# Presentation: 712191

## Avandia®  (rosiglitazone maleate)GlaxoSmithKlineNDA 21-071 Supplement 022 FDA META-ANALYSIS

**Joint Meeting of Metabolic & Endocrine Advisory Committee and Drug Safety & Risk Management Advisory Committee **
**July 30, 2007**
**Joy Mele**
**Statistician**
**Division of Biometrics 2**

## Meta-analysis Topics

**Motivation for FDA meta-analysis**
**Database of 42 studies**
**FDA Methods**
**Overall results**
**Active-controlled studies**
**Add-on to insulin studies**
**Placebo-controlled non-insulin studies**
**Subgroups**
**Studies 135, 211 and 352**
**Summary**

## Motivation for FDA meta-analysis

**GSK overall estimate for total myocardial ischemic events only**
**Suggestion of subgroup differences based on GSK analyses**
- Heterogeneous patient populations across studies
**Heterogeneity among the different treatment paradigms**
- Initial FDA pooled estimate of 1 for RSG mono vs. PLA
- Initial FDA pooled estimate of 3 for MET+RSG vs. MET+PLA
**No results by individual studies were shown by GSK and their analyses were not stratified by study**

## The FDA Meta-analysis Database

## Rosiglitazone Meta-analysis FDA database compared to NEJM databaseDiffer on 14 studies

**FDA**
**42  randomized, controlled trials (ICT)**
**All double-blind **
** ****4  trials 1-yr+**
**     ****38 trials 6 mos or less**
**14,237 Type 2 diabetics**
**Composite endpoints**
**Patient level data**

**NEJM**
**42  randomized, controlled trials**
**38 double-blind  4 open-label **
**DREAM+ADOPT****  3-4 years**
**	****10 trials 1-yr+; 30 trials ~6 mos**
**     **
**19,462  Type 2 diabetics**
**5,269   Pre-diabetics**
**3,112  Non-diabetics**
**MI and CV death**

## FDA Meta-analysis Database

**RSG monotherapy     15 trials **
**9 head to head to placebo**
**RSG in combination**** **
**Metformin (MET)    10 trials**
**Sulfonylurea (SU)  14 trials**
**Insulin (INS)              5 trials**
**Run-in period on active control, randomized to RSG or placebo**
**RSG added to background medication (BM)  3 trials**
**Patients remained on stable doses of the anti-diabetic medications they were taking at enrollment, randomized to RSG or placebo**
**A similar database for pioglitazone was predominantly active-controlled primarily with SU as a head-to-head comparator**

## FDA Meta-analysis DatabaseTrials in High Risk Populations

**Study 352**
**Patients on background medications randomized to RSG or placebo**
**16-weeks **
**61 CHD patients**
**Study 211**** **
**Patients on background medications randomized to RSG or placebo**
**1 year **
**224 CHF patients **
**Study 135**
**Run-in on SU, randomized to RSG or placebo**
**2 years**
**227 patients with mean age of 68 (range 59-78)**

## Myocardial Ischemia Endpoints

**Trials not designed to assess ischemia**
**Efficacy trials with HbA1c endpoint**
**Post-hoc adjudication of myocardial ischemic events**
**Non-serious & serious (IHD)**
**Serious (SIHD)**
**Composite of myocardial infarction / cardiovascular death / stroke **
**Provided to FDA 5/31/07**
**Identified using pre-defined MedDRA terms**
**No adjudication**** **
**To compare meta-analysis results to long-term study results**** **

## FDA Meta-analysis Methods

## Meta-groups for FDA Analysis

## How FDA dealt with low event rates

**Focus on composite endpoints **
**Results can vary considerably with analytical method when many trials have no events**
**MI  OR 1.2 to 1.6 NS  CV death OR 1.0 to 1.8 NS**
**For plots of OR on a forest plot, added 0.5 to each cell in studies with no events in one arm or both arms**
**Exact test drops studies with no events in both arms**
**Performed several sensitivity analyses**
**Stratified on study or meta-group **

## Steps in the FDA meta-analysis

**Determine whether computing an overall estimate was sensible**
**Assess heterogeneity within meta-groups and compute an overall estimate of risk for each meta-group**
**Exact test stratifying on study**
**Risk difference analysis using both fixed and random effects models**
**Robustness of meta-group results**
**Redefine meta-groups creating a separate group for the active-controlled comparisons**
**Compute overall odds ratios**
**Differences among meta-groups?**
**High risk subgroups?**

## Results of the FDA Meta-analysis

## Summary of the Findings

**Statistically significant overall estimate of risk of a non-serious or serious myocardial ischemic event associated with RSG **
**OR 1.4  95% CI of 1.1 to 1.8  p=0.02**
**No evidence of increased myocardial ischemic risk associated with RSG compared to MET or SU **
**OR 1.0 95% CI of 0.5 to 2.0  p=0.3**
**Increased myocardial ischemic risk associated with RSG compared to placebo**
**Results are heterogeneous**
**Across treatment paradigms/studies**
**Across subgroups**

## Results of FDA meta-analysisAll 42 studies IHD=serious + non-serious ischemia SIHD=serious ischemia 

**	****	****	****  ****RSG    Control****	****  OR (95% CI)         p**
**                                    **(n=8604)   (n=5633)
**IHD     ****	****   2.0%      1.5% ****	****  1.4   (1.1, 1.8)      0.02**
**SIHD   ****	****   1.0%      0.8% ****	****  1.44 (0.98, 2.1)    0.06**
**MI/CVD/ST****	****   0.73%    0.67%   1.2   (0.7, 1.8)       0.4**** **

## Serious + Non-serious Myocardial Ischemia By Meta-group For All 42 Studies

## Results For All 42 Studies And For The Placebo And Active Controlled Studies SIHD=serious ischemia IHD=serious+non-serious ischemia 

## Comparison of RSG to SU or MET  MI/CV Death/Stroke Meta-analysis database (ICT), ADOPT and RECORD

## Placebo- Controlled Trials Meta-Analysis Database

_**Placebo-controlled Trials  N=12,424**_
**Add-on to insulin trials ****	****N=1,530**
**Non-insulin trials****	****	****N=10,894**

## Incidence of Serious+Non-serioius Myocardial Ischemia All Placebo-controlled Trials Study Numbers shown for outliers

- Favors Control

- Favors RSG

- Favors Control

- Favors RSG

- 211

- 352

- 135

## Insulin+RSG vs. Insulin+Placebo

**6 month trials **
**867 I+R   663 I+P**
**IHD Incidence**
** ****2.8% I+R   1.4% I+P**
** ****RD +1.4%  (-0.05%, +3%)**
**Odds Ratios**
**IHD                  2.1 (0.9, 5)**
**Serious IHD    2.6 (0.8, 11)**
**MI/CVd/ST      1.9 (0.8, 5)**
**          **

**Notes:**
The results for those 5 insulin studies are depicted in the forest plot on this slide and in the handout.
These 5 6-month studies of rosiglitazone add-on to insulin enrolled about 1400 patients.

The average time since diagnosis of diabetes in these patients was 13 years  - about double what was seen in the overall database
Otherwise these patients  had similar baseline characteristics to the overall population

Across all 3 endpoints – Approximately a doubling of risk is seen with borderline significant results

Also CHF results showed a doubling of risk for this group while the other meta-groups showed a reduced risk

## Results for 35 placebo-controlled non-insulin studies (77% of database)

**	****	****	****  ****RSG    Control****	****       OR (95% CI)       p**
**                                    **(n=6447)   (n=4447)
**IHD     ****	****   1.9%      1.4%        1.4 (1.0, 1.9)      0.06**
**SIHD   ****	****   1.0%      0.7%        1.5 (0.9, 2.4)      0.08**
**MI/CVd/ST****	****   0.68%    0.58%      1.2 (0.7, 2.1)       0.5**** **

## Subgroup Results Serious + Non-serious Myocardial Ischemia Placebo-controlled Non-insulin Studies

## Study 135 – 227 Patients 60 years+Serious+Non-serious Myocardial Ischemic Events

## Serious + Non-serious Ischemia by Nitrate Use Placebo-controlled Non-insulin Studies

**N=10,446**

**N=448**

**Weighted Risk Diff 0.3%   p=0.2**

**Weighted Risk Diff 8%   p=0.02**

## Serious+Non-serious Myocardial Ischemia Treatment by Nitrate Use Interaction (INT) 1-year Study 211 (CHF) & 16-week Study 352 (CHD)

_**Study**__**	**__**	**__**   RSG              PLA           OR (95%)    INT p-value**_**	****	****	****	****	**
** ****352               5/31 (16%)     4/30 (13%)   1.2 (0.2, 6.9)      0.21**
** **
** ****211               9/110 (8%)     5/114 (4%)   1.9 (0.6, 7.5)      0.11**
_**211 By Nitrate use**_
** ****Nitrates          3/31 (10%)     0/37 (0%)    p=0.09 **
** ****No Nitrates     6/79 (8%)       5/77 (6%)   p>0.9**

## Ischemia Results Non-nitrate Users (n=10,446) & Nitrate Users (n=448)  Placebo-controlled Non-insulin Studies

##   Results By ACE Inhibitor UsePlacebo-controlled Trials of ICT And DREAM MI/CV Death/Stroke 

## Summary 

_**Placebo-controlled trials in meta-analysis database**_
**Nominally statistically significant increased risk of a myocardial ischemic event associated with RSG compared to placebo **
**High risk treatment paradigms**
**RSG add on to insulin**
**RSG add on to metformin: Avandamet?**
**High risk subgroups**
**Nitrates**
**Ace inhibitors?**
_**Active-controlled trials in meta-analysis database**_
**No clear evidence of increased risk associated with RSG compared to metformin or sulfonylurea**** **

## Summary

**Meta-analysis results have generated additional hypotheses**
**Formal FDA review of DREAM needed to examine the ACE inhibitor interaction**
**Results for nitrates and ace inhibitors should be examined in RECORD, a study with prospectively adjudicated CV endpoints**

## Acknowledgements

**Review team of DMEP and OSE**
**Statistical Colleagues:**
**Todd Sahlroot   Tom Permutt    Lee Pian**
**Bob O’Neill   Ed Nevius **
**Mat Soukup  Chris Holland  Mark Levenson**
**John Lawrence   Cynthia Liu    Janice Derr**
**Qian Li   Japo Choudhury   **