25 September 2014 EMA/CHMP/534845/2014 Committee for Medicinal Products for Human Use (CHMP) Assessment report Ketoconazole HRA International non-proprietary name: KETOCONAZOLE HRA Procedure No. EMEA/H/C/003906/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union Table of contents 1. Background information on the procedure .............................................. 5 1.1. Submission of the dossier ..................................................................................... 5 1.2. Manufacturers ..................................................................................................... 5 1.3. Steps taken for the assessment of the product ........................................................ 6 2. Scientific discussion ................................................................................ 6 2.1. Introduction ........................................................................................................ 6 2.2. Quality aspects .................................................................................................. 10 2.3. Non-clinical aspects ............................................................................................ 14 2.4. Clinical aspects .................................................................................................. 22 2.5. Clinical efficacy .................................................................................................. 31 2.6. Clinical safety .................................................................................................... 61 2.7. Pharmacovigilance ............................................................................................. 79 2.8. Risk Management Plan ........................................................................................ 79 2.9. Product information ............................................................................................ 84 3. Benefit-Risk Balance ............................................................................. 85 Benefits ................................................................................................................... 85 Risks ....................................................................................................................... 86 Benefit-risk balance .................................................................................................. 88 4. Recommendations ................................................................................. 89 Ketoconazole HRA Assessment report EMA/CHMP/534845/2014 Page 2/115 List of abbreviations ACTH Adrenocorticotrophin Hormone AE Adverse events AGT Aminoglutethimide AI Adrenal insufficiency ALT Alanine transaminase AP Alkaline phosphatase AST Aspartate transaminase AUC Area under the curve b.i.d Twice a day CD Cushing’s disease CRH Corticotropin Releasing Hormone CS Cushing’s Syndrome D Day DDD Defined Daily Dose DHEA Dehydroepiandrosterone DHEAS Dehydroepiandrosterone sulfate DOC Deoxycorticosterone EAS Ectopic ACTH Syndrome EC European Commission EIA Enzyme immunoassay EU European Union F Female GCP Good Clinical Practice HR Hour KC Ketoconazole M Male MET Metyrapone MTH Month NAH Nodular adrenal/adrenocortical hyperplasia NC Not controlled NIH National Institute of Health RIA Radio immunoassay SD Standard deviation SMR Standard mortality ratio THE Tetrahydrocortisone THF Tetrahydrocortisol TYMC Total yeast and mold count Ketoconazole HRA Assessment report EMA/CHMP/534845/2014 Page 3/115 UK United Kingdom UFC Urinary free cortisol ULN Upper limit of normal US United States WK Week Y Year Ketoconazole HRA Assessment report EMA/CHMP/534845/2014 Page 4/115 1. Background information on the procedure 1.1. Submission of the dossier The applicant Laboratoire HRA Pharma submitted on 5 February 2014 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Ketoconazole HRA, through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004 . The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 21 November 2013. Ketoconazole HRA was designated as an orphan medicinal product EU/3/12/965 on 23 April 2012. Ketoconazole HRA was designated as an orphan medicinal product in the following indication: treatment of Cushing syndrome. The applicant applied for the following indication: Treatment of Cushing’s syndrome. The legal basis for this application refers to: Article 10(a) of Directive 2001/83/EC – relating to applications relying on well-established medicinal use supported by bibliographic literature. The application submitted is composed of administrative information, complete quality data, non-clinical and clinical data based on bibliographic literature substituting all non-clinical tests and clinical studies together with a bioequivalent study aiming at bridging the literature data with the intended marketed product. Information on Paediatric requirements Not applicable. Information relating to orphan market exclusivity Similarity Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the applicant did submit a critical report addressing the possible similarity with authorised orphan medicinal products (Signifor). Protocol Assistance The applicant did not seek a Protocol Assistance at the CHMP. Licensing status The product was not licensed in any country at the time of submission of the application. 1.2. Manufacturers Manufacturer responsible for batch release Polfarmex S.A. ul. Jozefow 9 99-300 Kutno Poland Ketoconazole HRA Assessment report EMA/CHMP/534845/2014 Page 5/115 1.3. Steps taken for the assessment of the product The Rapporteur and Co-Rapporteur appointed by the CHMP: Rapporteur: Concepcion Prieto Yerro Co-Rapporteur: Patrick Salmon • The application was received by the EMA on 5 February 2014. • Accelerated Assessment procedure was agreed-upon by CHMP on 23 January 2014. • The procedure started on 26 February 2014. • The Rapporteur's first Assessment Report was circulated to all CHMP members on 13 May 2014. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 16 May 2014. In accordance with Article 6(3) of Regulation (EC) No 726/2004, the Rapporteur and Co-Rapporteur declared that they had completed their assessment report in less than 80 days. • During the meeting on 26 June 2014, the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 27 June 2014. • The applicant submitted the responses to the CHMP consolidated List of Questions on 23 July 2014. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 28 August 2014 and an updated Joint assessment report on 22 september 2014. • During the meeting on 25 September 2014, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to Ketoconazole HRA. • The CHMP adopted a report on similarity of Ketoconazole HRA with Signifor on 25 September 2014. 2. Scientific discussion 2.1. Introduction Problem statement Cushing Syndrome is divided into ACTH-dependent forms, either due to a corticotropic pituitary adenoma i.e. a Cushing’s disease (CD) or due to an ectopic ACTH production by a neuroendocrine tumor or an unknown source (occult ectopic ACTH syndrome), and ACTH-independent forms, due to adrenal adenoma/carcinoma or nodular adrenal hyperplasia (Boscaro, 2001; Newell-Price, 1998). According to the Committee for Orphan Medicinal Products (COMP) (Opinion dated 23/04/12) the prevalence of the “condition” Cushing’s syndrome is approximately 0.9 in 10,000 people in the European Union (EU). This is equivalent to a total of around 46,000 people, and is below the ceiling for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor. The median age at first admission was 41.4 years (range 3.6-77.7) and the female to male ratio was 3:1. Less than 10% of cases occur in pediatrics and unlike in adults no female preponderance is observed (Shah, 2011). Ketoconazole HRA Assessment report EMA/CHMP/534845/2014 Page 6/115 The clinical consequences of excess endogenous cortisol exposure are generally severe: glucose tolerance impairment or diabetes; hypertension; dyslipidemia; clotting disorders; vascular fragility; muscular weakness; osteoporosis; diminished resistance to infection; depression and psychiatric disorders; healing defects; gonadal dysfunction with hirsutism and acne (Arnaldi, 2012; Bolland, 2011; Boscaro, 2001; Cavagnini, 2001; Newell-Price, 1998). Obesity and growth arrest are the most common findings in children with CS (Shah, 2011). Because of complications such as hypertension, diabetes mellitus, cardiac abnormalities and alteration in hemostatic parameters, cortisol excess leads to an increased cardiovascular risk (Whitworth, 2005; Arnaldi, 2012) with increased frequency of arterial atherosclerosis (Neary, 2013). Inadequately treated CS is a life-threatening condition. In a Danish study (Lindholm, 2001),