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

Ketek Regulatory History:Ketek Regulatory History:OutlineOutline

• US Submissions: 1998-2004– 3 Review Cycles

• Two Advisory Committees:– April, 2001; January, 2003

• Division of Scientific Investigation Reports• Efficacy & Safety Data

3Joint 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: First Cycle 1998-2001First 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

4Joint 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: First CycleFirst 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

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Ketek Regulatory History: Ketek Regulatory History: First CycleFirst Cycle

April 2001 Advisory: Phase III Clinical Database by Type of Study and Indication

3 Controlled3 Uncontrolled

CAP

2 Controlled

AECB

2 Controlled1 Uncontrolled

ABS

2 Controlled

G ABHS T/P

1 3 P h a se III C lin ica l S tu d ies

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Ketek Regulatory History: Ketek Regulatory History: First CycleFirst Cycle

Controlled (9 tria ls)2045 Ketek

1672 Com parator

Uncontrolled (4 trials)1220 Ketek

Post-baseline safety follow -up4937 pts (Ketek + com parator)

3265 Ketek1672 Com parator

Random ized/treated4985 pts (Ketek + com parator)

Phase 3 Safety Data

7Joint 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- April 2001 Advisory Ketek- April 2001 Advisory Committee MeetingCommittee 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

8Joint 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 - April 2001 Advisory Ketek - April 2001 Advisory Committee MeetingCommittee Meeting

Chief safety concerns:

• Cardiac• Hepatic• Visual

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Ketek- April 2001 Ketek- April 2001 Advisory Committee VoteAdvisory Committee Vote

• Do the efficacy and safety data presented support the use of Ketek in – community-acquired pneumonia 7 yes 3

no– AECB 0 yes 10

no– acute bacterial sinusitis 2 yes 8 no

• Are the data sufficient for a claim of pneumonia due to pen-resistant S. pneumoniae? 3 yes 7 no

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Ketek - April 2001 Ketek - April 2001 Advisory Committee VoteAdvisory 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

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Ketek Regulatory History: Ketek Regulatory History: First Cycle First Cycle

Approvable Letter June 2001 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

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Ketek Regulatory History:Ketek Regulatory History:Second CycleSecond 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

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Ketek Regulatory History:Ketek Regulatory History:Second CycleSecond Cycle

January 8, 2003 AdvisoryJanuary 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.

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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

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Ketek Regulatory History:Ketek Regulatory History:Third CycleThird Cycle

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.”

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Ketek Regulatory History:Ketek Regulatory History:Third CycleThird Cycle

March 6, 2003 Closed Advisory MeetingMarch 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.

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Ketek Regulatory History:Ketek Regulatory History:Third CycleThird 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.

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Ketek Regulatory History:Ketek Regulatory History:Third CycleThird 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.

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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.

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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.

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