1 postmarketing drug safety and risk intervention studies evelyn m rodriguez md, mph director,...
TRANSCRIPT
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Postmarketing Drug Safety and Risk Intervention Studies
Evelyn M Rodriguez MD, MPH
Director, DDREII, OPDRA
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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
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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
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Postmarketing Safety Surveillance
• Database reporting system:
Adverse Event Reporting System
(AERS)• Cost effective• Signal generation• Receives > 250,000 reports per year
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Postmarketing Causality Assessment
• Temporal Relationship
• Biological Plausibility
• Known Class Effect
• Previous Pre-marketing Findings
• Dose-related Effect
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Postmarketing Causality Assessment
• Onset Time and Progression
• Confirmed Diagnosis
• Dechallenge - discontinue drug
• Rechallenge - restart drug
• Underlying Disease
• Concomitant Drugs
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Use of Cases Identified in AERS
• Case definition - reporter’s clinical
diagnosis or one from the literature
• Develop Case Series
– Causality Assessment
– Conditions of exposure
– Risk Factors and Confounders
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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
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Underreporting of Adverse Drug Reactions From the Literature
Country Drug Reaction Reporting Rate
UK Practolol Oculocutaneous syn << 2%
UK NSAIDS Aplastic anemia 11%
UK OCs TE death in women 15%
US Digitalis Hosp for toxicity 0.3%
US Isoniazid Fatal hepatitis 10%
US DPT SIDS 10-20%
US RI survey Serious << 3%
US MD survey Medically serious < 8-13%
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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)
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Possible Next Steps
• Incidence Study for Serious Outcomes–Ischemic Colitis and
Constipation difficult to ascertain in automated databases (ICD-9 codes and underreporting)
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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
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Possible Next Steps
• Implement Risk Interventions (e.g. Education, Labeling change)
• Evaluate whether the Risk
Interventions are achieving
desired goals
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First Drug History
Risk Intervention Study
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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
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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
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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
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Overview of Study in the United HealthGroup Database
Cohort 1n = 2307
Cohort 2n = 2823
Cohort 3n = 1411
25 Oct 97 1 Dec 97 30 Jun 98 1 Aug 98 31 Dec 9825 Oct 97 1 Dec 97 30 Jun 98 1 Aug 98
Cohort 3n = 1411
31 Dec 98Mar 97 25 Oct 97* 1 Dec 97* 30 Jun 98 1 Aug 98*
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LT Monitoring at Baseline after the First Prescription by Cohort
% with Baseline Test
Cohort 1(n=2307)
24.5
Cohort 2(n=2823)
37.0
Cohort 3(n=1411)
45.1
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Full Compliance with Monthly LT Monitoring by Cohort among Drug Users
Month*
1 2 3 4 5 6
Cohort 1 2.6 0.8 0.3 0 0 0
Cohort 2 7.3 2.5 1.0 0.7 0.6 0.8
Cohort 3 9.3 4.2 2.7 0.5
4.3
*Data Shown as Percentage of Eligible Subjects at Each Time Period
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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%
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Investigators
FDA Dave Graham MD, MPH Evelyn M Rodriguez MD,
MPH
FDA Cooperative Agreement Program
UHG Carol Drinkard, PhD Deborah Shatin, PhD
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Second Drug History
Risk Intervention Study
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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
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Second Drug History
• Black Box Warning with Contraindication for QT interval prolonging drugs and Cardiovascular and Medical Conditions, 2nd line indication & DHPL 6/98
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Study Objective
• To describe the impact of the labeling changes through 6/98–CYP P450 3A4 Enzyme Inhibitor
Drugs
–QT Prolonging Drugs
–Contraindicated Comorbidities
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Methods• Automated Databases:
–Sites A, B, and C
• Time Periods–Before DHPL: 7/97 - 6/98
–After DHPL: 7/98 - 6/99
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Study Sites
Model N, Millions
A IPA 3.2
B Medicaid Managed 1.4
C HMO 2.2N based on calendar 1998; no material change for any of databases in 1999.
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Cohorts Before and After Labeling Changes through
6/98Pre Post
Site N
A 16,934 15,088
B 4,823 4,924
C 8,271 7,508
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Results: Contraindicated Drug or Disease
Pre Post
Site % of Cohort
A 29.4 26.6
B 59.7 57.5
C 29.6 27.5
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Conclusion
• No reduction in
contraindicated use was
found following labeling
changes and DHPL of 6/98
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Study GroupFDA 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)
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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
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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
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Future Directions
• Determine –How information,
contraindications, and monitoring recommendations are used
• Feasibility of constipation as contraindication
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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
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Back Up Slides
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Sample Size of Study Population, UHG
Ever received drug 9,369
Total person-years 4,873
90 day prior enrollment 7,568
Included in LT
monitoring study 6,541
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Criteria for Inclusion in the Study Cohort for LT Monitoring
• Enrollment Date 90 days prior to 1st troglitazone prescription
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Study Method for Measuring Liver Transaminase Monitoring in UHG
Baseline Month 1
…….. Last Rx.
-30d 30d1st Rx. 60d
-30d - + 7d +/- 7d +/- 7d
Month 2
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Cohorts
7/97 6/98 7/98 6/99
PostPre
Pre and post cohorts included persons with any cisapride use in that study period.Zero time (t
0) date first dispensed prescription in study period.
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0
10
20
30
40
50
0
10
20
30
40
<3 3-19 20-39 40- 59 60-79 80+0
10
20
30
40
Site A
Site B
Site C
Age in Years
Age Distribution (%) of Cisapride Users, Pre Year
% Female:
Site A: 60.3
Site B: 67.2
Site C: 62.8
%
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Contraindicated Drugs
P450-3A4 QT-Label QT-ClassClarithromycinErythromycinTroleandomycinNefazodoneFluconazoleItraconazoleKetoconazoleIndinavirRitonavir
QuinidineProcainamideSotalolAmitriptylineMaprotilineAstemizoleBepridilSparfloxacinTerodiline
Antiarrhythmics, IA or IIICyclic AntidepressantsAntipsychotics
(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
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Pre (%) Post (%)Site A: Any 14.4 12.6 P450 3A4 7.4 5.5 QT-Label 4.0 4.1 QT-Class 8.1 7.9
Site B: Any 33.8 33.6 P450 3A4 10.4 9.8 QT-Label 11.4 12.0 QT-Class 26.5 26.4
Site C: Any 18.3 16.1 P450 3A4 9.3 7.5 QT-Label 5.4 5.2 QT-Class 10.4 9.7
Contra-indicatedDrugs
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Contraindicated Comorbidity
• Heart Failure
• Other Ischemic Heart Disease
• Electrolyte Disorder
• Ventricular Arrhythmia
• Renal Failure
• Respiratory Failure
Any diagnosis in the 180 days preceding t0. Restricted to cohort members with 180+ days prior enrollment
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Contraindicated Comorbidity
Pre PostSite %
A 14.9 14.0
B 41.3 38.8
C 15.3 14.5
Based on (pre/post) persons with 180+ days of enrollment: Site A: 13613/12418; B: 4379/4229; C: 6848/5812
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<3 3-19 20-39 40-59 60-79 80+
Age, years
0
20
40
60
80
100%
Cis
aprid
e U
sers
Contraindicated Drug or Comorbidity, By Age
Site B only
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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
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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