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Concentrate of Proteolytic Enzymes Enriched in Bromelain

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Concentrate of Proteolytic Enzymes Enriched in Bromelain 20 September 2012 EMA/648483/2012 Committee for Medicinal Products for Human Use (CHMP) Assessment report NexoBrid Concentrate of proteolytic enzymes enriched in bromelain Procedure No. EMEA/H/C/002246 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 8416 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2012. 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 .................................................................................................. 9 2.3. Non-clinical aspects .......................................................................................... 20 2.4. Clinical aspects ................................................................................................ 29 2.5. Clinical efficacy ................................................................................................ 36 2.6. Clinical safety .................................................................................................. 89 2.7. Pharmacovigilance...........................................................................................110 2.8. User consultation ............................................................................................118 3. Benefit-Risk Balance............................................................................ 118 4. Recommendations ............................................................................... 122 List of abbreviations aa amino acid BLQ below the Limit of Quantitation BSA Bovine Serum Albumin CDU Casein Digestion Unit CFU Colony Forming Unit c.f. compare (abbr. also: cp. from Latin: confer, “compare”) cm Centimeter CoA Certificates of Analyses CPMP Committee for Proprietary Medicinal Products CPP Critical Process Parameter curr. Ed. Current Edition CV Column Volumes Da Dalton DF Diafiltration DIN Deutsches Institut für Normierung German Industrial Standard DP Drug Product DS Drug Substance EDTA-Na2 Ethylenediaminetetraacetic acid Disodium salt EC European Commission EP European Pharmacopoeia g gram(s) GACP good agricultural and collection practice GMP Good Manufacturing Practice HACCP Hazard analysis and critical control point HAV Hepatitis-A virus HVAC Heating, Ventilating, and Air Conditioning HCl Hydrochloric Acid HMPC Committee on Herbal Medicinal Products HPLC high performance liquid chromatography hrs Hours ICH International Conference on Harmonisation ICP inductively coupled plasma IPA isopropyl alcohol IPC In- Process Controls IR infrared ISO International Organization for Standardization kDa Kilodalton kg Kilogram(s) l litre(s) LAL Limulus Amoebocyte Lysate LFGB Lebensmittel-, Bedarfsgegenstände- und Futtermittelgesetzbuch Law for foodstuffs, consumer goods and feeding stuff (Germany) LOD Limit of Detection LOQ Limit of Quantitation MAA Marketing Authorisation Application mg milligram(s) ml millilitre(s) min minutes mM Millimolar MVD Maximum Valid Dilution Mw Molecular Weight NaCl Sodium chloride NaHSO3 Sodium bisulfite NaOH sodium hydroxide NGD NexoBrid NIR Near- Infrared Analysis nm Nanometer NOAEL No Observed Adverse Effect Level NoV Norovirus OOS Out of Specification OD Optical Density OP Operating Parameter Pa Pascal PAMP pathogen-associated molecular pattern PBS phosphate buffered saline PDE Permitted Daily Exposure Ph. Eur. European Pharmacopoeia pH power of hydrogen (scale measuring acid / alkaline nature of solution) ppm parts per million PTWI Provisional Tolerable Weekly Intake QL Quantitation Limit QP Qualified Person q.s. quantum satis QWP Quality Working Party resp. respectively RH Relative humidity RPM Revolutions per minute RS Reference Standard RSD Relative Standard Deviation RT Room Temperature RT Retention Time SD Standard Deviation SM Starting Material SPC Summary of Product Characteristics TSE Transmissible Spongiform Encephalopathy USP United States Pharmacopoeia UV Ultraviolet V Volt WFI Water for Injection WHO World Health Organisation w/v weight/volume w/w weight/weight 1. Background information on the procedure 1.1. Submission of the dossier The applicant Teva Pharma GmbH submitted on 29 October 2010 an application for Marketing Authorisation to the European Medicines Agency (EMA) for NexoBrid, 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 17 December 2009. NexoBrid was designated as an orphan medicinal product EU/3/02/107 on 30 July 2002. NexoBrid was designated as an orphan medicinal product in the following indication: Treatment of partial deep dermal and full thickness burns. The applicant applied for the following indication: Timely, selective removal of eschar in patients with deep partial- and/or full-thickness burns. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC - 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 and bibliographic literature substituting/supporting certain tests or studies. Information on Paediatric requirements Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision P/227/2010 on the agreement of a paediatric investigation plan (PIP). At the time of submission of the application, the PIP EMEA-000142-PIP02-09 was not yet completed as some agreed measures were deferred. Information relating to orphan market exclusivity NexoBrid has an Orphan Drug designation. On 30 July 2002 orphan designation (EU/3/02/107) was granted by the European Commission for purified Bromelain for the treatment of partial deep dermal and full thickness burns. Upon request by the MAH a revised opinion was edited in June 2010 (14 June 2010 EMA/COMP/1413/2002 Rev.2). According to the conclusion of this opinion the prevalence of the partial deep dermal and full thickness burns affected approximately 1 in 10,000 people in the European Union (EU). Similarity Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised orphan medicinal products because there is no authorised orphan medicinal product for a condition related to the proposed indication. Applicant’s request for consideration New active Substance status The applicant requested the active substance concentrate of proteolitic enzymes enriched in bromelain contained in the above medicinal product to be considered as a new active substance in itself. Protocol Assistance The applicant received Protocol Assistance from the CHMP in NexoBrid on 14 June 2005, 14 May 2008, 18 December 2008 and 19 February 2009. The Protocol Assistance 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. 1.2. Steps taken for the assessment of the product The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur: Harald Enzmann Co-Rapporteur: RobertJames Hemmings The application was received by the EMA on 29 October 2010. The procedure started on 17 November 2010. The Rapporteur's first Assessment Report was circulated to all CHMP members on 07 February 2011. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 04 February 2011. During the meeting on 17 March 2011, 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 18 March 2011. The applicant submitted the responses to the CHMP consolidated List of Questions on 11 October 2011. The summary report of the inspection carried out at the following sites: MediWound Ltd., 42 Hayarkon St., 81227 Yavne, Israel between 22 and 25 August 2011 and Analyst Research Laboratories, 12 Hamada St, 76703 Rehovot, Israel on 23 August 2011 was issued on 26 September 2011. The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 28 November 2011. During the CHMP meeting on 12-15 December 2011, the CHMP agreed on a list of outstanding issues to be addressed in writing and/or in an oral explanation by the applicant. The applicant submitted the responses to the CHMP List of Outstanding Issues on 10 February 2012. The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Outstanding Issues to all CHMP members on 9 March 2012. During a meeting of an Ad-hoc Expert group on 7 March 2012, experts were convened to address questions
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