Applicant (Invented) Name Strength Pharmaceutical form. Eformax 12 µg. Σĸóvη για εισπνοή. Eformax 12 mcg. Prášek k inhalaci.

Transcription

1 ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANTS AND MARKETING AUTHORISATION HOLDER IN THE MEMBER STATES

2 Member State Marketing Authorisation Holder Applicant (Invented) Name Strength Pharmaceutical form Route of administration Content (concentration) Denmark (trading as Ivax Pharmaceuticals UK) Ivax Quays, Albert London, E16 2QJ, Eformax 6 µg Inhalation Eformax 12 µg Inhalation Cyprus (trading as IVAX Pharmaceuticals UK), IVAX Quays, Albert London, E16 2QJ Eformax 6 mcg Σĸóvη για εισπνοή Eformax 12 mcg Σĸóvη για εισπνοή Inhalation Inhalation Czech Republic Teva Pharmaceuticals CR, s.r.o Radlická 3185/1c Praha 5 Czech Republic Eformax 6 µg Prášek k inhalaci Eformax 12 µg Prášek k inhalaci Inhalation Inhalation Estonia Teva Pharma B.V. Computerweg 10, 3542 DR, Utrecht, The Netherlands Eformax Inhalation Eformax Inhalation 2

3 Germany Latvia (trading as IVAX Pharmaceuticals UK), IVAX Quays, Albert London, E16 2QJ Teva Pharma B.V. Computerweg 10, 3542 DR, Utrecht, The Netherlands Eformax 6 Mikrogramm Pulver zur Inhalation Eformax 12 Mikrogramm Pulver zur Inhalation Inhalation Inhalation Eformax Inhalation Eformax Inhalation Lithuania Teva Pharma B.V. Computerweg 10, 3542 DR, Utrecht, The Netherlands Eformax 6 mikrogramų/dozėje inhaliaciniai milteliai Eformax 12 mikrogramų/dozėje inhaliaciniai milteliai Inhalation Inhalation Malta (trading as IVAX Pharmaceuticals UK), IVAX Quays, Albert London, E16 2QJ Eformax 6 Trab li jittieħed bin-nifs Eformax 12µg Trab li jittieħed bin-nifs Inhalation Inhalation 3

4 Poland (trading as IVAX Pharmaceuticals UK), IVAX Quays, Albert London, E16 2QJ Eformax 6mcg proszek do inhalacji Eformax 12mcg proszek do inhalacji Inhalation Inhalation Portugal Teva Pharma Produtos Farmacêuticos, Lda.Lagoas Park, Edifício 1, Piso 3, Porto Salvo, Portugal Eformax Inhalation Eformax Inhalation Slovak Republic (trading as IVAX Pharmaceuticals UK), IVAX Quays, Albert London, E16 2QJ Eformax 6 Inhalačnŷ prášok Eformax 12 µg Inhalačnŷ prášok Inhalation Inhalation Sweden Teva Sweden ABBox Helsingborg, Sweden Eformax 6 µg inhalationspulver Eformax 12µg inhalationspulver Inhalation Inhalation 4

5 ANNEX II SCIENTIFIC CONCLUSIONS AND GROUNDS FOR OPINION 5

6 SCIENTIFIC CONCLUSIONS OVERALL SUMMARY OF THE SCIENTIFIC EVALUATION OF EFORMAX Eformax is a generic inhalation formulation of formoterol, as fumarate dihydrate, containing 6 and 12 µg respectively. The products are intended for the treatment of broncho-obstructive symptoms in asthmatic patients when treatment with corticosteroids is insufficient. Formoterol is a long-acting β 2 - agonist which acts locally as a relaxant on bronchial smooth muscle cells. The drug is rapidly absorbed into the bloodstream where maximal plasma concentrations are typically found within 15 minutes of inhalation, depending on formulation and pulmonary function. The applicant submitted an application for Mutual Recognition of the Marketing Authorisation granted by Denmark for the above mentioned medicinal product in the framework of Article 29 of Directive 2001/83/EC, as amended. The referral procedure was initiated with Denmark as The Reference Member State (RMS) due to the concerns of potential serious risk to public health raised by Germany, the Czech Republic, Norway and Sweden, on the grounds of lack of an established therapeutic ratio, considerable in vitro characteristics divergences and a lack of systematic product safety data documentation. - Quality issues - The applicant was asked to clarify the therapeutic ratio between Eformax and the originator. While containing a qualitatively similar active pharmaceutical ingredient and excipient and considered to deliver comparable doses, Eformax produces aerosolised formoterol particles with a smaller mass median aerodynamic diameter (MMAD) and a slightly higher fraction of particles collected within Stages 4 and 5 of multistage liquid impinger (MSLI). Five studies intending to establish demonstration of in vitro equivalence were performed, however it was the opinion of the CHMP that sufficient provision for a correlation of the in vitro parameters studied and the therapeutic ratio between Eformax and Foradil was not provided and therefore considered that the data submitted was not sufficient to ensure the therapeutic ratio due to the complexity of the administration device. - Efficacy issues - The applicant was asked to justify that the therapeutic equivalence had been established and that the clinical studies were sensitive enough to detect differences. The Applicant considered that the pharmacodynamic studies performed were entirely appropriate for testing a longacting bronchodilator and concluded, based on publications, that Eformax provides therapeutically equivalent bronchodilation to Foradil, thus demonstrating that Foradil and Eformax (12 µg) are pharmaceutically equivalent. The Applicant considered that equivalence could only be shown by clinical studies and that since the five pharmacodynamic studies demonstrated that the single dose bronchodilator profiles of Eformax 6-12 µg are similar to those of Foradil µg, the products should be considered identical in terms of efficacy and safety in repeated dose use. The CHMP considered that the Applicant did not address the question. The Applicant should have justified the validity of the study design and the statistical analysis employed and while pharmacodynamic studies utilising change in FEV 1 are appropriate for testing a long-acting bronchodilator, the CHMP believes that the whole AUC of FEV 1 should be measured. The CHMP did not consider the three pivotal studies as valid to conclude therapeutic equivalence in efficacy and that the supportive studies were not able show therapeutic equivalence. Changing the initially applied 1:2 relationship to a 1:1 relationship based on one of the supportive studies is not acceptable. - Safety issues - The Applicant was asked to justify that the safety of the product is well documented taking into account the different distribution of particle size compared to the reference product. The Applicant considered that little difference in clinical outcome between Eformax and Foradil was evident in terms of either bronchodilator effect or safety/tolerability in the clinical studies and that the five clinical studies showing higher extrafine particle fraction did not result in an inferior safety profile to Foradil. The Applicant considered that a PK study would not further clarify the dose relationship and therapeutic effect. Three cumulative dose escalation studies were provided, indicating that the in vitro differences between the two products should not result in greater systemic safety effects. While the CHMP agreed with the Applicant that a greater systemic absorption from a higher fine particle dose is expected and that this is more relevant in terms of adverse effects, the committee did not consider that a lack of evidence of differences in the safety profile can be considered as proof 6

7 of equivalent safety. The CHMP did not consider the submitted studies to be adequate to assess the safety profile at a 1:1 ratio. The CHMP is of the opinion that a specific equivalence study for safety is required and that this can be performed by means of a confirmative PK study or a PD study. Conclusion after Assessment of the Applicant responses to the List of Questions The CHMP was of the opinion that Eformax 6 and 12 µg has not adequately shown to be equivalent to the reference product with regards to efficacy and safety. The CHMP therefore drafted a List of Outstanding Issues, which was adopted at the September 2007 CHMP. In addition to an response during an Oral Explanation at the November 2007 CHMP, the Applicant was asked to address the following two questions in writing. - Efficacy issues - The Applicant was asked to discuss why the therapeutic equivalence between Eformax and the reference product in terms of efficacy had not been shown and why a demonstration of equivalence relative potency (comparison of the dose-response curve on the x-axis) had not been provided. The Applicant acknowledged that the initial 1:2 dose ratio for comparing Eformax to Foradil was based on an incomplete understanding of the clinical relevance of the in vitro differences of the two products but that this in vitro data did demonstrate a similar FPD and quantity of formoterol deposition, showing that a 3 µm particle size is optimal for inducing maximal bronchodilation. Hence, the Applicant was of the opinion that changing the comparison to a 1:1 ratio was justified by the original data and would more accurately reflects the relationship between the two products in vivo. The Applicant acknowledged the limitations of the use of the cumulative dose design but considered that they could serve to compare the relative safety of two products. The Applicant considers that the new relative potency analysis submitted on the data of study 00-FOR-01 support the 1:1 relationship between Eformax and Foradil and also demonstrates the sensitivity of FEV1 AUC in being able to discriminate between dosages of formoterol, as there is a clear dose response for the two products. The CHMP agrees with the Applicant that the use of FEV 1 AUC over a 12 hour dosing interval is an acceptable clinical variable and that it is more relevant than the use of FEV 1 peak, which is insensitive due to a ceiling effect. The CHMP also agrees that the insensitivity of the peak effect cannot be used to justify that these studies lacked sensitivity since the AUC of FEV1 showed statistical significant differences between 6 and 12 mcg of Eformax. Sensitivity in this context has little to do with superiority; it is the ability to distinguish the effect of a formulation given at two (or more) dose levels. The CHMP also considered the statistical analysis of data obtained in study 00-FOR-01 to be incomplete since confirmation of parallelism had not been provided at that time. It is the opinion of the CHMP that with the bronchodilation model the steepness of the dose response curve is flatter and the number of subjects needs to be increased to obtain a narrow confidence interval. Furthermore, as the in vitro characteristics of the inhaler devices used in the study are different, it is questionable if the conclusions obtained in the study in adults can be extrapolated to patients with different inspiratory capacity (e.g. severe patients and children of 6 years of age or more). - Safety issues - The Applicant was asked to discuss whether the safety data provided supports a similar safety profile of Eformax compared to the reference product, and whether the different distribution of particle size impacts on its safety profile. With the availability of an improved formoterol assay for detecting picogram quantities in serum, the Applicant acknowledged the usefulness of a pharmacokinetic study in assessing comparative systemic safety of formoterol and intends to perform such a study. However, the Applicant also considers that the large amount of patient exposure data submitted do not warrant concerns regarding the safety/tolerability profile in terms of adverse events, heart rate, ECG findings, blood pressure and serum potassium and glucose. A lung deposition study was not considered valuable for assessing safety since it only assesses the local exposure in the lungs and not the amount absorbed into the systemic circulation. While the CHMP agrees that differences in the fraction of particles collected at stages 4 and 5 of the multi-stage liquid impinger (MSLI) may not translate into meaningful efficacy differences since these particles reach the peripheral airways and the alveoli but this has to be shown in a clinical setting. It also considers that it is precisely this fraction of the drug which is rapidly absorbed into the blood stream and might have safety consequences. Therefore, the CHMP considers that confirmative 7

8 efficacy and safety studies are required. The CHMP also considered that a similar safety profile could be demonstrated by a bioequivalence pharmacokinetic study for systemic exposure or by a safety PD study. The lack of differences in the safety profile observed in the present studies at a 1:2 ratio and the absence of pharmacovigilance notifications can not be considered as a demonstration of equivalence in the safety profile at a 1:1 ratio. Finally, a limitation of the top dose to 24 mcg bid daily is not always feasible in the clinical practice of some Member States and raises doubts regarding the similarity to the reference product. Conclusion after Assessment of the Applicant responses to the List of Outstanding Issues and oral response during the Oral Explanation With regards to efficacy, the CHMP is of the opinion that the Applicant / Marketing Authorisation Holder has not provided conclusive evidence of equivalence for the applied product, Eformax 6 and 12 µg, in a confirmative study. The confidence interval remains too wide to demonstrate the equivalence of Eformax to the originator and in addition, valid confirmative studies are not available for all subpopulations. With regards to safety, the CHMP is of the opinion that the Applicant / Marketing Authorisation Holder did not provide confirmative evidence of an equivalent safety profile at the proposed dose ratio. Furthermore, the Applicant / Marketing Authorisation Holder proposal to limit the maximum dose of Eformax to 12 mcg bid does not resolve the safety concerns, and is likely to be impractical in certain MS. Conclusion after Assessment of the Applicant detailed grounds for the re-examination procedure In the response to the grounds for refusal, the Applicant developed the arguments put forward during the previous assessment, including the oral explanation. The data from the Finney analyses are helpful to stimulate further drug development (i.e. a conclusive pharmacodynamic study), but are insufficient for regulatory approval of the product. The fact that the initially proposed 1:2 dose relationship has been changed after further analyses to a 1:1 for adolescents and adults, or 1:1.5 for children 6-12 years old, indicates that the dose response curve is flat, but also suggests that there is a difference between the two products, although the available data are insufficient to assess the magnitude, or clinical relevance of it. Thus, the CHMP considered that additional clinical data are needed to solve this issue. The importance of a Phase I pharmacokinetic study remains, as such data is of value for the safety assessment. Whether such a study is required for approval, in addition to further clinical data, will depend on the totality of the safety documentation in the future application. The CHMP also considered that the most important issue that should have been addressed by the Applicant was the lack of correlation between the studied in vitro parameters and the therapeutic ratio between Eformax and Foradil. Furthermore, the Applicant decision to carry out cumulative dose without taking in account the differences in inspiration flow of individual subjects and between studies subjects has lead to wide numerical differences in the response, which were considered worrying by the CHMP, because they could lead to dosing problems especially in situations where one inhaler is replaced by the other. The CHMP welcomed the decision to conduct a pharmacokinetic study of Eformax and Foradil in order to assess the comparability of the dose potency and safety profiles of Eformax and Foradil. The results of such a study should be carefully assessed, especially with regards to the effect of β 2 -agonists on the heart, even when they are highly selective, as the use of β 2 -agonist has been associated with an increased risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death. Therefore, the benefit-risk ratio of Eformax cannot be established properly. In accordance with the Guideline on the definition of a potential serious risk to public health in the context of Article 29(1) and (2) of Directive 2001/83/EC, a Potential Serious Risk to Public Health can be concluded because adequate proof for equivalence to the reference medicinal product is lacking. This principle is identically applicable to a product such as Eformax. 8

9 GROUNDS FOR REFUSAL Whereas - the applied product, Eformax 6 and 12 µg, has not shown to be equivalent to the reference product (Foradil Aerolizer) with regards to efficacy and safety with the adequate methodology, - the benefit-risk is unknown, and therefore considered a potential serious risk to public health in accordance with the Guideline on the definition of a potential serious risk to public health in the context of Article 29(1) and (2) of Directive 2001/83/EC, the CHMP therefore retains its negative opinion and consequently recommends the refusal of the granting of a Marketing Authorisation for Eformax 6 and 12 µg in the Concerned Member States, and the suspension of the Marketing Authorisation in the Reference Member State until the therapeutic equivalence with regards to efficacy and safety of Eformax 6 and 12 µg has been demonstrated. 9

10 ANNEX III CONDITIONS FOR THE LIFTING OF THE SUSPENSION 10

11 The National Competent Authorities, coordinated by the Reference Member State, shall ensure that the following conditions are fulfilled by the Marketing Authorisation Holders: The Applicant / Marketing Authorisation Holder should conduct sensitive studies showing that the relative dose potency is equivalent, (both in adult and children populations as a consequence of the identified differences), within an adequate acceptance range. In addition, the Applicant / Marketing Authorisation Holder should demonstrate an equivalent safety profile for Eformax by means of an adequate study design (PK or PD). The data resulting from the studies should be provided to the Member States for assessment. 11