# Presentation: 811424

## Elizabeth B. Andrews,Ph.D., M.P.H.

**Director, Worldwide Epidemiology**

## Risk Management Plan

## GW Program of Responsible Product Stewardship

***Scientific foundation***** to understand the risks and predictors of serious events**
***Communication program***** to educate physicians, pharmacists and patients**
***Program evaluation***** to determine if and when additional efforts are warranted**

## Risk Management StrategyAn Integrated Approach

_**Communication**_

_**Program Evaluation**_

**Systematic Evaluation**

_**Risk Definition**_

**Mechanistic Studies**

**Clinical Studies**

**Risk Management Strategy****An Integrated Approach**

**Appropriate Use Program**
**Healthcare Practitioners**
**Pharmacists**
**Patients**

**Testing Comprehension of Communication Vehicles**
**Tracking Awareness and Source of Knowledge**
**Lotronex Utilization Study**
**Ongoing pharmacovigilance**

## Risk Management StrategyAn Integrated Approach

_**Communication**_

_**Program Evaluation**_

**Systematic Evaluation**

_**Risk Definition**_

**Mechanistic Studies**

**Clinical Studies**

**Risk Management Strategy****An Integrated Approach**

**Appropriate Use Program**
**Healthcare Practitioners**
**Pharmacists**
**Patients**

**Testing Comprehension of Communication Vehicles**
**Tracking Awareness and Source of Knowledge**
**Lotronex Utilization Study**
**Ongoing pharmacovigilance**

## Risk Management StrategyAn Integrated Approach

_**Program Evaluation**_

**Systematic Evaluation**

_**Risk Definition**_

**Mechanistic Studies**

**Clinical Studies**

**Risk Management Strategy****An Integrated Approach**

_**Communication**_

**Appropriate Use Program**
**Healthcare Practitioners**
**Pharmacists**
**Patients**

**Testing Comprehension of Communication Vehicles**
**Tracking Awareness and Source of Knowledge**
**Lotronex Utilization Study**
**Ongoing pharmacovigilance**

## Risk Management StrategyAn Integrated Approach

**Systematic Evaluation**

_**Risk Definition**_

**Mechanistic Studies**

**Clinical Studies**

**Risk Management Strategy****An Integrated Approach**

_**Program Evaluation**_

_**Communication**_

**Appropriate Use Program**
**Healthcare Practitioners**
**Pharmacists**
**Patients**

**Testing Comprehension of Communication Vehicles**
**Tracking Awareness and Source of Knowledge**
**Lotronex Utilization Study**
**Ongoing pharmacovigilance**

## Risk Management StrategyAn Integrated Approach

_**Communication**_

_**Program Evaluation**_

**Systematic Evaluation**

_**Risk Definition**_

**Mechanistic Studies**

**Clinical Studies**

**Risk Management Strategy****An Integrated Approach**

**Appropriate Use Program**
**Healthcare Practitioners**
**Pharmacists**
**Patients**

**Testing Comprehension of Communication Vehicles**
**Tracking Awareness and Source of Knowledge**
**Lotronex Utilization Study**
**Ongoing pharmacovigilance**

## Recent launch
Interest high
Many options considered
Strategy consistent with the evidence
Appropriate patients
Early recognition

**Interest high**
**Many options considered**
**Strategy consistent with the evidence**
**Appropriate patients**
**Early recognition**

**Risk Management Strategy Opportunity**

## Risk DefinitionEpidemiology Program

## Contributions of Epidemiology Studies vs Clinical Trials

**Large numbers of patients**
**Real world experience**
**more heterogeneous patients**
**treatment and compliance less controlled**
**Estimate infrequent/rare events**
**Explore risk factors for events**
**Trade depth (trial) for breadth (epidemiology)**

## Program of Epidemiology Research: Questions Addressed

**Frequency of complications of constipation in patients treated with Lotronex in actual practice**
**Frequency of ischemic colitis in patients treated with Lotronex compared with other populations – persons with IBS, persons who consult GI specialists, general population**
**Potential risk factors**

## General Study Designs

**Observational cohort studies to define incidence of complications of constipation and ischemic colitis**
**Nested case-control studies to evaluate risk factors**

## Methodologic Issues

**Methodologic Issues**

**Challenges**
**Spectrum of disease**
**ICD-9 code is non-specific**
**Approaches**
**Broad capture of ICD-9 codes**
**Development of computer algorithms**
**Validation through chart review**

## Epidemiology Commitments

**GW and FDA agreed to a Phase IV observational cohort study**
**10,000 patients treated with Lotronex**
**GW is modifying the study to include complications of constipation**

## Observational Cohort Study of Safety in Patients Receiving Lotronex

**Objectives**
**1.****	****Incidence and risk factors for complications of constipation in patients receiving Lotronex **
**2.****	****Incidence and risk factors for ischemic colitis in patients receiving Lotronex**
**3.****	****Incidence of these events in the general population and in patients with IBS not receiving Lotronex**

## Datasource 
United HealthCare (UHC) Research Database
Second largest health care company in the United States: >300,000 physicians, >14 million members
UHC Research Database subset comprised of 7 million members since 1990 with medical and prescription coverage

**United HealthCare (UHC) Research Database**
**Second largest health care company in the United States: >300,000 physicians, >14 million members**
**UHC Research Database subset comprised of 7 million members since 1990 with medical and prescription coverage**

**Observational Cohort Study of Safety in Patients Receiving Lotronex**

## Study Conduct: 
Phase IDevelopment of algorithms using computerized claims to identify patients with diagnoses under study
Phase IIIncidence of events in patients receiving Lotronex
Phase IIIFurther characterize events in patients with IBS, and in general population

_**Phase I**_**Development of algorithms using computerized claims to identify patients with diagnoses under study**
_**Phase II**_**Incidence of events in patients receiving Lotronex**
_**Phase III**_**Further characterize events in patients with IBS, and in general population**

**Observational Cohort Study of Safety in Patients Receiving Lotronex**

## Utilization Study 

**Question:****Descriptive study of utilization patterns over time in United HealthCare  **
**Population:****All persons receiving a prescription for Lotronex **
**Analysis:****Descriptive evaluation of users by :**
**Age****	****	****	**
**Gender**
**History of constipation**
**History of IBS-related visits and prescriptions**

## This study is also part of Program Evaluation
Systematic evaluation
First review December 2000, quarterly thereafter

**Systematic evaluation**
**First review December 2000, quarterly thereafter**

**Utilization Study **

## Epidemiology:Program of Research

**Study****	****Population****	****Timeline**
**Phase IV Study of Safety ****	****UHC Research****	****•**** First interim ****in 10,000 patients ****	****Database****	****   report ****treated with Lotronex ****	****•**** 7 million members****	****   December 2000 ****	**
**Disease frequency/ ****	****GPRD (UK)****	****•**** Complete****risk factors in ****	****•**** 6 million patients****	****   December 2000 ****general population ****and patients with IBS**

## Epidemiology:Program of Research (continued)

**Study****	****Population****	****Timeline**
**Disease frequency ****	****TN Medicaid****	****•**** Complete Fall ****and risk factors****	****•**** 1.4 million patients ****	****   2002 ****	**
**Disease frequency ****	****Mayo Clinic &****	****•**** Complete Fall ****and risk factors ****	****Foundation****	****   2002 ****	****•**** Residents of****	****   Olmstead County**
**Case control study ****	****Patients in GW****	****•**** Initiate Summer****in GW Clinical Trials ****	****Clinical Trials****	****   2000****	**

## Risk DefinitionClinical Studies

## Program of Clinical Studies

**Study on constipation management**
**Laxatives**
**Interruption of therapy**
**Dose reduction**
**Studies for other indications/populations**
**Male IBS**
**Functional Dyspepsia**

## Risk DefinitionMechanistic Studies

## Mechanistic Studies

**Phase IV commitment**
**Cultured endothelial cell integrity**
**Mesenteric blood flow in humans with PET scanning**
**Coagulation factors**

## Risk Management StrategyAn Integrated Approach

_**Communication**_

_**Program Evaluation**_

**Systematic Evaluation**

_**Risk Definition**_

**Mechanistic Studies**

**Clinical Studies**

**Risk Management Strategy****An Integrated Approach**

**Appropriate Use Program**
**Healthcare Practitioners**
**Pharmacists**
**Patients**

**Testing Comprehension of Communication Vehicles**
**Tracking Awareness and Source of Knowledge**
**Lotronex Utilization Study**
**Ongoing pharmacovigilance**