Minutes
of the AntiInfective Drugs Advisory Committee Meeting (68th)
Center
for Drug Evaluation and Research
March 24,
2000
Committee Members
L.
Barth Reller, M.D.
Robert L. Danner, M.D.
Keith
A. Rovold, Pharm.D.
P.
Joan Chesney, M.D.
Celia D. C. Christe-Samuels, M.D.
David E. Soper, M.D.
Barbara E. Murray, M.D.
Judith R. O’Fallon, Ph.D.
Consultants
Carl Norden, M.D.
James Leggett, Jr., M.D.
Executive Secretary
Kimberly
Littleton Topper
Guest Experts
Joyce
Drayton, M.D.
Matthew
J. Kuehnert, M.D.
Franklin
David Lowy, M.D.
Janet
Wittes, Ph.D.
FDA
Gary
Chickami, M.D.
Janice
Soreth, M.D.
David Ross, M.D., Ph.D.
Diane
Murphy, M.D.
These
summary minutes for the March 24, 2000, meeting of the AntiInfective Drugs
Advisory Committee were approved on _________________.
I
certify that I attended the March 24, 2000, meeting of the AntiInfective Drugs
Advisory Committee and that these minutes accurately reflect what occurred.
_______//S//_________________ _____//S//___________________
Kimberly L. Topper L. Barth
Reller, M.D.
Executive Secretary Chairman
Minutes
of the AntiInfective Drugs Advisory Committee Meeting (68th)
Center
for Drug Evaluation and Research
March
24, 2000
The
meeting was called to order at 8:30 and Dr Reller welcomed the members. The Executive Secretary read the conflict of
interest statement. Dr. Reller asked all
the members at the table to introduce themselves.
Dr. Chickami, Director of Division of AntiInfective Drug Products
provided organizational comments and set the stage for the presentations and
discussions.
Dr.
Tarpley, Discovery Research at Pharmacia and Upjohn, introduced Linezolid as a
new anti-bacterial from an entirely new structure class. The drug was coming for discussion and
approval for the following indications: nosocomial pneumonia, community
acquired pneumonia, complicated and uncomplicated skin and skin structure
infections and vancomycin-resistant enterococcus faecalis and e. faecium
infections. He stated that they expected
that linezolid therapy will be initiated in a hospital or the institutional
care setting.
Dr.
Hafkin, P&U, spoke
on the pharmacokinetic profile of linezolid and it’s oral bioavailability and
the time concentration curve data. Testing has shown that drug exposure is
equal whether the drug is given intravenously or orally so no dose adjustments
are required for route of administration changes. Gender and age do not affect the AUC or
exposure to the drug because the concentration of the active drug doesn’t
change with severe, minimal or no renal insufficiency.
Dr.
Ross, Medical Reviewer,
Division of AntiInfective Drug Products presented the agency’s
analysis of Linezolid and discussed the studies one by one. He provided a review of the clinical
pharmacology, clinical/statistical analyses of efficacy, clinical/statistical
analyses of safety and the development of resistance.
The
committee questioned many aspects of the presentations and clarified issues
prior to addressing the following questions.
1) Community-acquired pneumonia (CAP)
a) Do the data support the efficacy and safety of linezolid in the
treatment of adult patients with CAP? 10
YES 0 NO
No additional comments
b) Include in your discussion whether there are sufficient data to
support the efficacy of linezolid for the treatment of CAP due to: 5 YES 5 NO
Methicillin-resistant Staphylococcus
aureus (MRSA)
YES: based on aggregate data in other sites and in
hospital acquired pneumonia
Penicillin-resistant Streptococcus
pneumoniae (PRSP) 3
YES 7
NO
YES: more evaluation on
numbers already collected and based on pathogens.
NO: Need more data and
patient numbers are too small
Despite the sponsors
efforts there were not enough cases overall with penicillin resistant isolates
2) Hospital-acquired pneumonia (HAP)
a) Do the data support the efficacy and safety of linezolid in the
treatment of adult patients with HAP? 9 YES 1 NO
NO: Confidence intervals
are a concern
b) Include in your discussion whether there are sufficient data to
support the efficacy of linezolid for the treatment of HAP due to:
I) MRSA 10
YES 0 NO
ii) PRSP 2
YES 8 NO
NO: More experience needed and higher numbers
needed for resistant stains
3) Uncomplicated skin and skin structure infections (uSSSI)
a) Do the data support the efficacy and safety of linezolid in the
treatment of adult patients with uSSSI? 10
YES 0 NO
b) Include in your discussion whether there are sufficient data to
support the efficacy of linezolid for the treatment of uSSSI due to: 2 YES 8
NO
I) MRSA
YES: overall information shows - if it will
work in CAP it will work in SSSI because of pathogen site.
NO: be sure to address
dosage issue, it may be a concern with lower dose, i.e., higher dose may be
required for efficacy
4) Complicated skin and skin structure infections (cSSSI)
a) Do the data support the efficacy and safety of linezolid in the
treatment of adult patients with cSSSI? 9
YES 1 NO
b) Include in your discussion whether there are sufficient data to
support the efficacy of linezolid for the treatment of cSSSI due to: 5 YES 5
NO
I) MRSA
5) Infections due to vancomycin-resistant enterococci (VRE)
a) Do the data support the efficacy and safety of linezolid in the
treatment of adult patients with infections due to VRE? 9 YES 1 NO
Look for more data
b) What additional study(ies), if any, would
the committee recommend?
1) more
information on metabolism of drug to assist in use of drug
2) more
absorption rates of drug (gastric tube, IV, pill, etc.,)
3) more
post marketing e. faecalis data and have information in data sheet
4) break
out bacteremia data
5) collect
more data using compassionate use data
6) need
more population pharmacokinetics
7) put in the labeling how
many isolates of e. faecalis have been treated and indicate the comfortability
factor
8) breakout
the bacteremia data because it is most convincing for new drugs
9)test in osteomyelitis