1. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 Ketek  (telithromycin) Regulatory History Janice Soreth, M.D. Director Division of Anti-Infective & Ophthalmology Products CDER/FDA Janice Soreth, M.D. Director Division of Anti-Infective & Ophthalmology Products CDER/FDA

2. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 2 Ketek Regulatory History: Outline US Submissions: 1998-2004 –3 Review Cycles Two Advisory Committees: –April, 2001; January, 2003 Division of Scientific Investigation Reports Efficacy & Safety Data US Submissions: 1998-2004 –3 Review Cycles Two Advisory Committees: –April, 2001; January, 2003 Division of Scientific Investigation Reports Efficacy & Safety Data

3. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 3 Ketek Regulatory History: First Cycle 1998-2001 1998: clinical trials for phase 3 program discussed with FDA community-acquired pneumonia, acute bacterial sinusitis, acute exacerbation of chronic bronchitis, tonsillopharyngitis FDA advice to sponsor on specific trial design based upon then current (1998) updated guidance 2000: NDA 21-144 filed 2001: Advisory Committee held 1998: clinical trials for phase 3 program discussed with FDA community-acquired pneumonia, acute bacterial sinusitis, acute exacerbation of chronic bronchitis, tonsillopharyngitis FDA advice to sponsor on specific trial design based upon then current (1998) updated guidance 2000: NDA 21-144 filed 2001: Advisory Committee held

4. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 4 Ketek Regulatory History: First Cycle At April 2001 Advisory Committee, four indications were discussed: –community-acquired pneumonia* –acute exacerbations of chronic bronchitis* –acute sinusitis* –tonsillopharyngitis * including penicillin- and erythromycin-resistant Streptococcus pneumoniae At April 2001 Advisory Committee, four indications were discussed: –community-acquired pneumonia* –acute exacerbations of chronic bronchitis* –acute sinusitis* –tonsillopharyngitis * including penicillin- and erythromycin-resistant Streptococcus pneumoniae

5. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 5 Ketek Regulatory History: First Cycle April 2001 Advisory: Phase III Clinical Database by Type of Study and Indication

6. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 6 Ketek Regulatory History: First Cycle Phase 3 Safety Data

7. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 7 Ketek- April 2001 Advisory Committee Meeting Focus on safety data FDA’s efficacy analyses consistent with those of the sponsor for pneumonia, AECB, and acute bacterial sinusitis Study in tonsillitis/pharyngitis did not meet pre-specified endpoint Advisory Committee in 2001 did not take issue with efficacy data derived from non- inferiority trials Focus on safety data FDA’s efficacy analyses consistent with those of the sponsor for pneumonia, AECB, and acute bacterial sinusitis Study in tonsillitis/pharyngitis did not meet pre-specified endpoint Advisory Committee in 2001 did not take issue with efficacy data derived from non- inferiority trials

8. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 8 Ketek - April 2001 Advisory Committee Meeting Chief safety concerns: Cardiac Hepatic Visual Chief safety concerns: Cardiac Hepatic Visual

9. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 9 Ketek- April 2001 Advisory Committee Vote Do the efficacy and safety data presented support the use of Ketek in –community-acquired pneumonia7 yes 3 no –AECB0 yes 10 no –acute bacterial sinusitis2 yes 8 no Are the data sufficient for a claim of pneumonia due to pen-resistant S. pneumoniae? 3 yes 7 no Do the efficacy and safety data presented support the use of Ketek in –community-acquired pneumonia7 yes 3 no –AECB0 yes 10 no –acute bacterial sinusitis2 yes 8 no Are the data sufficient for a claim of pneumonia due to pen-resistant S. pneumoniae? 3 yes 7 no

10. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 10 Ketek - April 2001 Advisory Committee Vote Recommendations for additional Ketek studies: Safety –Larger number of patients need to be studied to determine safety –Special populations should be targeted (elderly, patients with hepatic impairment, renal impairment); more PK –Drug interactions should be evaluated Efficacy –More data requested in patients with drug- resistant S. pneumoniae (including bacteremia), H. influenzae Recommendations for additional Ketek studies: Safety –Larger number of patients need to be studied to determine safety –Special populations should be targeted (elderly, patients with hepatic impairment, renal impairment); more PK –Drug interactions should be evaluated Efficacy –More data requested in patients with drug- resistant S. pneumoniae (including bacteremia), H. influenzae

11. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 11 Ketek Regulatory History: First Cycle Approvable Letter June 2001 Ketek Regulatory History: First Cycle Approvable Letter June 2001 Ketek approvable for pneumonia, bronchitis, and sinusitis. Additional safety and efficacy data requested to assess risks/benefits –large safety trial in respiratory tract infections –PK studies, special populations –additional experience with drug-resistant S. pneumoniae, H. influenzae, bacteremia Ketek approvable for pneumonia, bronchitis, and sinusitis. Additional safety and efficacy data requested to assess risks/benefits –large safety trial in respiratory tract infections –PK studies, special populations –additional experience with drug-resistant S. pneumoniae, H. influenzae, bacteremia

12. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 12 Ketek Regulatory History: Second Cycle July 24, 2002- resubmission included Study 3014 (24,000 patients, 1800 investigators), data from additional efficacy studies (CAP, AECB), PK studies, and some postmarketing data January 8, 2003: second Advisory meeting July 24, 2002- resubmission included Study 3014 (24,000 patients, 1800 investigators), data from additional efficacy studies (CAP, AECB), PK studies, and some postmarketing data January 8, 2003: second Advisory meeting

13. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 13 Ketek Regulatory History: Second Cycle January 8, 2003 Advisory Additional efficacy and safety data discussed: focus on study 3014, in addition to PK studies and community-acquired pneumonia targeting resistant S. pneumoniae Advisory Committee judged that safety and efficacy for the 3 requested indications had been demonstrated, in large measure on the safety data in study 3014 DSI report of January 21, 2003: 3 clinical sites in study 3014 inspected; concerns raised about data integrity. Additional efficacy and safety data discussed: focus on study 3014, in addition to PK studies and community-acquired pneumonia targeting resistant S. pneumoniae Advisory Committee judged that safety and efficacy for the 3 requested indications had been demonstrated, in large measure on the safety data in study 3014 DSI report of January 21, 2003: 3 clinical sites in study 3014 inspected; concerns raised about data integrity.

14. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 14 Ketek Regulatory History: Second Cycle Approvable Letter Jan 23, 2003 Safety could not be fully assessed –questions of data integrity raised by the conduct of study 3014 –incomplete postmarketing safety data submitted from foreign marketing experience Requested additional information –on auditing, monitoring, and irregularities or violations of Good Clinical Practices in order to further evaluate data integrity in study 3014 –complete reports (original and follow-up) and analyses of foreign postmarketing safety information Safety could not be fully assessed –questions of data integrity raised by the conduct of study 3014 –incomplete postmarketing safety data submitted from foreign marketing experience Requested additional information –on auditing, monitoring, and irregularities or violations of Good Clinical Practices in order to further evaluate data integrity in study 3014 –complete reports (original and follow-up) and analyses of foreign postmarketing safety information

15. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 15 Ketek Regulatory History: Third Cycle CDER Regulatory Briefing February 19, 2003 “Issues of data integrity with Study 3014 are of concern and should be resolved before an approval action (if warranted) can be taken. Additional sites should be identified for future DSI inspections. If data provided by study 3014 cannot be used to support safety of Ketek, the Division might be able to rely on post-marketing data from those countries where Ketek has already been approved.” “Issues of data integrity with Study 3014 are of concern and should be resolved before an approval action (if warranted) can be taken. Additional sites should be identified for future DSI inspections. If data provided by study 3014 cannot be used to support safety of Ketek, the Division might be able to rely on post-marketing data from those countries where Ketek has already been approved.”

16. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 16 Ketek Regulatory History: Third Cycle March 6, 2003 Closed Advisory Meeting Closed AC meeting held to update the Anti-infective Advisory Committee on other development programs in the division. Committee was apprised of data integrity issues concerning study 3014 that precluded approval action. Closed AC meeting held to update the Anti-infective Advisory Committee on other development programs in the division. Committee was apprised of data integrity issues concerning study 3014 that precluded approval action.

17. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 17 Ketek Regulatory History: Third Cycle October 2003: Sponsor submitted analyses of foreign postmarketing data. Additional DSI inspections requested to provide an overall assessment of data integrity in study 3014. March 2004 DSI findings: Monitoring of study sites by sponsor failed to detect problems found by FDA inspections. Hence, integrity of data from all 1800 sites could not be assured with any degree of confidence. October 2003: Sponsor submitted analyses of foreign postmarketing data. Additional DSI inspections requested to provide an overall assessment of data integrity in study 3014. March 2004 DSI findings: Monitoring of study sites by sponsor failed to detect problems found by FDA inspections. Hence, integrity of data from all 1800 sites could not be assured with any degree of confidence.

18. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 18 Ketek Regulatory History: Third Cycle Clinical Review Summary Safety information included post-marketing adverse event reports generated from an estimated 3.7 million uses in foreign countries (2.2 million in France and Germany). All available safety data led to conclusion that Ketek appeared similar to other antibiotics in terms of hepatic and cardiac toxicity. Life-threatening exacerbation of myasthenia gravis noted in foreign use. Review of all available safety data supported approval of Ketek in April, 2004. Clinical Review Summary Safety information included post-marketing adverse event reports generated from an estimated 3.7 million uses in foreign countries (2.2 million in France and Germany). All available safety data led to conclusion that Ketek appeared similar to other antibiotics in terms of hepatic and cardiac toxicity. Life-threatening exacerbation of myasthenia gravis noted in foreign use. Review of all available safety data supported approval of Ketek in April, 2004.

19. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 19 Ketek Regulatory History: Approval April 1, 2004 The data that provided substantial evidence of safety and efficacy for Ketek (telithromycin) at the time approval included: –Multiple comparative studies of community- acquired pneumonia (CAP), acute bacterial sinusitis (ABS), acute exacerbation of chronic bronchitis (AECB): –These comparative studies were the basis for efficacy claims in CAP, ABS, and AECB. The studies also served as the basis for safety claims, providing information on the rates of adverse effects seen with Ketek compared to other antibiotics used for these indications. The data that provided substantial evidence of safety and efficacy for Ketek (telithromycin) at the time approval included: –Multiple comparative studies of community- acquired pneumonia (CAP), acute bacterial sinusitis (ABS), acute exacerbation of chronic bronchitis (AECB): –These comparative studies were the basis for efficacy claims in CAP, ABS, and AECB. The studies also served as the basis for safety claims, providing information on the rates of adverse effects seen with Ketek compared to other antibiotics used for these indications.

20. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 20 Ketek Regulatory History: Approval April 1, 2004 (continued) –Non-comparative studies of CAP with Ketek: In addition to the comparative CAP studies, these studies of CAP provided additional data on outcomes in patients with CAP due to multi- drug resistant Streptococcus pneumoniae. –These non-comparative studies also provide safety data on the use of Ketek in the treatment of CAP. –Non-comparative studies of CAP with Ketek: In addition to the comparative CAP studies, these studies of CAP provided additional data on outcomes in patients with CAP due to multi- drug resistant Streptococcus pneumoniae. –These non-comparative studies also provide safety data on the use of Ketek in the treatment of CAP.

21. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 21 Ketek Regulatory History: Approval April 1, 2004 (continued) –Phase 1 Visual study: This study of high- doses of telithromycin was performed to study the mechanism of the visual effects of Ketek. –Multiple other phase 1 studies evaluating the pharmacokinetics of Ketek. These studies included food effect studies, drug interaction studies, QT prolongation, and studies of the pharmacokinetics of Ketek in patients with renal or hepatic impairment. –Phase 1 Visual study: This study of high- doses of telithromycin was performed to study the mechanism of the visual effects of Ketek. –Multiple other phase 1 studies evaluating the pharmacokinetics of Ketek. These studies included food effect studies, drug interaction studies, QT prolongation, and studies of the pharmacokinetics of Ketek in patients with renal or hepatic impairment.

22. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 22 Ketek Regulatory History: Approval April 1, 2004 (continued) Foreign post-marketing data in 3.7 million exposures were evaluated as part of the assessment of safety to identify uncommon serious adverse effects of Ketek (hepatic, visual, cardiac) based upon post-marketing reports from France, Germany, other European countries, and Latin America where Ketek was already approved.

23. Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees December 14-15, 2006 23 ReturnReturn Return to agenda Return to agenda