# Presentation: 388993

## Case Study: A Quantitative Approach to Assess A Genomic Design and A Biomarker Titration Design for A Phase III Clinical Study 

**Clinical Pharmacology Subcommittee **
**Advisory Committee for Pharmaceutical Science**
**November 14, 2005**
**Yaning**** ****Wang, Ph.D.**
**Office of Clinical Pharmacology and Biopharmaceutics**
**Center of Drug Evaluation and Research**
**Food and Drug Administration**

## Outline

**Introduction**
**Clinical pharmacology**
**Clinical trial considerations**
**PK/PD modeling**
**Clinical trial simulation**
**Stratification by genotype design**
**Titration by biomarker design**
**Conclusion**
**Questions to the committee**

## Drug X

**Treatment for a chronic disease**
**Polymorphism in metabolic enzyme **
**a/a  20%**
**a/b  50%            **
**b/b  30%     ****Poor metabolizers (PM’s)**
**↓ ****Biomarker (B) & Surrogate (S) levels**
**Goal: How to manage a genotypic influence on drug clearance in dose selection for Phase III trial design**

**Extensive metabolizers (EM’s)**

## Genotype Caused PK Difference

**EM’s**

**PM’s**

**a/a**

**a/b**

**b/b**

**Dose Normalized AUC (ng.h/ml/1 mg)**

## Genotype Caused PD Difference (Week 12, QD, 20 mg)

**Genotype Caused PD Difference** **(Week 12, QD, 20 mg)**

**EM’s**

**PM’s**

**a/a**

**a/b**

**b/b**

**Surrogate Change from Baseline**

## Modeling Strategy

**Pharmacokinetics (Drug X)**
**Phase 1 data for population PK model**
**Phase 2 data for model update**
**Pharmacodynamics (Biomarker and Surrogate)**
**Model established using clinical trial data available to FDA from drugs in this class & other classes**
**Simultaneous modeling biomarker and surrogate**
**Models updated with Drug X data**

## Surrogate

- Biomarker

- Drug Conc.

- Time (Week)

## Modeling Results for Biomarker & Surrogate(Drug Y in 900 patients)

**Modeling Results for ****Biomarker & Surrogate****(Drug Y in 900 patients)**

**Surrogate**

**Biomarker**

**Observed S Level**

**Observed B Level**

**Observed Level**

**Week**

**Observed Level**

**Week**

**Individual Predicted**
** ****Biomarker Level**

**Individual Predicted**
** ****Surrogate Level**

## A Hybrid Dataset

**A Hybrid Dataset**

**+**

**=**

**Drug X **
**in 400 patients**

**Drug Y **
**in 100 patients**

**Hybrid dataset**
**in 500 patients**

**Observed Level**

**Week**

**Observed Level**

**Week**

**Week**

**Week**

**Week**

**Week**

**Surrogate**

**Biomarker**

## Drug X: Model Fits(individual patients)

**a/a, 20 mg**

**b/b, 20 mg**

**Week**

**Biomarker **
**Level**

**Surrogate**
**Level**

**Drug X: Model Fits****(individual patients)**

## Simulation Strategy & Assumptions

**Population PK model**
**Two-compartment model**
**Clearance dependent on genotype (a/a, a/b and b/b)**
**Exposure-response model**
**Drug-Biomarker-Surrogate model**
**Trial designs**
**Stratification by genotype **
**Titration by biomarker**
**Inclusion criterion**
**Baseline Surrogate>70 and <100**
**Analysis**
**Response rate at week 26 (Surrogate reduction > 10)**
**100 clinical trial replicates**

## Stratification by Genotype (Genotype 1st, Parallel Dose, Placebo Control)100 Patients = 20 a/a, 50 a/b, 30 b/b

**0**

**26**

**Time (weeks)**

**Dose mg/day**

**PM**

**EM**

**40**

**20**

**120**

**10**

**60**

**30**

**PBO**

**PBO**

**100**

**100**

**100**

**100**

**EM**

**PM**

## Titration by Biomarker(Parallel Dose, Titration at 12 wk, Placebo Control)

**0**

**26**

**Time (weeks)**

**Dose mg/day**

**All **

**40**

**20**

**10**

**PBO**

**Titration by Biomarker (****Biomarker ******** <13****)**

**30 (Biomarker non-responder)**

**100**

**100**

**100**

**100**

**12**

**10 (Biomarker responder)**

**60 (Biomarker non-responder)**

**20(Biomarker responder)**

**120 (Biomarker non-responder)**

**40 (Biomarker responder)**

**3X (Biomarker non-responder)**

**PBO (Biomarker responder)**

## Clear Dose-Response Relationship for Various Regimens

**Clear Dose-Response Relationship for Various Regimens**

**Response Rate at Week 26 (%)**

## Higher Response Rate at Week 26 for Stratification by Genotype

**Higher Response Rate at Week 26 for Stratification by Genotype**

**Response Rate at Week 26 (%)**

## Smaller Difference in Response Rates at Later Weeks

**10%**

**5%**

## Better Response Rates at Week 26 for BID than QD

**Better Response Rates at Week 26 for BID than QD**

**Response Rate at Week 26 (%)**

## Larger Difference in Response Rates for EM Patients

**Response Rate at Week 26 (%)**

## Some PM Patients Will Have Exposures beyond Previous Experience

**Proportion of PM patients receiving high doses not studied **

## Conclusion

**At week 26, higher response rates were achieved in stratification by genotype design than titration by biomarker design. But the difference is getting smaller at later weeks.**
**BID regimens perform better than QD regimens, especially in EM population.**
**High-dose safety data in PM is needed.**
**Biomarker-Surrogate relationship can be applied to other drugs with similar mechanism of action.**

## Post-Meeting Evaluation

**Sponsor attendees: 3 Clin Devel, 1 Reg, 2 Proj. Mgmt, 2 Biostats, 1 Clin Pharm**
**How valuable did you find this meeting? (5 pivotal-1 worthless) (****mean 4.3 (range 4-5)**
**‘****Pivotal importance. We were at a juncture in development that required detailed discussion and feedback with FDA’ ****Clinical**
**‘****The technical discussion about the M&S approach in the development of this drug was of high-quality and, therefore, very valuable. It is good to experience that the FDA supports the use of (new) biometrical techniques in drug development’. ****Biostats**
**Did the meeting change the development plan? (sponsor: 7 yes, 1 no)**
**‘****The modeling offered alternative development scenarios that may impact the final development plan.’ ****Regulatory****, ****Clinical**
**Do you believe this meeting will have value in:**
**Decreasing Phase 3 attrition? 8 yes, 1 no**
**Designing Phase 3 trials with ↑ success chance? 8 yes**
**Was the time and effort required to prepare for the meeting**
**Adequate? 8 yes**
**Worth the results? 8 yes**

## QUESTIONS TO THE COMMITTEE

**Comment on the quantitative approach used in this case study**
**Comment on how we would incorporate & evaluate genotype clinical trial design recommendations in different scenarios**
**metabolism genotype**
**pharmacodynamic genotype**
**disease genotype**
**narrow vs wide therapeutic index**