Anti-Infective Drug Products and Drug Safety and Risk Management Advisory Committees Meeting

1. Anti-Infective Drug Products and Drug Safety and Risk ManagementAdvisory Committees Meeting December 14 & 15, 2006 Edward Cox, MD MPH Acting Director, Office of Antimicrobial Products OND/CDER/ FDA

2. Welcome • Welcome • Topic for discussion • NDA 21-144 Ketek® (telithromycin) Tablets • Overall benefits and risks based upon what we know today • Information in the original NDA & the additional information that we have since the drugs was approved in April 2004 • Primary purpose of the meeting • To seek the Advisory Committee’s advice on the overall assessment of risks and benefits of Ketek for each of its approved indications based upon what we know today

3. Ketek (telithromycin) • Complex NDA Review • Spanned 3 review cycles • March 2000 to April 2004 • 2 Previous FDA Anti-Infective Drug Product Advisory Committees • April 2001 & January 2003 • Ketek (telithromycin) Tablets - Approved in April 2004

4. Ketek Indications INDICATIONS AND USAGE KETEK tablets are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below for patients 18 years old and above. Acute bacterial exacerbation of chronic bronchitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. Acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, or Staphylococcus aureus. Community-acquired pneumonia (of mild to moderate severity) due to Streptococcus pneumoniae, (including multi-drug resistant isolates [MDRSP*]), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae.

5. Other Drugs with Similar Indications • Acute bacterial sinusitis • amoxicillin, amoxicillin/clavulanate • cefdinir, cefpodoxime proxetil, cefprozil, cefuroxime axetil, loracarbef, • azithromycin, clarithromycin • ciprofloxacin, levofloxacin, moxifloxacin • Acute bacterial exacerbation of chronic bronchitis • cefaclor, cefdinir, cefditoren pivoxil, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, loracarbef • azithromycin, clarithromycin, dirithromycin • gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin • trimethoprim/sulfamethoxazole • Community-acquired pneumonia • amoxicillin/clavulanate • cefdinir, cefditoren pivoxil, cefpodoxime proxetil, loracarbef, • azithromycin, clarithromycin, dirithromycin • gemifloxacin, levofloxacin, moxifloxacin • linezolid • Lower respiratory tract infections(past indication - AECB & CAP) • amoxicillin, amoxicillin/clavulanate ─ erythromycin • cefaclor ─ ciprofloxacin

6. Other Drugs with“Older” Related Indications • Amoxicillin • Infections of the ear, nose, and throat due to Streptococcus spp. (alpha and beta hemolytic strains only), Streptococcus pneumoniae, Staphyloccocus spp., or H. influenzae • Ampicillin • Infections of the respiratory tract: non-penicillinase producing H. influenzae and staphylococci, and streptococci including Streptococcus pneumoniae • Tetracycline & Doxycycline • Respiratory tract infections caused by M. pneumoniae • Respiratory tract infections caused by H. influenzae and Klebsiella spp.(when susceptibility testing indicates appropriate) • Upper Respiratory tract infections caused by S. pneumoniae (formerly Diplococcus pneumoniae)(when susceptibility testing indicates appropriate)

7. Demonstrating Efficacy – Historical Perspective - 1 • The science of clinical trial design has advanced over time • 1938 Federal Food, Drug and Cosmetic (FD&C) Act - Pre-clearance of drugs for safety & Pre-market notification • did not include evaluation of efficacy • 1962 Kefauver Harris Amendments added a requirement that drugs be shown to be effective • Required a positive act of approval before a new drug could be marketed • Required that the FDA review all drugs approved since 1938 for effectiveness • Efficacy of earlier antibiotics approved from 1938 -1962 were evaluated as part of the Drug Efficacy Study Implementation (DESI) review

8. Demonstrating Efficacy – Historical Perspective - 2 • Post 1962- Efficacy studies that enrolled patients with any of a variety of different infections in the same study • 1992 Points to Consider and 1992 IDSA/FDA guidelines in Clinical Infectious Diseases 1992 -- Indication specific trials, including active controlled studies designed to equivalence or superiority • 1998 Draft Guidances – similar or superior effectiveness to an approved product in indication specific trials • More recently, questions on the ability of non-inferiority studies to provide informative data on efficacy in milder, typically self-limited infections

9. Clinical Studies - Ketek • A number of clinical studies including studies in: • CAP • AECB • ABS • Active controlled trials designed to show non-inferiority

10. Adequate and well controlled studies 21 CFR § 314.126 Adequate and well-controlled studies. (a) The purpose of conducting clinical investigations of a drug is to distinguish the effect of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation. • Active treatment concurrent control… • The test drug is compared with known effective therapy; for example, where the condition treated is such that administration of placebo or no treatment would be contrary to the interest of the patient. • If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity of test drug and active control can mean either that both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should be considered effective in the study, for example, by reference to results in previous placebo-controlled studies of the active control drug.

11. ICH E-10 • Assay sensitivity is a property of a clinical trial defined as the ability to distinguish an effective treatment from a less effective or ineffective treatment. • if a trial is intended to demonstrate efficacy by showing a test treatment to be noninferior to an active control, but lacks assay sensitivity, the trial may find an ineffective treatment to be non-inferior and could lead to an erroneous conclusion of efficacy • The presence of assay sensitivity in a non-inferiority or equivalence trial may be deduced from two determinations: • Historical evidence of sensitivity to drug effects, i.e., that similarly designed trials in the past regularly distinguished effective treatments from less effective or ineffective treatments and • Appropriate trial conduct, i.e., that the conduct of the trial did not undermine its ability to distinguish effective treatments from less effective or ineffective treatments. Guidance for Industry: E 10 Choice of Control Group and Related Issues in Clinical Trials: available at: http://www.fda.gov/cder/guidance/4155fnl.htm

12. Active Controls & Non-inferiority -1 Case# 1: Large treatment effect Low spontaneous resolution rate Test Inactive (e.g. placebo) margin Active Control Effect

13. Active Controls & Non-inferiority - 2 Test Case #2: Unclear treatment effect High spontaneous resolution rate margin Active Control Inactive (e.g. placebo) Effect

14. Active Controls & Non-inferiority - 3 Case# 1: Large treatment effect Low spontaneous resolution rate Test Inactive (e.g. placebo) margin Active Control Effect Test Case #2: Unclear treatment effect High spontaneous resolution rate margin Active Control Inactive (e.g. placebo) Effect

15. Trial Design – ABS & ABECB ABS • AIDAC Oct 2003 – General discussion on trial design in ABS • recommendation for superiority trials in ABS • placebo-controlled or adjunctive therapy controlled • with close follow-up & safety provisions • AIDAC Sept 2006 – product specific meeting on a fluoroquinolone for ABS using active controlled non-inferiority studies • On the question on efficacy (alone) based upon non-inferiority the committee voted Yes: 4 and No: 10 ABECB • AIDAC 2002 – general discussion on placebo controlled studies in non-severely ill patients • CDER Regulatory Briefing July 2005 – For ABECB there was not adequate basis for non-inferiority trials

16. Clinical Trials - Considerations Perspective • Antibacterial drugs were first discovered many years ago • Represented a major advance • Antibacterial therapy Incorporated into clinical practice before sophisticated clinical trial designs developed Considerations • Risk of progression or extension of infection • Risk of adverse reactions to antimicrobial • Clinical Trials should • not expose patients to significant risk • be informative • be ethical & acceptable based upon IRB review • Study design probably can impact upon population enrolled • inclusion / exclusion criteria and investigator patient selection • provisions for “rescue therapy” • consider role of DSMB

17. Ketek Label – Safety (selected) • CONTRAINDICATIONS • previous history of hepatitis or jaundice assoc. with Ketek or any macrolide • Concomitant administration of Ketek with cisapride or pimozide is contraindicated • WARNINGS • Hepatotoxicity – acute hepatic failure and severe liver injury, in some cases fatal (June 2006) • Exacerbation of myasthenia gravis (strengthened June 2006) • QT prolongation • Pseudomembranous colitis • PRECAUTIONS • Visual disturbances and syncope • Hepatic dysfunction – increased liver enzymes and hepatitis • Drug Interactions – CYP 450 3A4 inhibition; CYP 450 3A4 & 2D6 substrate

18. Ketek Label – Safety (additional) see previous slide • CONTRAINDICATIONS • history of hypersensitivity too telithromycin and/or any components of Ketek tablets or any macrolide antibiotic • WARNINGS • PRECAUTIONS • Dose reduction in severe renal impairment see product label for complete information

19. clarithromycin CONTRAINDICATION – co-administration with interacting drugs-postmarketing reports of cardiac arrhythmias WARNINGS re: use in pregnancy Pseudomembranous colitis Drug interactions – CYP P450 3A ADVERSE REACTIONS: Post-Marketing Experience Hepatic effects QT prolongation & arrhythmias erythromycin CONTRAINDICATED In patients taking terfenadine or astemizole WARNINGS prolonged QT in geriatric patients hepatic dysfunction pseudomembranous colitis PRECAUTIONS aggravate weakness of patients with myasthenia gravis Drug interactions azithromycin WARNINGS Rare serious allergic reactions For outpatient mild severity CAP not for moderate or severe CAP pseudomembranous colitis PRECAUTIONS macrolides and QT ADVERSE REACTIONS liver and biliary adverse reactions Safety – Other Antimicrobials (selected)-1

20. Beta-lactams CONTRAINDICATIONS Allergy to Cephs/PCNs WARNINGS Hypersensitivity to Cephs / PCNs Pseudomembranous colitis Tetracyclines WARNINGS Effect on tooth development pregnancy, children Pseudomembranous colitis photosensitivity Fluoroquinolones WARNINGS Peds – arthropathy juvenille animals CNS disorders Hypersensitivity reactions anaphylactic rash, fever, ↑Eos, jaundice, hepatic necrosis, fatal outcomes (rarely reported) Peripheral neuropathy Tendon effects PRECAUTIONS Effects on QT - arrhythmia Safety – Other Antimicrobials (selected)-2

21. Pediatrics • Only approved for use in adults • Pediatric studies in • acute bacterial otitis media, • tonsillopharyngitis • community-acquired pneumonia • Sanofi Aventis voluntarily paused the Pediatric studies on June 8, 2006 • Pediatric patients are not being enrolled

22. Day 1 Respiratory tract infections – treatment and epidemiology Premarket data Postmarketing data EMEA Datamining Hepatic AEs Day 2 Postmarketing Data Visual AEs Disturbances of consciousness Exacerbations of Myasthenia Gravis Summary Open Public Hearing Committee Discussion and Vote Agenda Return to agenda

23. Discussion Committee Discussion Please discuss whether the benefits outweigh the risks for each of the approved indications for Ketek (community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis). Please take into consideration the current safety information (specifically including hepatic, visual, loss of consciousness, and exacerbation of myasthenia gravis adverse reactions). Please also consider the information supporting efficacy for these indications as well as the recent efficacy discussions on the use of non-inferiority trial designs.

24. Questions 1 • Based on your discussions of whether or not Ketek’s benefits outweigh its risks, do the available data support the continued marketing of any of the following approved indications? Please vote separately for each of the indications. • Community-acquired pneumonia • Acute bacterial exacerbation of chronic bronchitis • Acute bacterial sinusitis

25. Question 2 2. If continued marketing is recommended for any of the indications, please address the following: • Should any of the indications for which continued marketing is recommended be modified or limited? • Does the product label adequately describe the adverse reactions? Please specifically address hepatic, visual, loss of consciousness and exacerbation of myasthenia gravis adverse reactions. • Should any additional communication strategies or risk management programs be implemented to assure the safe use of Ketek? If yes, please describe. • Please recommend any additional studies to further define the benefits of Ketek for each indication. • Please recommend any additional studies to further define the risks of Ketek for each indication.

26. Question 3 3. If continued marketing is not recommended for any of the indications, please address what evidence is needed to show that the benefits of Ketek outweigh the risks for those indications.

27. Return Return to agenda