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Postmarketing Drug Safety and Risk Intervention Studies. Evelyn M Rodriguez MD, MPH Director, DDREII, OPDRA. Topics for Today’s Discussion. Postmarketing Drug Safety Two Risk Intervention Case Studies Review of the Labeling History Study Objective, Methods, Results and Conclusions

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Postmarketing drug safety and risk intervention studies

Postmarketing Drug Safety and Risk Intervention Studies

Evelyn M Rodriguez MD, MPH


Topics for today s discussion
Topics for Today’s Discussion

  • Postmarketing Drug Safety

  • Two Risk Intervention Case Studies

    • Review of the Labeling History

    • Study Objective, Methods, Results and Conclusions

  • Summary / Considerations

  • Future Directions

Why post marketing surveillance
Why Post-Marketing Surveillance?

  • Limitations of Phase 3 Trials

    • Too few, too simple, too median aged, too narrow, too brief

  • Population of Users Expands After Drug Approval

    • Age, Sex, Race/Ethnicity, Use in pregnancy

  • Rare Events

Postmarketing safety surveillance
Postmarketing Safety Surveillance

  • Database reporting system: Adverse Event Reporting System (AERS)

  • Cost effective

  • Signal generation

  • Receives > 250,000 reports per year

Postmarketing causality assessment
Postmarketing Causality Assessment

  • Temporal Relationship

  • Biological Plausibility

  • Known Class Effect

  • Previous Pre-marketing Findings

  • Dose-related Effect

Postmarketing causality assessment1
Postmarketing Causality Assessment

  • Onset Time and Progression

  • Confirmed Diagnosis

  • Dechallenge - discontinue drug

  • Rechallenge - restart drug

  • Underlying Disease

  • Concomitant Drugs

Use of cases identified in aers
Use of Cases Identified in AERS

  • Case definition - reporter’s clinical diagnosis or one from the literature

  • Develop Case Series

    • Causality Assessment

    • Conditions ofexposure

    • Risk Factors and Confounders

Underreporting barriers to reporting
Underreporting:Barriers to Reporting

  • Voluntary System

  • Recognize , Attribute , and Establish Adverse Event to Drug

  • Labeled adverse events less likely reported

  • Constraints, Litigation Fear, Desire to Publish Findings, Privacy Concerns


  • Pre-marketing cases of ischemic colitis and constipation

  • Postmarketing reports of serious cases

    • Ischemic colitis

    • Serious complications of Constipation

  • Early in marketing (3 months)

Possible next steps
Possible Next Steps

  • Incidence Study for Serious Outcomes

    • Ischemic Colitis and Constipation difficult to ascertain in automated databases (ICD-9 codes and underreporting)

Possible next steps1
Possible Next Steps

  • Risk Factor Study

    • Risk factor identification may be feasible for Ischemic Colitis IF complete ascertainment is assured

    • Constipation as a risk factor for serious GI outcomes hard to evaluate because it is associated with IBS, the indication for the drug

Possible next steps2
Possible Next Steps

  • Implement Risk Interventions (e.g. Education, Labeling change)

  • Evaluate whether the Risk Interventions are achieving desired goals

First drug history

First Drug History

Risk Intervention Study

First case history
First Case History

  • Approved in January 1997

  • Marketed in March 1997

  • Seven months after marketing, first

    Acute Liver Failure death

  • Several Re-labelings and Dear Healthcare Practitioner letters including recommendations for Liver Transaminase (LT) testing

Risk intervention study objective
Risk Intervention Study Objective

  • To assess the impact of the labeling changes regarding LT monitoring in a large managed care organization automated claims database using ICD-9 and CPT codes

Risk intervention study objective1
Risk Intervention Study Objective

  • Recommended LT monitoring varied slightly with each labeling change

  • Last labeling change recommended a baseline test with monthly monitoring for first 8 months, data presented to AC 3/99

Overview of Study

in the United HealthGroup Database

Mar 97

25 Oct 97*

25 Oct 97

25 Oct 97

1 Dec 97

1 Dec 97

1 Dec 97*

30 Jun 98

30 Jun 98

30 Jun 98

1 Aug 98

1 Aug 98

1 Aug 98*

31 Dec 98

31 Dec 98

Cohort 1

n = 2307

Cohort 3

n = 1411

Cohort 3

n = 1411

Cohort 2

n = 2823

Full compliance with monthly lt monitoring by cohort among drug users
Full Compliance with Monthly LT Monitoring by Cohort among Drug Users

*Data Shown as Percentage of Eligible Subjects at Each Time Period

Conclusion Drug Users

  • Poor compliance with full LT monitoring scheme recommended by labeling

  • Better compliance with baseline LT testing that improved with each labeling change to a maximum of 45%


FDA Drug Users

Dave Graham MD, MPH

Evelyn M Rodriguez MD, MPH

FDA Cooperative Agreement Program


Carol Drinkard, PhD

Deborah Shatin, PhD


Second drug history

Second Drug History Drug Users

Risk Intervention Study

Second drug history1
Second Drug History Drug Users

  • Approved in July 1993

  • First reports of Ventricular Arrhythmia with an antifungal drug 12/94

  • Multiple Dear Healthcare Practitioner letters that described new contraindications and warnings for specific drugs and conditions

Second drug history2
Second Drug History Drug Users

  • Black Box Warning with Contraindication for QT interval prolonging drugs and Cardiovascular and Medical Conditions, 2nd line indication & DHPL 6/98

Study objective
Study Objective Drug Users

  • To describe the impact of the labeling changes through 6/98

    • CYP P450 3A4 Enzyme Inhibitor Drugs

    • QT Prolonging Drugs

    • Contraindicated Comorbidities


Automated Databases: Drug Users

Sites A, B, and C

Time Periods

Before DHPL: 7/97 - 6/98

After DHPL: 7/98 - 6/99


Study sites
Study Sites Drug Users

N based on calendar 1998; no material change for any of databases in 1999.

Conclusion Drug Users

  • No reduction in contraindicated use was found following labeling changes and DHPL of 6/98

Study group
Study Group Drug Users

  • FDA Investigators

    • Diane Wysowski Ph.D., Evelyn M. Rodriguez, Dave Graham M.D., M.P.H.

  • United Health Group (Site A)

    • Deborah Shatin, Ph.D., Stephanie D. Schech, Ph.D.

  • Tennessee Medicaid (Site B)

    • Walter Smalley, M.D., M.P.H., Jim Daugherty, M.S., Wayne Ray, Ph.D.

  • Harvard Consortium (Site C)

    • Jerry Gurwitz, M.D, Susan Andrade, D.Sc., Jackie Cernieux, M.P.H. (Meyers Primary Care Institute, Fallon Healthcare System); Richard Platt, M.D., M.S., Arnold Chan, M.D., Dr.P.H. (Harvard Pilgrim Healthcare, Michael Goodman, Ph.D. (HealthPartners)

Summary considerations
Summary / Considerations Drug Users

  • Risk Intervention studies are useful to assess the effect of labeling and DHPL

  • These two studies suggest labeling fatigue phenomenon

  • Other strategies, such as Education targeting Prescribers and Patients, may be useful to encourage the implementation of recommended risk management efforts

Future directions
Future Directions Drug Users

  • Determine

    • How prescribers interpret information from DHPL & other educational materials

    • Best format to inform prescribers and patients of drug safety concerns -- PPI, Med Guide, company sales materials, CME courses

Future directions1
Future Directions Drug Users

  • Determine

    • How information, contraindications, and monitoring recommendations are used

      • Feasibility of constipation as contraindication

Future directions2
Future Directions Drug Users

  • Conduct risk intervention studies in multiple databases that reflect the range of health care services delivery systems

  • Validate the findings in databases with medical record review

Back up slides

Back Up Slides Drug Users

Sample size of study population uhg
Sample Size of Study Population, UHG Drug Users

Ever received drug 9,369

Total person-years 4,873

 90 day prior enrollment 7,568

Included in LT

monitoring study 6,541

Criteria for inclusion in the study cohort for lt monitoring
Criteria for Inclusion in the Study Cohort for LT Monitoring Drug Users

  • Enrollment Date  90 days prior to 1st troglitazone prescription

Study method for measuring liver transaminase monitoring in uhg
Study Method for Measuring Liver Transaminase Monitoring in UHG


Month 1

Month 2

-30d - + 7d

+/- 7d

+/- 7d

…….. Last Rx.


1st Rx.



Cohorts UHG

Age Distribution (%) of Cisapride Users, Pre Year UHG

% Female:

Site A: 60.3

Site B: 67.2

Site C: 62.8


Contraindicated drugs
Contraindicated Drugs UHG

(At least 1 day of use concurrent with cisapride use)

Antiarrhythmics: procainamide, quinadine, sotalol, amiodarone, disopyramide

Antipsychotics: chlorpromazine, mesoridazine, thioridazine, trifluoperazine, thiothixene, haloperidol, fluphenazine, triflupromazine, pimozide, risperidone, perphenazine

Cyclic antidepressants: amitriptyline, clomipramine, imipramine, doxepin, trimiprramine, amoxapine, desipramine, nortriptyline, protiptyline, maprotiline

Contra-indicated UHG


Contraindicated comorbidity

Heart Failure UHG

Other Ischemic Heart Disease

Electrolyte Disorder

Ventricular Arrhythmia

Renal Failure

Respiratory Failure

Contraindicated Comorbidity

Any diagnosis in the 180 days preceding t0. Restricted to cohort members with 180+ days prior enrollment

Contraindicated comorbidity1
Contraindicated Comorbidity UHG

Based on (pre/post) persons with 180+ days of enrollment: Site A: 13613/12418; B: 4379/4229; C: 6848/5812

Future directions3
Future Directions UHG

  • Conduct studies among prescribers to identify the “best communication practices” that will enhance timely and useful communication by industry and FDA

  • Assess the impact of the health care services delivery system on prescribing and medical practice in the context of safer drug use

Future directions4
Future Directions UHG

  • Form industry-government partnerships & interagency collaborations to conduct further studies to identify effective risk intervention strategies

  • Using the results from these studies, implement strategies and evaluate success