Joint Meeting of Anti-Infective Drugs & Joint Meeting of Anti-Infective Drugs & Drug Safety and Risk Management Advisory Committees Drug Safety and Risk Management Advisory Committees December 14-15, 2006 December 14-15, 2006 Ketek Ketek (telithromycin) (telithromycin) Regulatory History Regulatory History Janice Soreth, M.D. Director Division of Anti-Infective & Ophthalmology Products CDER/FDA
Ketek (telithromycin) Regulatory History. Janice Soreth, M.D. Director Division of Anti-Infective & Ophthalmology Products CDER/FDA. Ketek Regulatory History: Outline. US Submissions: 1998-2004 3 Review Cycles Two Advisory Committees: April, 2001; January, 2003 - PowerPoint PPT Presentation
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Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
KetekKetek (telithromycin) (telithromycin) Regulatory History Regulatory History
Janice Soreth, M.D.Director
Division of Anti-Infective & Ophthalmology ProductsCDER/FDA
2Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
• 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
13Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
• 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.
14Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
Ketek Regulatory History:Ketek Regulatory History:Second Cycle Second Cycle
Approvable Letter Jan 23, 2003Approvable 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
15Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
CDER Regulatory Briefing February 19, 2003CDER 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.”
16Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
• 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.
18Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
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.
19Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
Ketek Regulatory History:Ketek Regulatory History:Approval April 1, 2004Approval 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.
20Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
Ketek Regulatory History:Ketek Regulatory History:Approval April 1, 2004 (continued)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.
21Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
Ketek Regulatory History:Ketek Regulatory History:Approval April 1, 2004 (continued)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.
22Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006
Ketek Regulatory History:Ketek Regulatory History:Approval April 1, 2004 (continued)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.
23Joint Meeting of Anti-Infective Drugs &Joint Meeting of Anti-Infective Drugs &Drug Safety and Risk Management Advisory CommitteesDrug Safety and Risk Management Advisory CommitteesDecember 14-15, 2006December 14-15, 2006