Assessment Report

31 July 2013 EMA/CHMP/41467/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Ovaleap International non-proprietary name: follitropin alfa Procedure No. EMEA/H/C/002608 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ...................................................................................... 8 1.2. Manufacturers ...................................................................................................... 9 1.3. Steps taken for the assessment of the product ......................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction....................................................................................................... 10 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction .................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 14 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 17 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 22 2.2.6. Recommendations for future quality development ............................................... 22 2.3. Non-clinical aspects ............................................................................................ 22 2.3.1. Introduction .................................................................................................... 22 2.3.2. Pharmacology ................................................................................................. 23 2.3.3. Pharmacokinetics............................................................................................. 25 2.3.4. Toxicology ...................................................................................................... 28 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 30 2.3.6. Discussion on the non-clinical aspects ................................................................ 30 2.3.1. Conclusion on the non-clinical aspects ................................................................ 31 2.4. Clinical aspects .................................................................................................. 31 2.4.1. Introduction .................................................................................................... 31 2.4.2. Pharmacokinetics............................................................................................. 32 2.4.3. Pharmacodynamics .......................................................................................... 35 2.4.4. Discussion on clinical pharmacology ................................................................... 37 2.4.5. Conclusions on clinical pharmacology ................................................................. 38 2.5. Clinical efficacy .................................................................................................. 38 2.5.1. Main study(ies) ............................................................................................... 38 2.5.2. Discussion on clinical efficacy ............................................................................ 54 2.5.3. Conclusions on the clinical efficacy ..................................................................... 55 2.6. Clinical safety .................................................................................................... 56 2.6.1. Discussion on clinical safety .............................................................................. 62 2.6.2. Conclusions on the clinical safety ....................................................................... 63 2.7. Pharmacovigilance .............................................................................................. 63 2.8. Risk Management Plan ........................................................................................ 63 Assessment report EMA/CHMP/41467/2013 Page 2/72 3. Benefit-Risk Balance ............................................................................. 67 4. Recommendations ................................................................................. 71 Assessment report EMA/CHMP/41467/2013 Page 3/72 List of abbreviations A277 Absorption at 277 nm AA Amino acid(s) AC Affinity chromatography (step) AE Adverse event AI Antennarity index AIEC Anion exchange chromatography AIEX Anion exchange chromatography step ANCOVA Analysis of covariance ANOVA Analysis of variance Anti-hTSH Anti human thyroid stimulating hormone API Active plasma ingredient ART Assisted reproductive technologies Asn Asparagine ATC Anatomical Therapeutic Chemical ATCC Atypical Type Culture Collection ATP According-to-protocol AUC Area under the concentration-time curve AUC0-24h Area under the concentration-time curve from zero to 24 hours post-dose BMI Body mass index BpyV Bovine polyomavirus BSA Bovine spongiform encephalopathy cAMP Cyclic adenosine monophosphate CDSF-1 CHO dhfr-serum free cell line no. 1 CFR Code of Federal Regulations CFU Colony forming units CLobs Clearance Cmax Maximum serum concentration CHMP Committee for medicinal products for human use CHO Chinese hamster ovary CHOSI Chinese hamster ovary SI cell line CI Confidence interval Assessment report EMA/CHMP/41467/2013 Page 4/72 CIP Clearing in place CMV Cytomegalovirus CL/f Apparent clearance Cmax Maximum plasma concentration CNS Central nervous system Da Dalton DF Diafiltration DNA Deoxyribonucleic acid ECG Electrocardiogram ECL Electrochemiluminescence EMA European Medicines Agency ELISA Enzyme linked immunoabsorbent assay EPAR European public assessment report FSH Follicle stimulating hormone GLP Good laboratory practice GMP Good manufacturing practice GnRH Gonadotropin releasing hormone h Hour hCG Human chorionic gonadotropin hFSH Human follicle stimulating hormone HIC Hydrophobic interaction chromatography step HRP Horseradish peroxidase ICH International conference on harmonisation ICSI Intracytoplasmic sperm injection IgG Immunoglobulin G IgM Immunoglobulin M INN International Non-proprietary Name ITT Intent-to-treat IU International Unit IVF In vitro fertilisation LH Luteinising hormone MCB Master Cell Bank Assessment report EMA/CHMP/41467/2013 Page 5/72 MedDRA Medical Dictionary for Regulatory Activities M Metre mg Milligram min Minute mL Millilitre Mm Millimetre mmol Milimole N Number of subjects / patients Neu5Ac N-acetylneuraminic acid Neu5Gc N-glycolylneuraminic acid ng Nanogram nm nanometre NIBSC National Institute for Biological Standards and Control NOAEL No observed adverse effect level OHSS Ovarian hyperstimulation syndrome Pg Picogram PhEur European pharmacopeia PK Pharmacokinetic(s) Pmol Picomole PN Pronucleus PT Preferred term r hFSH Recombinant human follicle stimulating hormone s.c. Subcutaneous SD Standard deviation SEC Size exclusion chromatography step SmPC Summary of product characteristics SOC System organ class SUSAR Suspected unexpected serious adverse reaction TEAE Treatment-emergent adverse event TEADR Treatment-emergent adverse drug reaction t½ Half-life Tmax Time at which Cmax occurred Assessment report EMA/CHMP/41467/2013 Page 6/72 Vz_obs Volume of distribution ZIP Zero-inflated Poisson Assessment report EMA/CHMP/41467/2013 Page 7/72 1. Background information on the procedure 1.1. Submission of the dossier The applicant, Teva Pharma B.V., submitted on 28 February 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Ovaleap, through the centralised procedure falling within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 23 June 2011. The applicant applied for the following indication: In adult women • Anovulation (including polycystic ovarian syndrome) in women who have been unresponsive to treatment with clomifene citrate. • Stimulation of multifollicular development in women undergoing superovulation for assisted reproductive technologies (ART) such as in vitro fertilisation (IVF), gamete intra- fallopian transfer and zygote intra fallopian transfer. • Ovaleap in association with a luteinising hormone (LH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials these patients were defined by an endogenous serum LH level < 1.2 IU/l. In adult men • Ovaleap is indicated for the stimulation of spermatogenesis in men who have congenital or acquired hypogonadotropic hypogonadism with concomitant human chorionic gonadotropin (hCG) therapy. The legal basis for this application refers to: Article 10(4) of Directive 2001/83/EC – relating to applications for a biosimilar medicinal

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