of ECG monitoring does not appear to be a fully satisfactory measure to control the effects of consuming iloperidone. It therefore does not appear possible to define a value that could serve as a warning to the professionals concerned. Ultimately, according to the CHMP, there was therefore reason to doubt the reliability of the use of that instrument as a means of controlling the risks presented by iloperidone. 142 In the fourth place, regarding the proposal that iloperidone be used as a second line treatment, namely in situations where the patient’s treatment with another medicinal product has not been satisfactory, it is necessary to examine, further to the above considerations, whether there is a comprehensible link between the scientific findings brought to the EMA’s attention and the negative recommendation at issue in the present case. 143 In that regard, it is apparent from the file submitted to the Court that it was following the CHMP’s negative opinion delivered on 20 July 2017 and in support of its request for re-examination that the applicant proposed that iloperidone should be ‘indicated for the treatment of schizophrenia in adults as a second line option’. 144 With that in mind, the applicant had distinguished two sub-categories of the overall population for which it intended to demonstrate that iloperidone’s risk-benefit balance was positive, namely, first, schizophrenia patients who are stabilised and, second, patients who are in an acute schizophrenia episode and are unable to be fully stabilised by another medicinal product on another medicinal product because of tolerability issues. 145 However, the risk-benefit balance was held to be negative in view of the major safety issues for these two sub-populations (in the same way as for the overall population). In that respect, the CHMP assessment report establishes a comprehensible link between the medical or scientific findings and its conclusions regarding the use of iloperidone as a second line treatment. 146 If, as the parties both acknowledge, patients with schizophrenia, particularly those with akathisia, continue, to date, to have unmet medical needs, that concerns, according to the data provided during the re-examination procedure that is the subject of the present case, patients who would need access to a medicinal product with no or almost no propensity to cause such a disorder. However, that is not the case for iloperidone, which, as indicated by the CHMP in its assessment report, has ‘a low but not uniquely low propensity to cause [extrapyramidal symptoms] in general’. 147 In the fifth and final place, as regards the claim that the CHMP did not provide reasons why the RMMs proposed, taken as a whole and not separately, would not be sufficient to manage the safety risks presented by iloperidone, that plea is unfounded. 148 In that regard, it should be recalled that the CHMP opinion states that ‘in consideration of the complex causal chain linking the exposure to [i]loperidone to events such as [t]orsade[s] de [p]ointes, including unknown and stochastic elements and elements subject to an unpredictable variability, it is considered that the [RMMs] proposed would not adequately address in clinical practice the risk identified’. 149 As is also apparent from the position of the ad hoc group of 30 October 2017, it was concluded that, regardless of how the RMMs were combined, a number of patients would be exposed to a substantial safety risk associated in particular with the development of torsades de pointes. Among other considerations, that group noted the following: ‘The experts reflected that the causal chain linking the exposure to [i]loperidone to events such as [t]orsade[s] de [p]ointes is complex and includes some unknown or stochastic elements which by definition would be of very difficult control in any risk minimisation plan to be implemented in the clinical setting. In consideration of this and of the available data, the experts concluded by majority that it is not possible to design a set of [RMMs] that would appropriately address the risks identified and that the measures proposed would end up providing a false reassurance.’ 150 In the light of all those considerations, it must be held that the conclusion that the RMMs proposed by the applicant with a view to the grant of an MA for iloperidone are insufficient is not vitiated by a failure to state reasons or manifest errors of assessment. – The complaint alleging a breach of the principle of proportionality 151 The applicant submits that the evaluation of the proposed RMMs is contrary to the principle of proportionality. It maintains that the summary rejection of those RMMs — and accordingly the refusal to grant an MA — goes beyond what is necessary to achieve the objective of balancing risks and benefits. That refusal is not the measure to minimise sufficiently the risks associated with iloperidone that is the least onerous. In the applicant’s submission, the CHMP could have imposed feasible RMMs to ensure that iloperidone is prescribed and administered in such a way as to manage risk and ensure an acceptable level of safety. 152 According to settled case-law, the principle of proportionality, now set out in Article 5 TEU, requires that acts of the EU institutions be appropriate for attaining the legitimate objectives pursued by the legislation at issue and do not exceed the limits of what is necessary in order to achieve those objectives; when there is a choice between several appropriate measures, recourse must be had to the least onerous, and the disadvantages caused must not be disproportionate to the aims pursued (see judgment of 4 May 2016, Pillbox 38, C‑477/14, EU:C:2016:324, paragraph 48 and the case-law cited). 153 In an area such as that at issue in the present case, in which the public authority concerned is called upon to undertake complex assessments, the legality of a measure adopted in that area can be affected only if the measure is manifestly inappropriate having regard to the objective which the competent institutions are seeking to pursue (see, to that effect, judgments of 4 May 2016, Pillbox 38, C‑477/14, EU:C:2016:324, paragraph 49 and the case-law cited, and of 16 March 2016, Dextro Energy v Commission, T‑100/15, EU:T:2016:150, paragraph 80 and the case-law cited). 154 In order to assess whether the principle of proportionality has been observed in the field of public health, account must be taken of the fact that human health and human life rank foremost among the assets and interests protected by the FEU Treaty (see, to that effect, judgment of 19 April 2012, Artegodan v Commission, C‑221/10 P, EU:C:2012:216, paragraph 99 and the case-law cited; see also, by analogy, as regards Member States’ observance of that principle in the field of public health, judgment of 8 June 2017, Medisanus, C‑296/15, EU:C:2017:431, paragraph 82 and the case-law cited). 155 The Court has held, having specific regard to the exclusive nature of the criteria of safety, efficacy and quality laid down in the context of the EU system for the harmonisation of the grant and management of MAs for medicinal products, that the assessment of the proportionality of a measure suspending or withdrawing an MA was to be guided by those criteria alone. It follows that the relevant interests in the context of the review of proportionality are the same as those related to the protection of public health, taken into consideration in the application of the relevant legislation (see, to that effect, judgment of 3 March 2010, Artegodan v Commission, T‑429/05, EU:T:2010:60, paragraph 128). 156 In the present case, it appears that the applicant’s arguments are essentially the same as those considered in paragraphs 125 to 150 above in the context of the considerations relating to the examination of the first complaint within the second plea, according to which the CHMP committed manifest errors of assessment in examining the RMMs proposed to address the safety problems associated with iloperidone. 157 Since the view was taken that those RMMs, either individually or in combination, were not sufficient ground for a conclusion that the risk-benefit balance was positive, a CHMP opinion recommending that the MA be refused for that medicinal product was the inevitable consequence. In other words, since, for a medicinal product with a negative risk-benefit balance, there is no less onerous alternative than providing a negative response to an MA application for that product, it cannot be claimed that the refusal of an MA, contained in the contested decision, is manifestly disproportionate. – The complaint alleging a breach of the principle of equal treatment 158 The applicant takes the view that the CHMP infringed the principle of equal treatment to the extent that it treated the RMMs proposed for iloperidone differently from the RMMs proposed for other medicinal products for the treatment of schizophrenia. As regards, in particular, sertindole, ECG monitoring and second line treatment were, according to the applicant, accepted as RMMs. Similarly, rather than refusing to grant an MA for cariprazine, the CHMP accepted that the safety concerns identified for that medicinal product should be reflected in the product information and in its specifications. 159 In that regard, it is well established that the principle of equal treatment requires that comparable situations not be treated differently and different situations not be treated in the same way unless such treatment is objectively justified (see judgments of 29 April 2004, Novartis Pharmaceuticals, C‑106/01, EU:C:2004:245, paragraph 69 and the case-law cited; of 4 May 2016, Pillbox 38, C‑477/14, EU:C:2016:324, paragraph 35 and the case-law cited; and of 9 September 2010, CSL Behring v Commission and EMA, T‑264/07, EU:T:2010:371, paragraph 113 and the case-law cited). 160 In the present case, since the scientific data relating to the safety of medicinal products is different, there can be no question of comparable situations. 161 As regards, in particular, the data relating to QT interval prolongation and, accordingly, to the arrhythmogenic potential of iloperidone, which were central to the evaluation of the risk-benefit balance in the present case, it is apparent from the data provided by the Commission, data which has not been seriously disputed by the applicant, that the scientific conclusions differ from those adopted for cariprazine and sertindole. With regard, in particular, to sertindole, the Commission explained that the data which had been presented had made it possible to exclude the existence of torsades de pointes indicators, which was not the case when evaluating iloperidone. As regards the comparability of the scientific evaluations for cariprazine and iloperidone, the Commission stated why there were objective differences in the results of the analyses regarding QT interval prolongation having regard to the safety thresholds defined in the QT Guidance. 162 Indeed, as is apparent from the CHMP assessment report, the experts consulted seem to have agreed that iloperidone has a significant arrhythmogenic potential due to QT interval prolongation, whereas that was not the case for cariprazine and sertindole. 163 Furthermore, in response to the written question put by the Court by way of measures of organisation of procedure, the Commission stated that for sertindole, the risk-benefit balance has not, following the suspension of its MA, been reassessed since 2002, and sertindole has not been found in any medicinal products authorised under the centralised procedure since that date. In response to a question raised at the hearing, it was confirmed that the parameters previously taken into consideration in the evaluation of the arrhythmogenic potential of certain substances were less stringent than those currently applicable and that the regulatory context applicable in that area had moved on since 1997. 164 It follows from all those considerations that the applicant’s claim regarding the alleged breach of the principle of equal treatment is unfounded and must be rejected. 165 The second plea should therefore also be rejected. The third plea in law: the evaluation of the consequences of the delayed onset of iloperidone is vitiated by a failure to state reasons and a breach of the principle of proportionality set out in Article 5(1) and (4) TEU 166 The applicant submits that the evaluation of the consequences of the delayed onset of iloperidone, which it claims to be internally inconsistent, is vitiated by a failure to state reasons and a breach of the principle of proportionality. It submits that, in considering that delayed onset of action was a ‘significant concern’ for the treatment of acute exacerbation of schizophrenia and, therefore, an additional ground for refusing an MA for that medicinal product, the CHMP failed to take into account three essential circumstances. First, it is apparent from the guidelines on clinical investigation of medicinal products, including depot preparations in the treatment of schizophrenia, published by the EMA on 20 September 2012 (EMA/CHMP/40072/2010 Rev. 1), which state that the short-term efficacy of a medicinal product may be demonstrated through a 6-week clinical trial, that immediate efficacy need not necessarily be demonstrated in order to attest to the efficacy of products intended for the treatment of that disease. Second, as regards the treatment of a chronic disease, the onset time of a medicinal product intended to treat that disease should not be decisive, especially when it is prescribed in second line, that is to say when the use of other products has been shown to be ineffective or when it has not been tolerated. Third, the CHMP itself acknowledged in its assessment report that the onset of efficacy ‘would not be considered in itself to be an impediment’ to the approval of iloperidone. The CHMP thus considered that the delayed onset would limit only the clinical situations in which the administration of that medicinal product might be considered. 167 The Court points out that, as is apparent from the CHMP opinion (see paragraph 16 above), the CHMP concluded that the delayed onset of iloperidone was ‘a significant concern in the treatment of acute exacerbation of schizophrenia’. 168 In the first place, as regards the claim that these conclusions are contradictory and therefore vitiated by a failure to state reasons, that is based on a flawed reading of the CHMP opinion and assessment report. 169 It is true that the CHMP stated in its assessment report that ‘the acknowledged delayed onset of efficacy would not be considered in itself to be an impediment for approval of iloperidone’. 170 However, that does not mean that the time period for onset of action cannot have an impact on the risk-benefit balance of a given medicinal product. 171 In the present case, the CHMP took the view in its assessment report that the delayed onset of the action of iloperidone could be clinically important in the treatment of acute exacerbations of schizophrenia, that is to say, in the treatment of patients in the second sub-population identified. That finding, in the circumstances of the present case, confirmed that the risk-benefit balance was negative. 172 The CHMP, in its assessment report, noted the following: ‘… [i]loperidone has a modest efficacy. In addition, it has shown a delayed onset of action, which is a significant concern in the treatment of acute exacerbation of schizophrenia. Therefore, … a patient population cannot be identified where the benefit of treatment is considered to outweigh the major safety concerns.’ 173 Second, the claim that the CHMP infringed the principle of proportionality, in so far as it did not authorise — or even consider — a limited indication for iloperidone, is no more convincing. 174 In that regard, it must be recalled that the principle of proportionality requires that acts of the EU institutions do not exceed the limits of what is appropriate and necessary in order to achieve the legitimate objectives pursued by the legislation at issue; when there is a choice between several appropriate measures, recourse must be had to the least onerous, and the disadvantages caused must not be disproportionate to the aims pursued (see the case-law referred to in paragraph 152 above). 175 As regards, more specifically, the question of whether or not to approve an MA application for a medicinal product, the risk-benefit balance is at the core of the assessment by the authorities responsible for examining that request. If the conclusion is that the risk-benefit balance is negative, the MA application must be rejected. As the Commission has stated, the prescription of such a medicinal product must be prevented and cannot therefore be left to the discretion of health professionals. 176 Consequently, to the extent that the CHMP opinion on the risk-benefit balance of iloperidone was negative, it cannot validly be accused of having infringed the principle of proportionality by refusing to grant a ‘limited’ MA for that medicinal product, since such ‘limited’ MA does not constitute a ‘less onerous’ and ‘appropriate’ measure that could be contemplated in order to achieve the objectives pursued. 177 It follows from all the foregoing considerations that the conclusions reached regarding the consequences of the delayed onset of action of iloperidone are neither vitiated by a failure to state reasons nor are they contrary to the principle of proportionality. 178 Consequently, the third plea cannot succeed and must be rejected as being unfounded. The fourth plea in law: the obligation to identify a population in which iloperidone would outperform other products constitutes a breach of the principles of conferral and proportionality (set out in Article 5(1) to (3) TEU), Article 12 and Article 81(2) of Regulation No 726/2004 and the principle of equal treatment 179 The applicant submits, in essence, that, in requiring evidence of the ‘superiority’ of iloperidone over other second line medicinal products for schizophrenia, the contested decision infringes the principle of conferral, the principle of subsidiarity, the principle of equal treatment and Articles 12 and 81(2) of Regulation No 726/2004, those latter provisions establishing the precise grounds on which an MA application may be refused. 180 First, the applicant maintains that, in requiring such evidence — in particular by asking the applicant to ‘identify a population’ for which iloperidone has unique advantages by comparison with other products designed to treat schizophrenia, and even by comparison with all products available at the time of the relevant facts, taken together — the CHMP formulated and applied an additional condition for approval. The applicant submits that, although it indicated during the re-examination procedure that that condition was contrary to EU law, the CHMP maintained and applied it in its assessment report. Consequently, the CHMP failed to observe the principles of conferral and subsidiarity and the provisions of Articles 12(1) and 81(2) of Regulation No 726/2004, according to which an MA may be refused only if the applicant has not properly or sufficiently demonstrated the quality, safety or efficacy of the medicinal product. 181 Second, the applicant maintains that, by imposing, in an unprecedented fashion, in the field of second-generation medicinal products for the treatment of schizophrenia, additional requirements for the granting of an MA for iloperidone, the contested decision infringes the principle of equal treatment. In the applicant’s submission, the CHMP has thus far never required, in the assessment of such products, that they produce better results, in particular in terms of tolerance and therapeutic efficacy. 182 The Commission disputes the applicant’s arguments and contends that this plea should be rejected. 183 In the present case, it is clear that the arguments put forward by the applicant in support of the fourth plea are based on the false premiss that the CHMP imposed on it a condition not provided for by the law applicable to the granting of an MA, namely the demonstration of iloperidone’s superiority over other medicinal products designed to treat the symptoms of schizophrenia. 184 A careful reading of the reasons underlying the contested decision, in particular the CHMP assessment report, clearly shows that it is in response to the applicant’s argument that iloperidone met an ‘unmet medical need’ — in that it is intended for persons with a condition for which there is no fully satisfactory method of treatment — that the CHMP was led to carry out a comparative review of the therapeutic benefits of that medicinal product in relation to other second generation medicinal products designed to treat the symptoms of schizophrenia currently on the market. In particular, the CHMP was asked to clarify whether and to what extent iloperidone was less likely than other medicinal products currently available to cause extrapyramidal effects, including akathisia. 185 Consequently, both the complaints alleging a breach of the principles of conferral and of subsidiarity and those alleging a breach of the provisions of Regulation No 726/2004 are unfounded. As the Commission has correctly pointed out, the reason why the MA for iloperidone was not recommended by the CHMP was to be found in its negative risk-benefit balance and not, as the applicant implies, in the result of a comparison between that substance and authorised medicinal products. 186 As regards the claim that the CHMP’s evaluation of iloperidone was (i) in breach of the principle of equal treatment and (ii) much more demanding than those relating to other medicinal products for the treatment of schizophrenia, that is no more convincing. 187 In that respect, it should be pointed out, further to what was stated in the context of the examination of the third plea (see paragraph 160 above), that since the scientific data regarding the safety of medicinal products is different, there can be no question of comparable situations. 188 That is all the more so when the medicinal products concerned belong to different therapeutic classes, given that the relevant scientific considerations for assessing their safety and efficacy vary by definition from one group of diseases to another. In particular, as the Commission has stated, without being contradicted by the applicant, iloperidone and cisapride belong to different therapeutic classes. Iloperidone is an anti-psychotic medicinal product which falls within the therapeutic area of nervous system disorders. By contrast, cisapride is a medicinal product designed for digestive tract and metabolic disorders. 189 In any event, and even if the authorities responsible for evaluating the risk-benefit balance of a medicinal product in the context of an MA application submitted under the centralised procedure were to have been less strict in identifying the risks presented by other medicinal products, that cannot be used as an argument to justify granting an MA. Indeed, the evaluation of the efficacy, and safety of a medicinal product must be based on an objective examination of the scientific analyses submitted in support of an MA application and not on a comparative review of the evaluations carried out by those bodies. Furthermore, it is important that it be established that the medicinal product in question has efficacy and safety advantages which justify a positive risk-benefit balance. 190 In the light of the foregoing, the fourth plea must be rejected as being unfounded. The fifth plea in law: the overall risk-benefit assessment of iloperidone lacks an adequate statement of reasons and, in any event, is manifestly erroneous 191 The applicant maintains, in essence, that the overall risk-benefit evaluation of iloperidone carried out by the CHMP lacks an adequate statement of reasons and is, in any event, manifestly erroneous. Even if the errors which it has identified in the context of the first four pleas in the present action could not be considered manifest on their own, when taken together they resulted in an overestimation of the risks and an underestimation of the undeniable benefits of iloperidone (namely low akathisia and a reduction in the rate of relapse) and, accordingly, in the conclusion that there was a negative risk-benefit balance. The applicant claims that, apart from those benefits, the CHMP appears to have lost sight of the fact that schizophrenia is a serious disease and of the extent of the unmet needs of the patients concerned. 192 The Commission contends that the plea must be rejected. 193 It should be noted that, by the present plea, the applicant does not add, in essence, anything new compared to what has been put forward in the first four pleas. In fact the applicant merely argues that the CHMP appears to have lost sight of the seriousness of schizophrenia, the extent of unmet needs and the benefits of iloperidone in treating the symptoms (namely low akathisia and a significant reduction in the rate of relapse). It concludes that these elements should reasonably have led the CHMP to make a positive recommendation regarding the MA for that medicinal product. 194 In that respect, it is important to recall that the decision whether or not to authorise the placing on the market of a medicinal product must be based on a thorough examination of the quality, safety and efficacy of the product, and that such an examination must generally be based on an objective evaluation of its likely effects in the light of the scientific data submitted by the MA applicants. It is established that public health requirements must be recognised as fundamentally important (see in particular paragraphs 45 and 46 above). 195 In the present case, while it is admittedly common ground that a significant medical need continues to exist in pharmacological treatments currently available to treat the symptoms of schizophrenia, that cannot cause the authorities responsible for examining MA applications submitted to them to be, in their examination of the risk-benefit balance of the relevant medicinal product, less demanding as regards the parameters that must be taken into account when evaluating the safety of that medicinal product. 196 It follows from all the foregoing that the fifth plea must be rejected and, consequently, that the action must be dismissed in its entirety. Costs 197 Under Article 134(1) of the Rules of Procedure, the unsuccessful party is to be ordered to pay the costs if they have been applied for in the successful party’s pleadings. Since the applicant has been unsuccessful, it must be ordered to pay the costs, in accordance with the form of order sought by the Commission. On those grounds, THE GENERAL COURT (Sixth Chamber) hereby: 1. Dismisses the action; 2. Orders Vanda Pharmaceuticals Ltd to pay the costs. Spielmann Csehi Spineanu-Matei Delivered in open court in Luxembourg on 19 December 2019. E. Coulon R. da Silva Passos Registrar President Table of contents Background to the dispute Procedure and forms of order sought Law Admissibility Substance Preliminary considerations on the nature and extent of judicial review – Review of the main features of the centralised procedure for MAs for medicinal products as governed by Regulation No 726/2004 – The extent and scope of the judicial review The first plea in law: the risk assessment of the arrhythmic potential of iloperidone is vitiated by a failure to state reasons, a manifest error of assessment and a breach of the principle of equal treatment – Whether the obligation to state reasons was complied with – The allegation that the iloperidone risk assessment is not consistent with the guidelines for QT/QTc prolongation – The claim that the CHMP assessment report is not consistent with current EMA practice at the material time as no account has been taken of the positive post-marketing experience of iloperidone – The claim that the CHMP was unduly influenced by the comments of the ad hoc experts group of 30 October 2017 The second plea in law: the evaluation of the RMMs proposed for iloperidone is vitiated by a failure to state reasons, a manifest error of assessment and a breach of the principle of proportionality, as set out in Article 5(1) and (4) TEU, and of the principle of equal treatment – The complaint that the evaluation of the RMMs is vitiated by a breach of the obligation to state reasons and manifest errors of assessment – The complaint alleging a breach of the principle of proportionality – The complaint alleging a breach of the principle of equal treatment The third plea in law: the evaluation of the consequences of the delayed onset of iloperidone is vitiated by a failure to state reasons and a breach of the principle of proportionality set out in Article 5(1) and (4) TEU The fourth plea in law: the obligation to identify a population in which iloperidone would outperform other products constitutes a breach of the principles of conferral and proportionality (set out in Article 5(1) to (3) TEU), Article 12 and Article 81(2) of Regulation No 726/2004 and the principle of equal treatment The fifth plea in law: the overall risk-benefit assessment of iloperidone lacks an adequate statement of reasons and, in any event, is manifestly erroneous Costs * Language of the case: English.