1. Ketek, FDA Hearing, Dec. 2006 ÖM Ketek (telithromycin) Decisions and procedures in the European Union Örjan Mortimer, MD, Senior Expert, Delegate EMEA/CHMP-PhVWP Medical Products Agency, Sweden

2. Ketek, FDA Hearing, Dec. 2006 ÖM Outline of the presentation Regulatory System in the European Union (EU) Ketek –indications, changes to product information –assessments of hepatic safety –renewal of Marketing Authorization –assessments after the renewal Summary

3. Ketek, FDA Hearing, Dec. 2006 ÖM WP PhVWP HMPC COMPCVMP FR UK NL DE SE CHMP EMEA A (De)Centralized Network

4. Ketek, FDA Hearing, Dec. 2006 ÖM European Medicines Agency (EMEA) The EMEA coordinates the evaluation and supervision of medicinal products throughout the European Union. The Agency brings together the scientific resources of the 25 EU Member States in a network of the national competent authorities.

5. Ketek, FDA Hearing, Dec. 2006 ÖM The EMEA A network of some 3,500 European experts underpins the scientific work of the EMEA and its committees. Began its activities in 1995, when the European system for authorizing medicinal products was introduced Is primarily involved in the Centralised Procedure (CP).

6. Ketek, FDA Hearing, Dec. 2006 ÖM CHMP Pharmacovigilance WP Herbal Medicinal Product WP Safety WP Biotechnology WP Efficacy WP Bloododucts Workin Party Scientific advisory groups (SAGs) Quality WP CHMP and Working Parties (WP)

7. Ketek, FDA Hearing, Dec. 2006 ÖM CHMP responsibilities Opinions on granting, variation, suspension, of an authorization according to the CP Opinion on any scientific matter concerning the evaluation of medicinal products for human use in the EU.

8. Ketek, FDA Hearing, Dec. 2006 ÖM CHMP responsibilities Should formulate an opinion whenever there is disagreement between member states within other procedures as the mutual recognition procedure and decentralised procedure. General guidance, provide Guidelines

9. Ketek, FDA Hearing, Dec. 2006 ÖM Regulatory Procedures in EU. The Centralised Procedure Where the centralised procedure is used, companies submit one single marketing authorization application to the EMEA. A single evaluation is carried out through the Committee for Medicinal Products for Human Use (CHMP).

10. Ketek, FDA Hearing, Dec. 2006 ÖM Regulatory Procedures in EU. The Centralised Procedure (CP) If the Committee concludes that quality, safety and efficacy of the medicinal product is sufficiently proven, it adopts a positive opinion. The opinion is sent to the Commission to be transformed into a single market authorization valid for the whole of the European Union.

11. Ketek, FDA Hearing, Dec. 2006 ÖM Scope of Centralised Procedure Mandatory for medicinal products Developed by biotech processes New therapies for AIDS, cancer, neurodegenerative disorders, diabetes, and in May 08, for auto-immune diseases other auto-immune dysfunctions, viral diseases Orphans Optional Other new active substances Generics (eligibility & applications) ‘Biosimilar” products

12. Ketek, FDA Hearing, Dec. 2006 ÖM The Centralised procedure 1 Peer Review 1 MS

13. Ketek, FDA Hearing, Dec. 2006 ÖM The Centralised Procedure 2 Peer Review 1 MS

14. Ketek, FDA Hearing, Dec. 2006 ÖM Rapporteur’s Obligations Presubmission Phase –Organising assessment team Agency and/or External –Contact with applicant Assessment of MAA –Responsible for assessment according to timetable scientific quality coordination with co-rapporteur, rest of CHMP, WP, external expertise contact with applicant Post authorisation –Life-cycle perspective Variations, specific obligations/FUMs Periodic Safety Update Reports (PSURs), Risk Management Plans (RMP), reassessments, renewals, etc

15. Ketek, FDA Hearing, Dec. 2006 ÖM Ketek granted EU-MA June 2001 Indications Treatment (in patients of 18 years or older) –mild to moderate community-acquired pneumonia, –acute exacerbation of chronic bronchitis, –acute sinusitis, –and as an alternative to beta-lactams for tonsillitis / pharyngitis (in patients 12 years or older). The dose recommendation is two 400 mg tablets once daily for 5 to 10 days.

16. Ketek, FDA Hearing, Dec. 2006 ÖM Ketek – usage in the EU In total estimated 13 million courses (world wide estimate 27 million courses) France > 50 % Also extensive use in Italy, Germany, Spain and Greece

17. Ketek, FDA Hearing, Dec. 2006 ÖM Most important Variations (= Update of Product Information) March 2002 – interaction with rifampicin November 2002 – update of information regarding visual disturbances April 2003 – aggravation of Myasthenia gravis

18. Ketek, FDA Hearing, Dec. 2006 ÖM Variations of product information October 2003 – –ADR section updated with info concerning hepatic ADRs, anaphylactic reactions and visual disorders –Driving section updated with information concerning visual disorders which may impair the ability to drive

19. Ketek, FDA Hearing, Dec. 2006 ÖM Variations of product information November 2004 – monitoring of PT-INR while patients are receiving telithromycin and anticoagulants simulataneously July 2005 –transient loss of consciousness added to ADR section and accordingly also a driving warning was introduced

20. Ketek, FDA Hearing, Dec. 2006 ÖM Variations of product information February 2006 – warnings regarding severe hepatitis and liver failure which may occur with short latency and in most cases were reversible. Patient should be informed of signs and symptoms September 2006 – contraindication in patients with previous liver reactions during exposure to telithromycin + hepatic fatalities

21. Ketek, FDA Hearing, Dec. 2006 ÖM Assessment of hepatic safety January 2006 The PhVWP and the CHMP considered that: –characteristics of serious hepatic reactions were not well described in the product information –that the short latency to onset of these reactions was of concern in patients treated in primary care –an update of product information be requested

22. Ketek, FDA Hearing, Dec. 2006 ÖM Hepatic safety January 2006 contd. –further assessment of available data needed –a Risk Management Plan on hepatic safety be requested Accordingly, the product information was updated and a List of Question was sent to the MAH

23. Ketek, FDA Hearing, Dec. 2006 ÖM Assessment hepatic safety, May 2006. (Follow-up measure 26). Most of the available data on hepatic safety was considered consistent with the current labelling. No risk factors could be identified except a tendency for patients with CAP to be at higher risk of liver reactions

24. Ketek, FDA Hearing, Dec. 2006 ÖM Assessment hepatic safety, May 2006. The RMP was considered satisfactory and the presented protocol for an epi-study of severe hepatic events in the USA should be updated. The risk-benefit of Ketek was still considered favourable

25. Ketek, FDA Hearing, Dec. 2006 ÖM Assessment hepatic safety, May 2006. The assessment of available data on hepatic safety of Ketek in the EU member states was continued.

26. Ketek, FDA Hearing, Dec. 2006 ÖM Renewal of the Marketing Authorization The application for renewal of the MA was assessed in parallell with the re-assessment of the hepatic safety In June 2006, the CHMP considered the benefit-risk of Ketek continues to be favourable based on a review of the available information (quality, efficacy and safety).

27. Ketek, FDA Hearing, Dec. 2006 ÖM Renewal of the Marketing Authorization Considering the increased awareness of safety issues, especially the hepatic safety, the CHMP was of the opinion that one additional five-year renewal on the basis of pharmacovigilance ground was required. The MAH should continue to submit annual Periodic Safety Update Reports

28. Ketek, FDA Hearing, Dec. 2006 ÖM Assessment of cases of serious hepatic ADRs reported in the EU (September 2006). 49 cases reported in the EU, most of them in France and Germany. For 3 fatal cases (all from France) limited information was provided and/or there were other factors causing the hepatic reaction

29. Ketek, FDA Hearing, Dec. 2006 ÖM Assessment of cases of serious hepatic ADRs reported in the EU (September 2006) The reporting rate or serious hepatic reactions was estimated to be 4-10 cases per million courses These data were in line with the current product information and did not alter the conclusions drawn by the CHMP in June 2006.

30. Ketek, FDA Hearing, Dec. 2006 ÖM Assessment of cases of serious hepatic ADRs reported in the EU (September 2006) Taking global data into consideration, information regarding the occurrence of fatal hepatic reactions should be added to the product information. Further evaluation of the prescription and reporting of ADRs in the EU warranted. A full Risk Management Plan was requested (according to the new legislation)

31. Ketek, FDA Hearing, Dec. 2006 ÖM Additional regulatory measures in the EU The product information has been updated with regard to hepatic safety –contraindication in patients who have experienced a hepatic reaction during treatment with Ketek –add information that fatal hepatic reactions have been reported

32. Ketek, FDA Hearing, Dec. 2006 ÖM Summary Ketek was authorized in the EU > 5 years ago The Product Information has been updated with safety information regarding –risk of interactions –visual disturbances –risk of aggravation of myasthenia gravis, some fatal –risk of loss of consciousness –risk of serious hepatic reactions, some fatal

33. Ketek, FDA Hearing, Dec. 2006 ÖM Summary Re-assessment of the hepatic safety was made in parallell with the renewal of the MA The Marketing Authorization was renewed by the EU-commission in July 2006, based on the CHMP opinion. A second five-year renewal will take place.

34. Ketek, FDA Hearing, Dec. 2006 ÖM Summary Annual Periodic Safety Update Reports should be submitted, and several safety issues are closely monitored. A full Risk Management Plan has been requested (Submitted 13 December 2006) The use of Ketek in the EU is extensive and will be followed closely.