TROGLITAZONE: PRESENTATION TO ADVISORY COMMITTEE Murray M. Lumpkin, M.D. Deputy Center Director...
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Transcript of TROGLITAZONE: PRESENTATION TO ADVISORY COMMITTEE Murray M. Lumpkin, M.D. Deputy Center Director...
TROGLITAZONE:
PRESENTATION TO ADVISORY COMMITTEE
Murray M. Lumpkin, M.D.Deputy Center DirectorCenter for Drug Evaluation & ResearchUS Food and Drug Administration19 May 2000
2
BackgroundTroglitazone - (Rezulin)
Approved January 29, 1997 Marketing in US began March 97 Adv Cmt (12/11/96) 8-0 vote for AP Priority review (first cycle) AP Total time to approval around 6 mo. 7 mo. later first reports of LVR death Several “Dear Dr” letters; relabeled Adv Cmt (3/26/99) 11-1 B>R for concomitant
use with insulin; 12-0 B>R for concomitant use with sulfonylureas; 3-9 B>R for monotherapy; addition ideas for labeling, study, etc
3
Background
Rosiglitazone (Avandia) AP in May 25, 1999 6 mo P review
Pioglitazone (Actos) AP in July 15, 1999 6 mo P review
4
CDER Definition of Liver Failure
Hepatic insufficiency that results in: Death Transplant Recovery after encephalopathy or
on transplant list Coagulopathy not sufficient alone
None of the 3 products had such pts in their NDA databases
5
Troglitazone: Analysis of AERS Reports* March 2000
Liver failures (n=90) 36 months of marketing 60 deaths without transplant 3 deaths with transplant 7 alive with transplant 10 recovered without transplant 10 with unknown outcomes
• probably deaths (but can’t confirm)
*Thought at least possibly or probably related to troglitazone at time of market WD
6
Rosiglitazone: Analysis of AERS Reports*March 2000
Liver failure (n=2) 10 months of marketing 1 death without transplant 1 recovered
*Thought at least possibly or probably related to rosiglitazone at time of troglitazone WD
7
Pioglitazone:Analysis of AERS Reports*March 2000
Liver failure (n=0) 8 months of marketing
* At time of troglitazone WD
8
Questions
Do the benefits of troglitazone no longer outweigh its risks given the availability of rosiglitazone and pioglitazone?
Is troglitazone less safe than rosiglitazone or pioglitazone?
Does troglitazone have any unique efficacy or niche population(s)?
9
Possible Comparisons:
No head-to-head data availableLaunch vs launch
date of disease onset all start therapy within 9 mo. of launch
Contemporaneous date of disease onset all start therapy after June 99 [launch of
rosiglitazone])Entire exposure vs entire exposure
date of disease onset in last 9 months start therapy anytime after launch
09months
Initial launch
# of
cas
es b
ased
on
dat
e of
on
set
of s
AD
Ron
set
of r
x fr
om la
un
ch d
ate
Rezulin
9months Initial launch
0
# of
cas
es b
ased
on
dat
e of
on
set
of s
AD
Ron
set
of r
x fr
om la
un
ch d
ate
Avandia
9months0
(6/99 thru 2/00)(3/97 thru 11/97)
Contemporaneous: # of cases based on date of onset of sADR onset of rx from June, 1999
Entire Exposure: # of cases based on date of onset of sADR onset of rx from March, 1997
Rezulin(6/99 thru 2/00)
11
Data Limitations
Spontaneous data Not clinical trials data
Voluntary reporting Reporter motivationNew drug biasesNo real denominator/numeratorUnder-reporting/magnitude?No control groupsConfounding factors
Veracity of causal attribution?
12
Spontaneous Reports
Great signal generator/detector Rare, serious, unexpected sADRs
Poor at determining the depth/strength of the signal Situational - especially poor with high
background rate of occurrenceCan NOT do incidence calculationsCan only do “reporting rates”Soft data at best, but all we often really
have
COMPARISON #1:
LAUNCH vs LAUNCH
09months
Initial launch
# of
cas
es b
ased
on
dat
e of
on
set
of s
AD
Ron
set
of r
x fr
om la
un
ch d
ate
Rezulin
9months Initial launch
0
# of
cas
es b
ased
on
dat
e of
on
set
of s
AD
Ron
set
of r
x fr
om la
un
ch d
ate
Avandia
9months0
(6/99 thru 2/00)(3/97 thru 11/97)
Contemporaneous: # of cases based on date of onset of sADR onset of rx from June, 1999
Entire Exposure: # of cases based on date of onset of sADR onset of rx from March, 1997
Rezulin(6/99 thru 2/00)
Launch vs LaunchTotal US Prescriptions
Total US prescriptions for Rezulin & Avandia (NPA)/ PER MO.
Rxs in thousands
First 3 quarters of marketing
0
50
100
150
200
250
300
350
400
450
1 2 3 4 5 6 7 8 9
months
pre
scri
pti
ons
RezulinAvandia
16
Troglitazone:First 5 Qtrs’ experience: LVR failure onset (cumulative)
1st Qtr: 0 cases 421,000 Rxs
2nd Qtr: 2 cases 1,228,000 Rxs
3rd Qtr: 16 cases 2,402,000 Rxs
4th Qtr: 24 cases 3,586,000 Rxs
5th Qtr: 40 cases 5,000,000 Rxs
(7 mo: 5)
12 (onset & reporting thru 3rd qtr) prob represents ~800K pts
17
Rosiglitazone:First 3 Qtrs’ experience: LVR failure onset (cumulative)
1st Qtr: 1 case 369,000 Rxs
2nd Qtr: 1 case 769,000 Rxs
3rd Qtr: 2 cases 1,563,000 Rxs
7 mo: 2
Questions:all reported for 3rd qtr? Is level of underreporting similar?
(prob represents ~500,000 pts
18
Troglitazone vs Rosiglitazone:Liver Failure Experience from Launch(Case onset by Quarter)
0
5
10
15
20
25
30
35
40
1st Qtr 2ndQtr
3rd Qtr4th Qtr5th Qtr
TroglitazoneRosiglitazone
(cumulative number of cases reported)
19
End of 3rd QTR comparison
TROGLITAZONE16/800,000 pts1/50,000
12/800,000 pts1/67,000
ROSIGLITAZONE2/500,000 pts1/250,000
20
Arguments AGAINSTLaunch/Launch Comparison
Dynamic in the community possibly quite different in 1997 and 1999 People possibly now more educated,
more aware of possibility of hepatotoxicity, and possibly acting accordingly
? Monitoring helping ? More appropriate patient selection
Comparison #2:Contemporaneous
09months
Initial launch
# of
cas
es b
ased
on
dat
e of
on
set
of s
AD
Ron
set
of r
x fr
om la
un
ch d
ate
Rezulin
9months Initial launch
0
# of
cas
es b
ased
on
dat
e of
on
set
of s
AD
Ron
set
of r
x fr
om la
un
ch d
ate
Avandia
9months0
(6/99 thru 2/00)(3/97 thru 11/97)
Contemporaneous: # of cases based on date of onset of sADR onset of rx from June, 1999
Entire Exposure: # of cases based on date of onset of sADR onset of rx from March, 1997
Rezulin(6/99 thru 2/00)
23
TroglitazoneCase onset in those starting therapy since 6/99N=0Around 150,000 new starts
(patients)
Aware of one that comes as close as possible without actually making the definition. Also working on one that might ultimately make definition.
24
RosiglitazoneCase onset in those starting therapy since 6/99
N=2500,000 new starts
(patients)
25
Arguments FOR Contemporaneous comparisonContend little underreporting of
troglitazone because of increased publicity
Physicians now monitoring appropriately
Physicians better selecting patients for glitazone therapy
People now stop therapy earlier when s/sx of liver tox begin
26
Arguments AGAINSTContemporaneous Comparison
New drug reporting effect Zenith - rosiglitazone ; Nadir - troglitazone
Liability concerns with reportingPeople more likely to report
rosiglitazone Not convinced monitoring helps or even
being done by physiciansNot convinced one can identify or select
appropriate patients
27
Arguments AGAINSTContemporaneous Comparison (contd)Often patients quite ill within 30
days from having “normal” liver enzymes drawn 9/12 showed rapid rise within 30 days
Jaundice is often the first evidence of liver involvement in most of the cases
Comparison #3:Total Experience vsTotal Experience
09months
Initial launch
# of
cas
es b
ased
on
dat
e of
on
set
of s
AD
Ron
set
of r
x fr
om la
un
ch d
ate
Rezulin
9months Initial launch
0
# of
cas
es b
ased
on
dat
e of
on
set
of s
AD
Ron
set
of r
x fr
om la
un
ch d
ate
Avandia
9months0
(6/99 thru 2/00)(3/97 thru 11/97)
Contemporaneous: # of cases based on date of onset of sADR onset of rx from June, 1999
Entire Exposure: # of cases based on date of onset of sADR onset of rx from March, 1997
Rezulin(6/99 thru 2/00)
30
Case Onset since 6/99 (troglitazone could have been started anytime)
Troglitazone n=11
Rosiglitazone n=2
“no deaths since June 99”
OTHER DATA/PRIORS
Clinical Trials ExperienceAERS Hepatitis/JaundiceUHC Epidemiology StudyAll other Population-
based StudiesDPP Study at NIH
32
Other Data/”Priors”:Clinical Trials Experience
Clinical trials database (pre-approval) no liver-related deaths or transplants in any application
Overall hepatotoxicity picture better with rosiglitazone and pioglitazone without cases of jaundice and less liver
enzyme elevation
33
Clinical Trials Database
Troglitazone
2 patients treated with troglitazone developed reversible jaundice 1 had liver Bx consistent with idiosyncratic
drug reaction
1 other patient treated with troglitazone also had a liver bx consistent with idiosyncratic drug reaction
Info in original approved label
34
ELEVATED ALT: NDAs
DRUG TroglitazoneULN = 34
PlaceboULN = 34
RosiglitazoneULN = 48
PioglitazoneULN =34
Patients N=2510 N=475 N=4421 N=3650
ALT>3X ULN 1.9% 0.6% 0.25% 0.33%
ALT>5X ULN 1.7% 0.23% 0.25%
ALT>8X ULN 0.9% 0.0% 0.05% 0.03%
ALT>30XULN
0.2% 0.0% 0.0% 0.0%
35
Other Data/”Priors”:Hepatitis/jaundice AERS reports
Post-marketing Cases of hepatitis or jaundice that didn’t meet previous definition of “LVR failure”, but did result in hospitalization or were considered “medically significant” or “life-threatening”
36
Other Data/”Priors”:Hepatitis/jaundice AERS reports
Troglitazone n=150 (75/1 million Rxs)
Rosiglitazone n=25 (16/1 million Rxs)
Entire database from launch of product through March 2000
37
Other Data/”Priors”:UHC Epidemiology Study
Cohort study in UHC database N = 9369 patients Avg use around 6 months 4873 person-years of exposure 1 case of fatal hepatotoxicity
Rate = 205/ 1 million patient- years
38
Other Data/”Priors”:Other population-based studies
All PD studies (March Adv Cmt) N=15,006 patients Most treated for 1-3 months 6227 person-years of exposure 1 case of fatal hepatotoxicity
Rate = 161/1 million person years
39
Other Data/”Priors”DPP Study at NIH
Prevention study in patients thought to be at higher risk to develop Type 2 diabetes; not Type 2 diabetics yet N = 585 patients Most treated for 12 months 1 case of fatal hepatotoxicity
Rate = 1724 / 1 million person years
40
CONCLUSIONS March 2000
Incidence of troglitazone-induced liver failure possibly around 1:8,000 - 20,000 (acute) 1:2000 (chronic) [modeling] Clearly a bracket with reasonable
arguments that it could be larger and smaller
41
CONCLUSIONS March 2000
Efficacy -- no consistent evidence that has demonstrated that the glitazones are not equivalent in efficacy (no special niches)
42
CONCLUSIONS March 2000
Other safety concerns with other products: fluid retention and CHF with rosiglitazone -
Does not appear worse than with troglitazone (post-marketing reporting)
43
CONCLUSIONS March 2000
Rosiglitazone and pioglitazone appear to have a better safety profile than troglitazone and offer patients same efficacy benefits
Troglitazone should come off US market (“outmoded drug”)
44
OUTMODED DRUGSBenefits outweighed risks at time of
initial approval; but with newer drugs with better safety profiles, that perspective changes will be seeing more and more another example is terfenadine not a failure of the system would be a failure not to take off once
convinced that a safer alternative available