Title: Anti-Infective Drug Products and Drug Safety and Risk Management Advisory Committees Meeting
1Anti-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
2Welcome
- 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
3Ketek (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
4Ketek 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.
5Other 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
6Other 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)
7Demonstrating 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
8Demonstrating 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
9Clinical Studies - Ketek
- A number of clinical studies including studies
in - CAP
- AECB
- ABS
- Active controlled trials designed to show
non-inferiority
10Adequate 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.
11ICH 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
12Active Controls Non-inferiority -1
Case 1 Large treatment effect
Low spontaneous resolution rate
Test
Inactive (e.g. placebo)
margin
Active Control
Effect
13Active Controls Non-inferiority - 2
Test
Case 2 Unclear treatment effect
High spontaneous resolution rate
margin
Active Control
Inactive (e.g. placebo)
Effect
14Active 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
15Trial 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
16Clinical 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
17Ketek 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
18Ketek 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
19Safety 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
20Safety 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
21Pediatrics
- 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
22Agenda
- 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
23Discussion
- 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.
24Questions 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
25Question 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.
26Question 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.
27Return