Postmarketing drug safety and risk intervention studies
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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

Director, DDREII, OPDRA


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


Underreporting of adverse drug reactions from the literature

Underreporting of Adverse Drug Reactions From the Literature


Lotronex

Lotronex

  • 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


Postmarketing drug safety and risk intervention studies

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


Lt monitoring at baseline after the first prescription by cohort

LT Monitoring at Baseline after the First Prescription by Cohort


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

Conclusion

  • 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%


Investigators

FDA

Dave Graham MD, MPH

Evelyn M Rodriguez MD, MPH

FDA Cooperative Agreement Program

UHG

Carol Drinkard, PhD

Deborah Shatin, PhD

Investigators


Second drug history

Second Drug History

Risk Intervention Study


Second drug history1

Second Drug History

  • 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

  • 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

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

    • CYP P450 3A4 Enzyme Inhibitor Drugs

    • QT Prolonging Drugs

    • Contraindicated Comorbidities


Methods

Automated Databases:

Sites A, B, and C

Time Periods

Before DHPL: 7/97 - 6/98

After DHPL: 7/98 - 6/99

Methods


Study sites

Study Sites

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


Cohorts before and after labeling changes through 6 98

Cohorts Before and After Labeling Changes through 6/98


Results contraindicated drug or disease

Results: Contraindicated Drug or Disease


Conclusion1

Conclusion

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


Study group

Study Group

  • 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

  • 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

  • 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

  • Determine

    • How information, contraindications, and monitoring recommendations are used

      • Feasibility of constipation as contraindication


Future directions2

Future Directions

  • 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


Sample size of study population uhg

Sample Size of Study Population, UHG

Ever received drug9,369

Total person-years4,873

 90 day prior enrollment 7,568

Included in LT

monitoring study6,541


Criteria for inclusion in the study cohort for lt monitoring

Criteria for Inclusion in the Study Cohort for LT Monitoring

  • 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

Baseline

Month 1

Month 2

-30d - + 7d

+/- 7d

+/- 7d

…….. Last Rx.

-30d

1st Rx.

30d

60d


Cohorts

Cohorts


Postmarketing drug safety and risk intervention studies

Age Distribution (%) of Cisapride Users, Pre Year

% Female:

Site A: 60.3

Site B: 67.2

Site C: 62.8

%


Contraindicated drugs

Contraindicated Drugs

(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


Postmarketing drug safety and risk intervention studies

Contra-indicated

Drugs


Contraindicated comorbidity

Heart Failure

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

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


Postmarketing drug safety and risk intervention studies

Contraindicated Drug or Comorbidity, By Age

Site B only


Future directions3

Future Directions

  • 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

  • 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


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