ASSESSMENT REPORT FOR IRESSA

1 European Medicines Agency Evaluation of Medicines for Human Use 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 75 23 70 51 E-mail: European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged : EMEA/CHMP/563746/2008 ASSESSMENT REPORT FOR IRESSA International Nonproprietary Name: gefitinib Procedure No. EMEA/H/C/001016 ASSESSMENT REPORT as adopted by the CHMP with all information of a commercially confidential nature deleted Page 2 of 86 TABLE OF CONTENTS 1.

2 BACKGROUND INFORMATION ON THE PROCEDURE .. 3 Submission of the dossier .. 3 Steps taken for the ASSESSMENT of the 4 2. SCIENTIFIC 5 5 Quality aspects .. 5 Non-clinical aspects .. 8 Clinical aspects .. 18 78 Overall conclusions, risk/benefit ASSESSMENT and recommendation .. 82 Page 3 of 86 1. BACKGROUND INFORMATION ON THE PROCEDURE Submission of the dossier The applicant AstraZeneca AB submitted on 06 May 2008 an application for Marketing Authorisation to the European Medicines Agency (EMEA) for IRESSA , through the centralised procedure falling within the Article 3(1) and point 3 of Annex of Regulation (EC) No 726/2004.

3 The eligibility to the centralised procedure was agreed upon by the EMEA/CHMP on18 December 2007. The legal basis for this application refers to: A - Centralised / Article 8(3) / New active substance. Article of Directive 2001/83/EC, as amended - complete and independent application. The application submitted is a complete dossier composed of administrative information, complete quality data, non-clinical and clinical data based on applicants own tests and studies and/or bibliographic literature substituting/supporting certain tests or studies The applicant applied for the following indication.

4 IRESSA is indicated for the treatment of adults with locally advanced or metastases Non Small Cell Lung Cancer (NSCLC) eligible for further chemotherapy after receiving prior platinum based chemotherapy. Scientific Advice: The applicant received Scientific Advice from the CHMP on the 26 October 1999, 1st June 2006 and 18 October 2006. A clarification letter was also received on 27th July 2006. The Scientific Advice pertained to the clinical aspects of the product development.

5 Licensing status: IRESSA has been given a Marketing Authorisation in the following countries: Country: Date of authorisation: Japan Australia USA Singapore Argentina South Korea Taiwan Malaysia Mexico Philippines Nicaragua Canada Curacao Dominican Republic Hong Kong Israel Honduras New Zealand Guatemala United Arab Emirates Thailand Indonesia India Peru El Salvador Page 4 of 86 Bahrain Panama Venezuela Chile Serbia and Montenegro Uruguay Qatar Russia China Sri Lanka The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur.

6 Tomas P Salmonson Co-Rapporteur: Eva Skovlund Steps taken for the ASSESSMENT of the product The application was received by the EMEA on 06 May 2008. The procedure started on 28 May 2008. The Rapporteur's first ASSESSMENT REPORT was circulated to all CHMP members on 15 August 2008. The Co-Rapporteur's first ASSESSMENT REPORT was circulated to all CHMP members on 15 August 2008. During the meeting on 22-25 September 2008, the CHMP agreed on the consolidated List of Questions to be sent to the applicant.

7 The final consolidated List of Questions was sent to the applicant on 25 September 2008. The applicant submitted the responses to the CHMP consolidated List of Questions on 21 November 2008. A GCP inspection was carried out at three investigator sites in of China, between 20-31 October 2008, in relation to the conduct of trial D791GC00001. The final integrated inspection REPORT was issued on 20 November 2008. On 15 December 2008 a clarification meeting was held with the applicant and the Rapporteurs.

8 The Rapporteurs circulated the Joint ASSESSMENT REPORT on the applicant s responses to the List of Questions to all CHMP members on 22 December 2008. During the CHMP meeting on 19-22 January 2009, the CHMP agreed on a list of outstanding issues to be addressed in writing and in an oral explanation by the applicant. The applicant submitted the responses to the CHMP list of outstanding issues on 16 February 2009. The Rapporteurs circulated the updated Joint ASSESSMENT REPORT on the applicant s responses to the CHMP list of outstanding issues on 02 March 2009.

9 During a SAG Oncology meeting on 06 March 2009, experts were convened to address questions raised by the CHMP. The applicant submitted further responses to the CHMP list of outstanding issues on 13 March 2009. The Rapporteurs circulated an updated Joint ASSESSMENT REPORT on the applicant s responses to the CHMP list of outstanding issues on 13 March 2009. During the CHMP meeting on 16-19 March 2009, outstanding issues were addressed by the applicant during an oral explanation before the CHMP.

10 The Rapporteurs circulated a further updated Joint ASSESSMENT REPORT to the CHMP on 17 April 2009. During the meeting on 20-23 April 2009, 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 IRESSA on 23 April 2009. The applicant provided the letter of undertaking on the follow-up measures to be fulfilled post-authorisation on date 22 April 2009. Page 5 of 86 2.