Summary of Considerations: Assessing the Overall Risks and Benefits of Telithromycin (Ketek®)

1. Summary of Considerations: Assessing the Overall Risks and Benefits of Telithromycin (Ketek®) FDA Anti-Infective Drugs Advisory Committee December 14-15, 2006 Rosemary Johann-Liang, MD Deputy Director Division of Drug Risk Evaluation Office of Surveillance and Epidemiology

2. Re-assessment of Ketek: Evaluation of Evidence • Based upon the evidence, does the benefit outweigh the risk (harm) in the year 2006 for each of the three currently approved indications • Acute Exacerbation of Chronic Bronchitis (AECB) • Acute Bacterial Sinusitis (ABS) • Mild to Moderate Community Acquired Pneumonia (Outpatient CAP) • Approvals of indications are based on diseases, not organisms

3. Safety Assessment Analysis of Harm from medical intervention “totality of Evidence” Efficacy Assessment Analysis of Benefit from medical intervention “Substantial Evidence” Evaluation of Evidence

4. Ketek Risk Summary: Totality of Evidence Ketek Risk in Perspective Antibiotic use data Other antibiotics for similar indications Outpatient (oral only) Use Antibiotics Cumulative exposure/Approval dates: safety track record Toxicity Profiles of Appropriate Antibiotic Comparators Ketek Benefit in Perspective Non-inferiority Trial design: Evidence of Benefit?? Ketek Efficacy Summary: Substantial Evidence?? AECB ABS Outpatient CAP Ketek Risk to Benefit

5. Ketek Risk Summary • Risks Highlighted in OSE presentations • Hepatotoxicity • Visual toxicity • Loss of consciousness • Exacerbation of myasthenia gravis (MG) • Currently labeled under Warnings/Precautions • Clinical Characteristics of Ketek Toxicity • Cannot Mitigate Risk • Must define population that would benefit from drug that justifies the risks

6. Reporting Rates by million person-yrs: “Rapid” Hepatotoxicity(Graham D. NEJM 355; 21: 2260-61 with additional analyses by DG)

7. Rapid Clinical Toxicity Manifestation • Vision Disorders • Of those reporting, more than half of the cases: first day of therapy within an hour or two of the dose • Disturbances of Consciousness • Of those reporting, over 70% with onset within first day of therapy with majority within 2 hours • Exacerbation of MG • 70% of cases with onset occurring after the first dose with median time of 1.25 hours.

8. Top 10 ICD-9 3-digit Diagnosis Codes Associated with U.S. Drug Uses for Oral Antimicrobials Year 2005 Source: Verispan, LLC Physician Drug and Diagnosis Audit (PDDA). Data extracted 8/23/2006. Review by Carol Pamer, RPh

9. Total Dispensed US Retail Prescriptions for Oral Antimicrobials Year 2005 Source: Verispan, LLC Vector One: National (VONA). Data extracted 8/23/2006.Review by Carol Pamer, RPh

10. Ketek: Risk in Perspective

11. Β-lactams Anaphylaxis/Hypersensitivity Pseudomembranous colitis Hepatic toxicity (Augmentin®) Macrolides Pseudomembranous colitis Hepatic dysfunction (increased liver enzymes, hepatocellular and/or cholestatic hepatitis) Drug interactions resulting in QT prolongation, ventricular arrythmias, and torsades de pointes erythromycin Inadequate concentrations to fetus to prevent congenital syphilis Rhabdomyolysis with or without renal impairment with lovastatin myasthenia gravis aggravation Infantile hypertrophic pyloric stenosis (IHPS) azithromycin Rare serious allergic reaction clarithromycin Do not use in pregnant woman - adverse effects in animal pregnancy Fluoroquinolones Peds safety and efficacy not established (except Cipro) Convulsions and toxic psychoses Hypersensitivity/anaphylactic reactions Peripheral neuropathy Pseudomembranous colitis Tendonopathy Moderate to severe phototoxicity Dysglycemia Torsades de pointes -------------------------------------- Levofloxacin and Moxifloxacin are also approved for more “serious indications” and have IV dosage form Gemifloxacin: precaution on ↑ rash Selected Highlights of Risk: Labeling: Warning/Precautions

12. Cumulative US Exposures 1/1995 – 6/2006:Oral Antimicrobial Molecules Source: Verispan, LLC Vector One®: National (VONA). Data extracted 8/23/2006.

13. Approved Indications/Dosage Forms (Modified from Farinas E. Appendix Table: Factive® AERS Review 9/06)

14. Most Appropriate Comparisons • Cefditoren • Safety Profile does not appear to stand out from class: cephalosporins • Gemifloxacin • Safety Profile like other FQ: ↑ cutaneous reactions • FDA Advisory Meeting 9/06 for ABS: Vote 11-2; no evidence of efficacy, risk not justified; sNDA withdrawn • Telithromycin • Safety Profile like other macrolides: special senses, liver, QT? • UNIQUE and Notable toxicities

15. Hepatotoxicity Drug-injury Rapid Clinical deterioration Exacerbation of MG Drug-injury Rapid clinical deterioration Visual toxicity Seen in clinical trials; Drug-induced Sudden blurry vision Loss of consciousness Not just syncope; Mechanism unknown Umbrella of issues: neurological? cardiac? Sudden loss Rapid/Sudden Clinical Toxicity Manifestations Cannot mitigate risk Must define population to benefit from drug that justifies the risks Ketek Risk in Perspective

16. Safety Assessment Analysis of Harm from medical intervention “totality of Evidence” Efficacy Assessment Analysis of Benefit from medical intervention “Substantial Evidence” Evaluation of Evidence

17. Efficacy: Substantial Evidence • FDA published regulations on criteria that define “substantial evidence” in 1970 • U.S. district court finds that Congress intended specific definition of substantial evidence and did not mean it to be opinion based • Pharmaceutical Manufacturers of America v. Richardson, 1970 • For medical interventions “substantial evidence” means data from “adequate and well controlled trials”, not individual interpretations. • Substantial evidence requirement applies to both serious and life threatening diseases as well as less serious diseases.

18. “Adequate and Well-Controlled” • Clear statement of objectives • Study design permits valid quantitative comparison with a control • Select patients with disease (treatment) or at risk of disease (prevention) • Baseline comparability (randomization) • Minimize bias (blinding, etc.) • Appropriate methods of assessment of outcomes • Appropriate methods of analysis • 21 CFR 314.126

19. Quantitation of Control • Clinical trials compare outcomes with drug to what would have occurred without drug. Cannot know for sure outcomes without drug so concurrent controls used for comparison – usually placebo-control used. • For Active-Controlled Trials - Quantitativeassessment • reliable and reproducible (based on trials that are themselves adequate and well controlled) of benefit of control over placebo, and • suitably conservative margin based on examination of confidence intervals • Non-inferiority (NI) trials: Inferior to Control “no-worse-than” by a certain suitable margin. SELECTION OF CONTROL “must be clearly established and quantifiedin well-designed and well-documented superiority trials and which can be reliably expected to have similar efficacy in the contemplated active controlled trial.” ICH E-9, Statistical Principles for Clinical Trials

20. Problems: Quantitation of Control • Active-controlled clinical trials with non-inferiority (“no –worse than control by a certain margin”) design does not assure benefit of test drug over placebo in diseases with high spontaneous cure rates. • Infectious diseases such as ABS and AECB are such types of diseases. • There is no concurrent negative control; thus, well-established and reliable data from previous placebo-controlled trials are needed to establish a quantifiable margin of benefit (a historical negative control).

21. placebo Non-Inferiority MarginsDetermining the Effect of a Test Drug control 100 control test 80 success rates 0 past trials current trial Powers J. AIDAC 9/06

22. Ketek: AECB and ABS clinical trials data: all NI setting(DAIOP Briefing Package; December 2006)

23. Placebo?? Ketek®: Lack of Substantial EvidenceAECB and ABS Indications test control 100 control 80 success rates 0 past trials current trial

24. Analysis of Placebo Controlled Trials in Acute Exacerbations of Chronic Bronchitis no significant difference in time to resolution of symptoms p = 0.20 oxytetracycline Elmes et al. 1957 n=88 no significant difference in time to resolution of symptoms p = 0.30 oxytetracycline d12 Fear et al. 1962 n=62 no significant difference in investigator clinical assessment of matched pairs ampicillin d7 Elmes et al. 1965 n= 56 no significant difference in mean change in Pa O2 between groups tetracycline d7 Nicotra et al. 1982 n=40 chloramphenicol d 10 Petersen et al 1967 n=19 amoxicillin d8 Jorgensen et al. 1992 n=278 amoxicillin or TMP-SMX d14 Sachs et al. 1995 n=71 oxytetracycline d14 Berry et al 1960 n=53 cefaclor d8 Manresa et al. 1987 n=19 (not randomized) TMP-SMX or doxycycline d21 Anthonisen et al. 1987a n = 116 (crossover) (first exacerbation only) ofloxacin d30 Nouira et al. 2001 n=93 penicillin +streptomycin d14 Pines et al. 1968 n=30 tetracycline or chloramphenicol d7 Pines et al.1972 n=259 amoxicillin-clavulanate d5 Allegra et al 1991 n=335 0 +50 +40 +30 +20 +10 -30 -40 -50 -10 -20 Favors study drug Favors placebo Powers J. ICAAC 2005

25. AECB: NI Regulatory Timeline • February 2002: AIDAC on non-inferiority margins for Antibiotics to treat infectious diseases ( e.g. AECB) • November 2002: IDSA/PhRma/FDA Working Group Meeting • January 2003: AIDAC on Ketek (telithromycin) • April 2003: Factive (gemifloxacin) NDA approval for AECB, Mild to moderate Community-acquired pneumonia (CAP) • April 2004: Ketek (telithromycin) NDA approval for AECB, ABS, Mild to moderate CAP • April 2004: FDA/IDSA/ISAIP Working Group (AECB) • July 2005: Regulatory Briefing on AECB

26. July 2005 FDA Regulatory Briefing(minutes) • Is there a scientific basis for continuing to base approvals for AECB/AECOPD on non-inferiority trials? • Regulatory Briefing Panel: “Based on current data, the panel believed there is NOT a scientific basis for non-inferiority trials in Acute Exacerbations of Chronic Bronchitisgiven both the lack of historical evidence of sensitivity to drug effects and issues with defining both the disease and lack of appropriate clinical outcome measures. Trials should be done as superiority trial designs. The panel asked about other disease indication where these issues with non-inferiority trials have arisen, and the discussion included trials in acute otitis media and acute bacterial sinusitis, where these same issues apply”.

27. July 2005 FDA Regulatory Briefing(minutes) • Are there precedents where superiority trials were successfully performed when there is reported resistance by sponsors of clinicians to performing these trials? How were these trials moved forward? • Regulatory Briefing Panel: “During the late 1990s, … the Director of Anesthetics, Critical Care and Addiction Drug Products, encountered years of significant resistance from industry before sponsors finally agreed to switch from conducting non-inferiority clinical trials to placebo- and active controlled studies in situations where sponsors submitted formulation changes of existing opiate products. It is important to note that when such trials were undertaken, it was discovered that some of the products did not prove to be more effective than placebo, substantiating the concerns regarding non-inferiority trials. The Panel emphasized that as science changes the standards for regulatory approval also must change to reflect what we have learned. In this case (AECB), the data point to the lack of information upon which to base non-inferiority trials.”

28. Analysis of Efficacy in Placebo Controlled Trials in Acute Bacterial Sinusitis cefuroxime d14 Kristo et al. 2005 n=82 pivampicillin d8 Norrelund et al. 1978 1978 n=135 doxycycline d10 Stalman et al. 1997 n=186 amox or amoxicillin-clav d14 Garbutt et al. 2001 n=161 Lindbaek et al. 1998 n=70 amoxicillin or penicillin d10 amoxicillin-clavulanate d14 Bucher et al. 2003 n=251 amoxicillin d14 Merenstein et al. 2005 n=135 amoxicillin d14 van Buchem et al. 1997 n=206 amoxicillin d10 deSutter et al. 2003 n=135 pencillin or lincomycin d10 Axelsson et al. 1970 n=142 amox or doxy or penicillin d 14 Varonen et al.2003 n=146 amoxicillin or amox-clav d10 Wald et al. 1986 n=93 azithromycin d8 b Kaiser et al. 2001 n=265a (77)b a penicillin d7 Hansen et al. 2000 n=127 azithromycin d14 Haye et al. 1998 n=168 amoxicillin or penicillin d10 Lindbaek et al. 1996 n=127 cyclacillin (not specified) Ganaca et al. 1973 n=50 0 50 40 30 20 10 30 40 50 10 20 Favors study drug Favors placebo Powers J. AIDAC 9/2006

29. ABS: NI Regulatory Timeline • November 2002: IDSA/PhRma/FDA Working Group Meeting • January 2003: AIDAC on Ketek (telithromycin) • October 2003: AIDAC on ABS • January 2004: sNDA approval for azithromycin for 3 days • April 2004: telithromycin NDA approval for AECB, ABS, Mild/moderate CAP • July 2005: Regulatory Briefing on AECB • August 2005: Levaquin (levofloxacin) for 5 days for ABS • September 2006: AIDAC on Factive and ABS Do the safety and effectiveness data presented demonstrate an acceptable risk/benefit profile of Factive® (gemifloxacin mesylate) for the 5-day treatment of patients with acute bacterial sinusitis? No:11, Yes: 2

30. Efficacy of Ketek • All clinical trials leading up to approval of Ketek for ABS, AECB and CAP were non-inferiority trials with >10% non-inferiority margins. Response rates in the 80% range with spread, similar for both Ketek and controls. • So the questions are for AECB and ABS • Has substantial evidence of drug efficacy via “adequate and well-controlled studies” standard been shown when the drug has been assessed exclusively in non-inferiority setting? • Did these non-inferiority trials provide substantial evidence that the use of Ketek added any benefit over and above the natural history of the disease? • Superiority trial designs have been recommended by members of this committee three months ago (at the Factive® FDA Advisory on ABS) in order to PROVE with substantial evidence that taking the drug benefits the patient and therefore is worth the risk of adverse reactions.

31. Ketek CAP considerations • Original benefit shown for pneumonia with “severe” disease with endpoint of mortality. Ketek is indicated for mild-moderate (Outpatient – treatment) pneumonia only, so the margin of benefit is less clear. However, this disease is less spontaneously resolving, so there is still probably a preservation of efficacy margin for study in non-inferiority setting. • Issue of Resistance: Ketek’s claim is for treating “resistant pathogens” , particularly “macrolide resistance”. This implies that Ketek is superior to older drugs which are ineffective against “resistant pathogens”. YET, all trials were performed as non-inferiority trials (no-worse-than-to-older drug). • Medical Need: Demonstration of evidence that Ketek is superior to older drug if Ketek is better for resistant pathogens. Active-controlled Trials demonstrating SUPERIORITY to older drugs Example: Demonstrate that CAP patients with macrolide- resistant organisms have BETTER clinical outcome than patients treated with other macrolides.

32. “Activity” not same as “Efficacy” • Pre-clinical in vitro and animal data provide hypotheses upon which clinical trials of antimicrobials based • In vitro activity and animal models alone do not define substantial evidence • “Recent studies that have assessed the impact of β-lactam and macrolide resistance on clinical outcomes in CAP fail to provide incontrovertible evidence for a direct link between in vitro resistance and treatment failure” Rothermel C. CID 2004:38 S346-49 “….. A couple people on the panel have made the comment …that ..so regardless of what the clinical trials have shown, that in vitro data are convincing enough that they feel comfortable that this drug would be efficacious for the treatment of acute bacterial sinusitis. I just want to say I m pretty uncomfortable with that approach. If all we need are in vitro data, there’s really not much point in doing clinical trials, at least for efficacy. ….Gregory Townsend, MD, AIDAC 9/06

33. Risk to Benefit Ratio: CAP • Hard to quantify with exact numbers for outpatient CAP treatment with Ketek • Superiority trials, using an active control (an older antibiotic) are needed to clinically demonstrate that patients ill with resistant pathogens and being treated with Ketek have better outcome those treated with comparator drug. • Can Risk be managed? “Sudden” and “Rapid” nature of clinical toxicity manifestation makes risk mitigation difficult. • Clear Risk communication to the patient • Clear Risk communication to the prescriber

34. Risk: “Totality of Evidence” Hepatotoxicity Exacerbation of MG Visual toxicity Loss of consciousness Rapid/Sudden Clinical Toxicity Manifestations Cannot mitigate risk Must define population to benefit from drug that justifies the risks Benefit: “Substantial Evidence” Based on non-inferiority trials without quantification of control for the indications of AECB and ABS. Uncertain as to drug effect over and above the natural history of disease resolution For CAP: Drug effect over and above the natural history of disease resolution Still need demonstration of clinical outcome superiority over older drugs for disease caused by “resistant” organisms Risk to Benefit Ratio

35. Acknowledgements Does Ketek’s Benefit Outweigh the Risks for each of the indications?? • Carol Pamer, R Ph • Jenna Lyndly, RN • Melissa Truffa, R Ph • David Graham, MD MPH • Evelyn Farinas, R Ph MS • John H. Powers, MD • Gerald DalPan, MD, MHS

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