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Refusal Public Assessment Report European Medicines Agency Evaluation of Medicines for Human Use London, 20 March 2007 EMEA/CHMP/273127/2007 REFUSAL CHMP ASSESSMENT REPORT FOR MYCOGRAB International Nonproprietary Name: Efungumab Procedure No. EMEA/H/C/658 Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 13 E-mail: [email protected] http://www.emea.europa.eu ©EMEA 2007 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged PRODUCT INFORMATION Name of the medicinal product: Mycograb Applicant: NeuTec Pharma plc 2nd Floor, Clinical Sciences Building Central Manchester & Manchester Children’s Hospital NHS Trust Oxford Rd Manchester, M13 9WL United Kingdom Active substance: Recombinant human monoclonal antibody to hsp90 International Nonproprietary Name: Efungumab Pharmaco-therapeutic group Not yet assigned (ATC Code): Not yet assigned. Applied therapeutic indication: Treatment of invasive candidiasis in adult patients, in combination with amphotericin B or a lipid formulation of amphotericin B. Pharmaceutical form: Powder for solution for injection Strength: 2 mg/ml Route of administration: Intravenous use Packaging: Vial (glass) Package size: 10 vials ©EMEA 2007 2/46 TABLE OF CONTENTS 1 BACKGROUND INFORMATION ON THE PROCEDURE ..........................................4 1.1 Submission of the dossier .......................................................................................................4 1.2 Steps taken for the assessment of the product.........................................................................4 1.3 Steps taken for the re-examination procedure.........................................................................5 2 SCIENTIFIC DISCUSSION................................................................................................7 2.1 Introduction.............................................................................................................................7 2.2 Quality aspects........................................................................................................................7 2.3 Non-clinical aspects..............................................................................................................13 2.4 Clinical aspects .....................................................................................................................19 2.5 Pharmacovigilance................................................................................................................37 2.6 Overall conclusions, risk/benefit assessment and recommendation .....................................37 3 RE-EXAMINATION OF THE CHMP OPINION OF 15 NOVEMBER 2006..............41 ©EMEA 2007 3/46 1 BACKGROUND INFORMATION ON THE PROCEDURE 1.1 Submission of the dossier The applicant NeuTec Pharma plc submitted on 11 March 2005 a full application for Marketing Authorisation referring to Art. 8.3 of Directive 2001/83/EC, as amended, to the European Medicines Agency (EMEA) through the centralised procedure for Mycograb, which was designated as an orphan medicinal product EU/3/01/073 on 5 December 2001. Mycograb was designated as an orphan medicinal product in the following indication: treatment of invasive fungal infections. The calculated prevalence of this condition was approx. 0.3 per 10,000 EU population. The applicant applied for the following indication: treatment of invasive candidiasis in adult patients, who are receiving co-therapy with amphotericin B or a lipid formulation of amphotericin B. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application Protocol Assistance The applicant received Protocol Assistance from the CHMP on 6 October 2003. The Protocol Assistance pertained to non-clinical and clinical aspects and significant benefit of the dossier. Licensing status: The product was not licensed in any country at the time of submission of the application. The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur: J. Ersbøll Co-Rapporteur: P. Kurki 1.2 Steps taken for the assessment of the product • The application was received by the EMEA on 11 March 2005. • The procedure started on 28 March 2005. • The Rapporteur's first Assessment Report was circulated to all CHMP members on 13 June 2005. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 8 June 2005. • The quality list of questions was discussed and adopted at the Biological Working Party (BWP) meeting of 18-20 July 2005. • During the meeting on 25-27 July 2005, 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 28 July 2005. • The applicant submitted the responses to the CHMP consolidated List of Questions on 23 March 2006. • Inspections were carried out at the manufacturing sites of the drug substance and drug product contract manufacturers. - Biomeva GmbH (prev. BioReliance Manufacturing GmbH) - Czernyring 22 - Heidelberg – Germany – on 10 January 2006 and 11 October 2006 respectively (two inspections); - Thymoorgan GmbH Pharmazie & Co. KG - Schiffgraben 23 - Viennenburg – Germany - on 17 February 2006 and 29 September 2006 respectively (two inspections). • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 16 May 2006. • The quality list of outstanding issues was discussed and adopted at the BWP meeting of 22-24 May 2006. ©EMEA 2007 4/46 • During the CHMP meeting on 29 May – 1 June 2006, the CHMP agreed on a List of Outstanding Issues to be addressed in an oral explanation and/or in writing by the applicant. • The applicant submitted the responses to the CHMP List of outstanding Issues on 21 September 2006. • The responses to the quality list of outstanding issues were discussed and a recommendation to the CHMP was adopted at the BWP meeting of 9-11 October 2006. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Outstanding Issues to all CHMP members on 11 October 2006. • During the CHMP meeting on 16 – 19 October 2006, the CHMP agreed on a second List of Outstanding Issues to be addressed in an oral explanation and/or in writing by the applicant. • The applicant submitted the responses to the second CHMP List of outstanding Issues on 1 November 2006 (clinical aspects) and 6 November 2006 (quality aspects). • The responses to the quality list of outstanding issues were addressed by the applicant in a hearing in front of the BWP and a recommendation to the CHMP was adopted at the BWP meeting of 7-8 November 2006. • The response to the clinical question of list of outstanding issues was addressed by the applicant in a hearing in front of the CHMP on 14 November 2006. • During the CHMP meeting on 13-16 November 2006, in the light of the overall data submitted and the scientific discussion within the Committee, the CHMP issued a negative opinion for granting a Marketing Authorisation to Mycograb on 16 November 2006. 1.3 Steps taken for the re-examination procedure The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur: M. Haase Co-Rapporteur: D. Lyons • The applicant submitted written notice to the EMEA on 24 November 2006 to request a re- examination of the Mycograb CHMP opinion of 16 November 2006. • During its meeting on 11-14 December 2006, the CHMP appointed Dr Manfred Haase as Rapporteur and Dr David Lyons as Co-Rapporteur for the re-examination procedure. • The detailed grounds for the re-examination request were submitted by the applicant on 19 January 2007. The re-examination procedure started on 20 January 2007. • The Rapporteur's Assessment Report was circulated to all CHMP and BWP members on 20 February 2007. The Co-Rapporteur's Assessment Report was circulated to all CHMP and BWP members on 21 February 2007. • The final list of questions for the SAG Anti-infectives and the BWP, respectively, were circulated on 5 March 2007. • During a meeting of the BWP on 12 March 2007, BWP members and additional experts addressed questions raised by the CHMP. During this meeting the applicant presented an oral explanation. A report of this meeting was forwarded to the CHMP. • During a meeting of the CHMP Scientific Advisory Group on Anti-infectives (SAG-Anti- infectives) on 13 March 2007, experts were convened to address questions raised by the CHMP. During this meeting the applicant presented an oral explanation. A report of this meeting was forwarded to the CHMP. • The Rapporteurs’ Joint Assessment Report was circulated to all CHMP members on 15 March 2007. • During the CHMP meeting on 19-22 March 2007, the applicant presented an oral explanation before the CHMP on 20 March 2007. ©EMEA 2007 5/46 • During the meeting on 19-22 March 2007, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a final Opinion recommending the refusal of the Marketing Authorisation for Mycograb. ©EMEA 2007 6/46 2 SCIENTIFIC DISCUSSION 2.1 Introduction The spectrum of diseases related to Candida species is wide, ranging from superficial candidiasis such as thrush to life threatening infections associated with an overall prognosis comparable with that of septic shock. Invasive candidiasis (also known as systemic or
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