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Title: 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 Committees 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

6
Other Drugs withOlder 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 (FDC) 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/guid
ance/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
Safety Other Antimicrobials (selected)-1
  • 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

20
Safety Other Antimicrobials (selected)-2
  • 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
  • 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

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
Agenda
  • 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

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
    Keteks 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
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