Food
and Drug Administration
Center for Drug Evaluation and Research (CDER)
Antiviral Drugs Advisory Committee
FINAL
QUESTIONS TO THE COMMITTEE
Question 1:
·
Do the data demonstrate that
tipranavir/ritonavir (TPV/r) is safe and effective for the multi-drug resistant
HIV-1 infected population?
•
If no, what additional data are needed to provide
evidence of safety and efficacy?
•
If yes, please address the appropriate population for
TPV/r use considering the following:
–
limited inclusion criteria of the RESIST trials
–
drug-drug interactions
–
resistance information and patterns associated with
optimal use
–
safety considerations
Question 2:
·
Given the data on transaminase elevations,
please provide your recommendations for:
•
TPV/r use in patients with underlying liver disease
•
Monitoring and management of hepatotoxicity during
clinical use
•
Future studies
Question 3:
·
The limited amount of data in females with HIV
infection in the TPV program shows an increased incidence of rash in
females. Please provide your
recommendations for:
–
Investigation of this safety signal in future studies
with TPV
Question 4:
·
Current information indicates the net effect of
TPV/r on substrates of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 is not known, and
there are competing effects of TPV/r on CYP3A (inhibition) and P-glycoprotein
(induction). Please comment on
additional post-marketing drug interaction studies.
Question 5:
·
Given the high inter-patient variability in TPV
exposures following fixed doses and exposure (blood levels)-virologic response
relationships, could a biomarker such as Cmin/IC50 be used for the
individualization of TPV/r therapy?
Please discuss the studies that would supplement the data presented
today.
Question 6
·
Please provide your recommendations regarding
the display of TPV/r resistance data/analyses in the TPV package insert that
would be useful to clinicians.
Background referring
to Question 6 on next page
(Question
6 Continued: Background)
Slide 1:
Slide 2:
Slide 3:
Question 7:
·
Please discuss and recommend future study
designs /data acquisition for the heavily pretreated population.