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

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Background

Rosiglitazone (Avandia) AP in May 25, 1999 6 mo P review

Pioglitazone (Actos) AP in July 15, 1999 6 mo P review

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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

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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

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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)?

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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

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Rezulin

9months Initial launch

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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)

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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?

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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

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dat

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Rezulin

9months Initial launch

0

# of

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Ron

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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

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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

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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

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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)

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End of 3rd QTR comparison

TROGLITAZONE16/800,000 pts1/50,000

12/800,000 pts1/67,000

ROSIGLITAZONE2/500,000 pts1/250,000

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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

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Rezulin

9months Initial launch

0

# of

cas

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ased

on

dat

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on

set

of s

AD

Ron

set

of r

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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)

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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.

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RosiglitazoneCase onset in those starting therapy since 6/99

N=2500,000 new starts

(patients)

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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

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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

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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

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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)

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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

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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

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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

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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%

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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”

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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

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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

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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

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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

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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

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CONCLUSIONS March 2000

Efficacy -- no consistent evidence that has demonstrated that the glitazones are not equivalent in efficacy (no special niches)

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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)

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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”)

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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