# Presentation: 783802

## Population Approach For Clinical Drug Safety Assessment in Regulatory Decisions

- He Sun, Ph.D.
- CDER, FDA

## Questions to committee	

- When should ADR data be treated as continuous variable and when it should be treated as categorical variable ?  What are the bases for the preference, if any?
- What are the utility and general limitations of using PopPK approach to determine individual / special population exposure parameters followed by subsequent E-R analyses ?
- What are the general considerations in E-R based dose adjustment for special populations ?

## Exposure-safety (E-R) data types

## E-R analysis method and process

- Managing/Editing data
- Conducting population PK analysis
- Establishing the base model
- Modeling variabilities
- Searching for significant covariates
- Validating the model, if needed
- Determining individual exposure parameters
- Via post-hoc estimation
- Via simulation
- Deriving secondary exposure parameters
*AUC, Tmic, Ce, and etc.*
*Accumulative exposure *

## E-R analysis method and process (cont.)

- Determining E-R relationship for individuals and/or special populations
- Classification methods
- Classification and regression tree methods
- Logistic regression methods
- Modeling methods
- Considering accumulative exposure time
- Performing statistical analysis on response for significance, per exposure or special populations
- Proposing needed dose adjustment for special populations based on E-R analysis results

## A example: background

- _Study Design_: Two phase 3 trials with 1500 evaluable drug-treated patients receive multiple doses, X, 2x and 4X.  Patient plasma drug concentration measures are sparse and unbalanced.
- _End points_: Safety measures were blood chemistry variables (continuous variable) with pre-defined values (cut-off point) for claiming No ADR.  ADR also presented as Yes/No for headache, liver toxicity, photo-toxicity and etc.  ADRs were future classified as mild, moderate and severe.
- _PK results_: Drug-drug interaction increases AUC by 310%, Cmax by 144 %.  AUC and Cmax are 132% and 79% higher in elderly vs. young healthy subjects.  AUC and Cmax dropped by 50% in Blacks.
- _Safety results_: The total frequency of ADRs ranged from 0.1% to 17%.  Severe cases were rare. There were no death.
- _Efficacy results:_ Clinically efficacy was well demonstrated from the trials.  Exposure - efficacy relationship was unclear.

## E-R analysis methods and results

- Classification on frequency:
- E data was divided into equally populated segments, or
-     E data was divided into equally distanced segments
- The frequency of ADR was then determined for each E segments
-      e.g.  Total ADR is 18% when AUC > 1200, 5% when AUC _<_ 1200
- Classification on severity:
- R data was classified for severity (e.g. Severe, moderate and ,mild)
- The average severity of ADR was then calculated
-     e.g.  Severe ADR occurs when Cmax >10, mild ADR apparent when Cmax <2 with similar frequencies
- Regression and Classification Trees:
- R data are successively split along coordinate axes of the E variables which maximally distinguishes the R variable.
*Classification tree.   First split on ADR frequency was at AUC =871.  Total ADR was 23% when AUC >871, 2.5% when AUC *_*<*_*871 *
*Regression tree on WBC count.*

## E-R analysis methods and results (cont.)

- Regression models on relationships
- Statistical vs. (semi) physiological based models
- Linear, nonlinear models
- Fixed effect, mixed-effect models
- Logistic regression:
- Relationship between E and each R. Odds ratios were determined along with 95% CI, in which the odds ratio denotes the scalar multiple for the likelihood of given ADR associated with unit change in E.
- e.g. The odds ratio of acute tissue rejection increase 23% when AUC0-24 decrease 10%.
- Modeling:
- _HDL drops_ below normal on day 95 when Cavg >10 ug/ml for patients with high body weight and low initial HDL baseline
- _Back Pain score_ (in 0-10) is nonlinearly correlated with plasma drug daily total AUC, the number of treatment days, and dose regimen (tid vs. bid).

## E-R analysis methods and results (cont.)

- Modeling (cont.)
- _QTc prolongation._  The relationship between QTc and drug C was described by a Emax model. Population E0 = 410 msc., Emax = 435 msc. and ED50 = 10 ug/ml.  E0 and Emax are gender and age dependent.
- _Photo toxicity_ Yes on day 10 when Cavg on day 10 greater than 8 ug/ml for female patients.
- _Liver toxicity_ frequency linearly correlate with Cint and time of exposure.
- _Blood chemistry score_ (in 0-10) is nonlinearly correlated with plasma drug AUC and the number of treatment days.
- _Blood chemistry toxicity_ nonlinearly increase as Cavg increase, and TD50 is correlated with drug Cmax.
- Descriptive
- Hypercholesterolemia, defined as >6.5 mmol/liter, ranged from 76 to 87% over the exposure range without a significant relation to Cmin (P=0.37).

## E-R analysis methods and results (cont.)

- Descriptive
- Hypertriglyceridemia, defined as >2.9 mmol/liter, rose from 59 to 77% across the exposure groups (P=0.02).
- Leukocytopenia, defined as <4x10(9)/liter, occurred in 11-19% of patients across the exposure quintiles showing no relationship to Cmin (P=0.76).
- Thrombocytopenia, defined as <100x10(9)/liter, occurred in <=10% of patients in the first 3 Cmin quintiles and was 23 and 28% in Cmin quintiles 4 and 5 (P=0.21).
- Because hyperlipidemias responded to counter-measure therapies and thrombocytopenia had an overall low incidence of 12%, drug-related ADRs were manageable up to the highest troughs observed in this population of 5 ug/ml.
- Dose adjustment in special populations:  The average upper therapeutic limits are likely to be 10 ug/ml for Cmax and 871 for AUC.  Female subject more sensitive to phototoxicity and Cavg < 8 ug/ml was considered.  bid dose regimen is preferred.

## Questions to committee	

- What are the utility and general limitations of linking PK obtained from population analysis to response endpoints ?
- What are the general considerations in E-R based dose adjustment for special populations ?
- When should ADR data be treated as continuous variable and when it should be treated as categorical variable ?  What are the bases for the preference, if any?