# Presentation: 891401

## TROGLITAZONE:PRESENTATION TO ADVISORY COMMITTEE

**Murray M. Lumpkin, M.D.**
**Deputy Center Director**
**Center for Drug Evaluation & Research**
**US Food and Drug Administration**
**19 May 2000**

## Background

**Troglitazone -  (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**

## Background

**Rosiglitazone (Avandia)**
**AP in May 25, 1999**
**6 mo P review**
**Pioglitazone (Actos)**
**AP in July 15, 1999**
**6 mo P review**

## 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**

## 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**

## 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**

## Pioglitazone:Analysis of AERS Reports*March 2000

**Liver failure (n=0)**
**8 months of marketing**
*** At time of troglitazone WD**

## 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)?**

## Possible Comparisons:

**No head-to-head data available**
**Launch 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**

## Rezulin 

**0**

**9**

**months**

**Initial launch**

**# of cases based on date of onset of sADR**
**onset of rx from launch date**

**Rezulin **

**9**

**months**

**Initial launch**

**0**

**# of cases based on date of onset of sADR**
**onset of rx from launch date**

**Avandia**

- 9

- months

- 0

**(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)**

## Data Limitations

**Spontaneous data**
**Not clinical trials data**
**Voluntary reporting **
**Reporter motivation**
**New drug biases**
**No real denominator/numerator**
**Under-reporting/magnitude?**
**No control groups**
**Confounding factors**
**Veracity of causal attribution?**

## 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 occurrence**
**Can NOT do incidence calculations**
**Can only do “reporting rates”**
**Soft data at best, ****but all we often really have**

## COMPARISON #1:LAUNCH vs LAUNCH

## Rezulin 

**0**

**9**

**months**

**Initial launch**

**# of cases based on date of onset of sADR**
**onset of rx from launch date**

**Rezulin **

**9**

**months**

**Initial launch**

**0**

**# of cases based on date of onset of sADR**
**onset of rx from launch date**

**Avandia**

- 9

- months

- 0

**(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 LaunchTotal US Prescriptions

**Total US prescriptions for Rezulin & Avandia (NPA)/ PER MO.**
**Rxs in thousands**
**First 3 quarters of marketing**

**months**

**prescriptions**

**Rezulin**
**Avandia**

## 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**

## 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**

## Troglitazone vs Rosiglitazone:Liver Failure Experience from Launch(Case onset by Quarter)

**(cumulative number of cases reported)**

## End of 3rd QTR comparison

**TROGLITAZONE**
**16/800,000 pts**
**1/50,000**
**12/800,000 pts**
**1/67,000**

**ROSIGLITAZONE**
**2/500,000 pts**
**1/250,000**

## Arguments AGAINSTLaunch/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

## Rezulin 

**0**

**9**

**months**

**Initial launch**

**# of cases based on date of onset of sADR**
**onset of rx from launch date**

**Rezulin**** **

**9**

**months**

**Initial launch**

**0**

**# of cases based on date of onset of sADR**
**onset of rx from launch date**

**Avandia**

- 9

- months

- 0

**(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)**

## TroglitazoneCase onset in those starting therapy since 6/99

**N=0**
**Around 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.**

## RosiglitazoneCase onset in those starting therapy since 6/99

**N=2**
**500,000 new starts (patients)**

## Arguments FOR Contemporaneous comparison

**Contend 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**

## Arguments AGAINSTContemporaneous Comparison

**New drug reporting effect**
**Zenith - rosiglitazone ; Nadir - troglitazone**
**Liability concerns with reporting**
**People more likely to report rosiglitazone **
**Not convinced monitoring helps or even being done by physicians**
**Not convinced one can identify or select appropriate patients**

## Arguments AGAINSTContemporaneous 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 vsTotal Experience

## Rezulin 

**0**

**9**

**months**

**Initial launch**

**# of cases based on date of onset of sADR**
**onset of rx from launch date**

**Rezulin **

**9**

**months**

**Initial launch**

**0**

**# of cases based on date of onset of sADR**
**onset of rx from launch date**

**Avandia**

- 9

- months

- 0

**(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)**

## 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 Experience**
**AERS Hepatitis/Jaundice**
**UHC Epidemiology Study**
**All other Population-****	****	****	****based Studies**
**DPP Study at NIH **
**	**

## 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**

## 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**** **

## ELEVATED ALT:  NDAs

## 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”**

## 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**

## 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**

## 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**

## 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**

## 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**

## CONCLUSIONS   March 2000

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

## 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)**

## 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”)**

## OUTMODED DRUGS

**Benefits 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**