Statistical Comments on Retrospective Analysis

Girish Aras, Ph.D.

Jonathan Ma, Ph.D.

Center for Drug Evaluation and Research, FDA

Data Analysis Plan

• Logistic Regression model

• Dependent variable (Virological Failure) is ‘explained’ with independent variables ( baseline covariates ).

Baseline Covariates• Baseline Log (HIV-1 RNA)• New Drug Covariate• Genotypic Measures

– Genotypic Sensitivity Score– No. of PI, NRTI and NNRTI mutations

• Phenotypic Measures– Overall Sensitivity Score– No. of PI, NRTI and NNRTI drugs with

Phenotypic sensitivity

Relative Risk (Risk Ratio, RR)

• P0 = Probability of virological failure when a covariate is at a given level

• P1 = Probability of virological failure when a covariate is at one unit higher than the previous level

• RR = P1/ P0

Odds ratio

• RR is the quantity of interest but typically not estimable from a retrospective study

• OR (Odds Ratio) = P1/(1-P1) ÷ P0/(1-P0)

• OR can be estimated from a retrospective study, but may not of interest in itself

• When P1 and P0 are small,RR OR

Odds Ratios for Various Relative Risks

0

1

2

3

4

5

6

7

8

9

10

0.08 0.1 0.15 0.15 0.2 0.3 0.23 0.3 0.45 0.3 0.4 0.6 0.38 0.5 0.75

— Relative Risk — Odds RatioP1

P0=0.05

P0=0.1P0=0.15

P0=0.2

P0=0.25

Odd

s R

atio

or

Rel

ativ

e R

isk

Odds Ratios for Various Relative Risks

0

1

2

3

4

5

6

7

8

9

10

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

P0

Odd

s R

atio

RR=3

RR=2.5RR=2 RR=1.5

Mutation-Drug Resistance Table

• Table 1 in DAP titled ‘mutations associated with resistance to specific antiretroviral drugs’ is largely based on in vitro data and/or exploratory subgroup analyses

• A general consensus is yet to emerge on this table.

Mutation-Drug Resistance Table

• Most of the studies were available to the resistance collaborative group before the DAP was developed

0 1 2 3 4

Odds Ratio

(E)Stanford (C)

(E)CPCRA GART (C)

(E)VIRADAPT Genotypic (C)

(E)VIRADAPT Control (C)

(E)CNAA2003,CNAB3001-2,CNAB3009 (C)

(E)CNAA2007 (C)

(E)ACTG372 (C)

(E)ACTG364 (C)

.

95% Confidence Interval for Odds Ratio for Overall Genotypic Sensitivity Score:

Model C (Univariate) and E (Multivariate)

1 3 5 7

Odds Ratio

(F)

Stanford (D)

(F)

CPCRA GART (D)

(F)

VIRADAPT Genotypic (D)

(F)

VIRADAPT Control (D)

(F)

CNAA2007 (D)

(F)

ACTG372 (D)

(F)

ACTG333 (D)

.95% confidence interval for Odds ratio for Number of

PI Mutations: Model D and F

0.0 0.5 1.0 1.5

Odds.Ratio

(G)

CNAA2003,CNAB3001-2,3009 (C)

(G)

CNAA2007 (C)

(G)

Mega-HAART (C)

.

95% Confidence Interval for Overall Phenotypic Score:

Model C (Univariate) and Model G (Multivariate)

Conclusions

• These exploratory analyses suggest predictive link between virological failure and genotypic and phenotypic measures at the baseline

• They will provide insight in generating specific hypotheses to be tested in future confirmatory studies