# Presentation: 729181

## Statistical issues in the analysis of 2-year HAQ for ARAVATM

**Suktae Choi, Ph.D.**
**Mathematical Statistician**
**FDA/CDER**
**March 5, 2003**

**Notes:**
Hello, I am Suktae Choi, a statistician from FDA.
This presentation is regarding statistical review.

## Issues Presented

**Problems of the statistical analysis for duration of 2 year clinical studies on ARAVA**
**High rate of dropouts or missing data**
**Early dropouts**

**Notes:**
This presentation will  focus on 2 issues.

First, the validity of LOCF analysis, which was used in the sponsor’s analysis to impute the missing data due to early terminated patients.
But the missing rates are too high to ignore. So we will verify the validity of LOCF.

Second, the results and findings of a quoted “sensitivity analysis”.

## Studies Reviewed

**US Study (US301)**
**Lef vs. Pbo vs. Mtx**
**Randomized, parallel, double-blind**
**Followup for 2 years**
**At 16 wk, non-responders switched treatment**
**2 European studies **
**MN301/303/305: Lef (vs. Pbo) vs. Ssz**
**MN302/304: Lef vs. Mtx**

**Notes:**
Sponsor submitted 1 US study and 2 EU studies.

508, 358 and 999 patients were randomized for each study, and treated arms are as shown.
All the studies are randomized, parallel, doubleblind and duration was 2 years

Indication of this NDA supplement was Prevention of Disability, and FDA guidance requires 2 to 5 years of the studies for this indication

The sponsor’s analyses using LOCF showed positive results on US study and one EU study, but the negative results on the other EU study.

My presentation will be focused only on US study because most cases, same arguments can be applied in two other EU studies.

## Efficacy AnalysisUS301

**Endpoints reviewed for year 2**
**HAQ, MHAQ**
**Change from baseline at end of year 2**
**Statistical analysis method**
**Last Observation Carried Forward (LOCF)**
**ANCOVA**

**Notes:**
HAQ and MHAQ with mean change from baseline at year 2 are considered as endpoints for Prevention of Disability Indication.

Sponsor’s statistical analysis method was Analysis of Covariance with LOCF.

## Number of Patients remaining at 2 years; US301

**Notes:**
This tabel shows the percentage of completers of 2year study.
As you see, only 190 patients complet4ed the study among 508 randomized patients, which was 37%. Especially for Pbo group, only 21 % completed the study.

Among these completers, patients who does not have HAQ at the end of year 2 are excluded from the analysis. So, the completers in the HAQ analysis are even smaller than this.

## Change from Baseline in HAQ at 2 years, US301

**Change from Baseline in HAQ at 2 years, US301**

**Mean and 95% confidence Intervals,    p-value: Lef vs. Pbo**

**(p<0.001)**

-            **LOCF****	**

**Notes:**
This figure shows the mean change from baseline of HAQ at the end of year 2 by trt group. Look at this LOCF. This green circle represents the mean value of Lef gorup, and this yellow circle represents the mean of pbo group.

You can see a big difference between these two groups with a very small p-value. But we have to see the other side of it.
Thses two are decomposition of LOCF into completers and incompleters so that forwarded.

Look at the completers. Lef group still is still better than Pbo, but the pvalue is .47. In other words, even the true mean value of these two trt groups are same, this much of difference c an come out with high probability by random sampling. So we can’t tell these two are different.Now look at this incompleters. As you see this p-value 0.023, these two trt groups are significantly different. 

Now this LOCF is combination of these two, about 70% from incompleters and 30% from completers. So, the difference shown in LOCF data is mainly from incompleters. Now we will look at these incompleters in more detail

## Change from Baseline in HAQ at 2 years, US301

**Change from Baseline in HAQ at 2 years, US301**

**Mean and 95% confidence Intervals,    p-value: Lef vs. Pbo**

**(p<0.001)**

**(p=0.467)**

**(p=0.023)**

-            **LOCF****	****              Completers            Imputed cases**

**Notes:**
This figure shows the mean change from baseline of HAQ at the end of year 2 by trt group. Look at this LOCF. This green circle represents the mean value of Lef gorup, and this yellow circle represents the mean of pbo group.

You can see a big difference between these two groups with a very small p-value. But we have to see the other side of it.
Thses two are decomposition of LOCF into completers and incompleters so that forwarded.

Look at the completers. Lef group still is still better than Pbo, but the pvalue is .47. In other words, even the true mean value of these two trt groups are same, this much of difference c an come out with high probability by random sampling. So we can’t tell these two are different.Now look at this incompleters. As you see this p-value 0.023, these two trt groups are significantly different. 

Now this LOCF is combination of these two, about 70% from incompleters and 30% from completers. So, the difference shown in LOCF data is mainly from incompleters. Now we will look at these incompleters in more detail

## Change from Baseline in HAQ at 2 years, US301

**Change from Baseline in HAQ at 2 years, US301**

**Mean and 95% confidence Intervals,    p-value: Lef vs. Pbo**

**(p<0.001)**

**(p=0.467)**

**(p=0.023)**

-    **: Lef         : Pbo         :Mtx**

-            **LOCF****	****              Completers            Imputed cases**

**Notes:**
This figure shows the mean change from baseline of HAQ at the end of year 2 by trt group. Look at this LOCF. This green circle represents the mean value of Lef gorup, and this yellow circle represents the mean of pbo group.

You can see a big difference between these two groups with a very small p-value. But we have to see the other side of it.
Thses two are decomposition of LOCF into completers and incompleters so that forwarded.

Look at the completers. Lef group still is still better than Pbo, but the pvalue is .47. In other words, even the true mean value of these two trt groups are same, this much of difference c an come out with high probability by random sampling. So we can’t tell these two are different.Now look at this incompleters. As you see this p-value 0.023, these two trt groups are significantly different. 

Now this LOCF is combination of these two, about 70% from incompleters and 30% from completers. So, the difference shown in LOCF data is mainly from incompleters. Now we will look at these incompleters in more detail

## Percent of patients remaining in study for HAQ;US301

- wk

## Reasons of dropouts from study; US301

## HAQ change from baseline; ITT, US301

**LOCF**

- wk

## MHAQ change from baseline; ITT, US301

**MHAQ change from baseline; ITT, US301**

**LOCF**

- wk

## Number of Patients remaining at 2 years; MN301/303/305

**Notes:**
This tabel shows the percentage of completers of 2year study.
As you see, only 190 patients complet4ed the study among 508 randomized patients, which was 37%. Especially for Pbo group, only 21 % completed the study.

Among these completers, patients who does not have HAQ at the end of year 2 are excluded from the analysis. So, the completers in the HAQ analysis are even smaller than this.

## Number of Patients remaining at 2 years; MN302/304

**Notes:**
This tabel shows the percentage of completers of 2year study.
As you see, only 190 patients complet4ed the study among 508 randomized patients, which was 37%. Especially for Pbo group, only 21 % completed the study.

Among these completers, patients who does not have HAQ at the end of year 2 are excluded from the analysis. So, the completers in the HAQ analysis are even smaller than this.

## Conclusions

**Less than 30% of patients with a measurement of 2-year HAQ**
**With high rate of missing data, validity of 2-year analysis with imputation of year one data becomes problematic**