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Assessment Report for Halaven Eribulin Procedure No. EMEA/H/C

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Assessment Report for Halaven Eribulin Procedure No. EMEA/H/C 20 January 2011 EMA/514195/2011 Committee for Medicinal Products for Human Use (CHMP) Assessment report For Halaven eribulin Procedure No. EMEA/H/C/002084 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 7523 7455 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 5 1.1. Submission of the dossier.................................................................................... 5 1.2. Steps taken for the assessment of the product ....................................................... 6 2. Scientific discussion ................................................................................ 7 2.1. Introduction ...................................................................................................... 7 2.2. Quality aspects .................................................................................................. 8 2.2.1. Introduction ................................................................................................... 8 2.2.2. Active Substance............................................................................................. 8 2.2.3. Finished Medicinal Product .............................................................................. 10 2.2.4. Discussion on chemical, pharmaceutical and biological aspects............................. 13 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ..................... 13 2.3. Non-clinical aspects .......................................................................................... 14 2.3.1. Introduction ................................................................................................. 14 2.3.2. Pharmacology ............................................................................................... 14 2.3.3. Pharmacokinetics .......................................................................................... 16 2.3.4. Toxicology.................................................................................................... 18 2.3.5. Ecotoxicity/environmental risk assessment........................................................ 22 2.3.6. Discussion on non-clinical aspects.................................................................... 22 2.3.7. Conclusion on the non-clinical aspects .............................................................. 25 2.4. Clinical aspects ................................................................................................ 25 2.4.1. Introduction ................................................................................................. 25 2.4.2. Pharmacokinetics .......................................................................................... 27 2.4.3. Pharmacodynamics........................................................................................ 29 2.4.4. Discussion and conclusions on clinical pharmacology .......................................... 30 2.5. Clinical efficacy ................................................................................................ 31 2.5.1. Dose response studies.................................................................................... 31 2.5.2. Main study ................................................................................................... 32 2.5.3. Discussion on clinical efficacy .......................................................................... 49 2.5.4. Conclusions on the clinical efficacy ................................................................... 50 2.6. Clinical safety .................................................................................................. 51 2.6.1. Discussion on clinical safety ............................................................................ 61 2.6.2. Conclusions on the clinical safety ..................................................................... 64 2.7. Pharmacovigilance............................................................................................ 64 2.8. Benefit-Risk Balance......................................................................................... 66 2.8.1. Discussion on the benefit-risk balance .............................................................. 69 2.8.2. Risk management plan................................................................................... 69 2.9. Recommendation ............................................................................................. 70 CHMP assessment report doc ref EMA/CHMP/5019/2011 Page 2/70 List of abbreviations 1A9PTX10 Human ovarian cancer cell line (paclitaxel resistant) 1A9PTX22 Human ovarian cancer cell line (paclitaxel-resistant) AE Adverse event AETP All eribulin treated patients ALT Alanine aminotransferase ANC Absolute neutrophil count AST Aspartate aminotransferase AUC Area under the plasma concentration time curve BCP Breast cancer patients BSA Body surface area BUN Blood urea nitrogen CFC-GEMM Colony forming cell-granulocyte, erythrocyte, macrophage, megakaryocyte CFU-GM Colony forming unit-granulocyte, macrophage CHMP Committee for Medicinal Products for Human Use CI Confidence Interval Cmax Maximum observed concentration CNS Central nervous system CR Complete response CSR Clinical study report CT Chemotherapy regimens CTCAE Common Terminology Criteria for Adverse Events DLT Dose limiting toxicity DoR Duration of Response E7389 Eribulin mesylate ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group EU European Union GC Gas chromatography GCP Good Clinical Practice G-CSF Granulocyte colony stimulating factor GD Gestation days GLP Good Laboratory Practice HALO Hematotoxicity Assay via Luminescence Output HER2/neu Human epidermal growth factor receptor 2 hERG Human ether a-go-go related gene HPLC High performance liquid chromatography HR Hazard ratio IC Ion chromatography IC50 Half-maximal inhibitory concentration IC90 Inhibitory concentration 90% IR Infrared Spectroscopy ITT Intent-to-treat IV Intravenous IVRS Interactive voice recognition system LLDPE Linear low density polyethylene LRBC Locally recurrent breast cancer MBC Metastatic breast cancer MedDRA Medical Dictionary for Regulatory Activities MS Mass spectrometry MTD Maximum tolerated dose NA Not applicable NCI National Cancer Institute NOAEL No-Observed-Adverse-Effect Level NSCLC Non-small cell lung cancer ORR Objective response rate OS Overall survival CHMP assessment report doc ref EMA/CHMP/5019/2011 Page 3/70 PD Progressive disease PFS Progression-Free Survival P-gp Permeability glycoprotein PO Per os PP Per protocol PR Partial response PTFE Polytetrafluoroethylene Pts Patients Q2D×3 Every other day for 3 injections with a two-day rest between weekly cycles (Monday-Wednesday-Friday schedule) Q4D×3 Once every four days for a total of 3 injections Q7D×3 Once a week for 3 weeks RBC Red blood cell RECIST Response Evaluation Criteria In Solid Tumours RET Reticulocyte RMP Risk management plan S9 Liver metabolic activation system, designates a supernatant from centrifugation at 9000×g, used for metabolic activation tests SAE Serious adverse event SD Stable disease SEG Neutrophil SmPC Summary of product characteristics SOC System Organ Class TEAE Treatment emergent adverse event TPC Treatment of Physician’s Choice UK United Kingdom ULN Upper limit of normal UV Ultraviolet spectroscopy WBC White blood cell CHMP assessment report doc ref EMA/CHMP/5019/2011 Page 4/70 1. Background information on the procedure 1.1. Submission of the dossier The applicant Eisai Europe Ltd. submitted on 30 March 2010 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Halaven, through the centralised procedure falling within the Article 3(1) and point 3 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 26 May 2009. The applicant applied for the following indication: HALAVEN monotherapy is indicated for the treatment of patients with breast cancer who have received at least two chemotherapeutic regimens for locally advanced or metastatic disease. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application The application submitted is composed of administrative information, complete quality data, non- clinical and clinical data based on applicants’ own tests and studies. Information on Paediatric requirements Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision P/47/2008 for the following condition(s): Treatment of breast carcinoma. on the granting of a class waiver. Information relating to orphan market exclusivity Similarity Not applicable. Market Exclusivity Not applicable. Scientific Advice: The applicant received Scientific Advice from the CHMP on 14 December 2005, 28 June 2006 and 22 January 2009. The Scientific Advices pertained to quality and clinical aspects of the dossier. Licensing status The product was not licensed in any country at the time of submission of the application. A new application was filed in the following countries: Switzerland on 26 May 2009 and Singapore on 26 May 2009. CHMP assessment
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