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![Page 1: National Health Policy Conference, Washington, DC February 6, 2006 1 Drug Safety Challenges: Considerations for Sources of Data Gerald J. Dal Pan, MD,](https://reader035.fdocuments.in/reader035/viewer/2022081518/5514e92e550346b0478b5b3e/html5/thumbnails/1.jpg)
National Health Policy Conference, Washington, DC February 6, 2006
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Drug Safety Challenges:Considerations for Sources of Data
Gerald J. Dal Pan, MD, MHS
Director
Office of Drug Safety
Center for Drug Evaluation and Research
FDA
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Sources of Risk From Medical Products
Known Side Effects
Unavoidable Avoidable
Medication and Device Errors
Product Defects
Preventable Adverse Events
Remaining Uncertainties:
•Unexpected side effects•Unstudied uses
•Unstudied populations
Injury or Death
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
• A fundamental goal of post-marketing drug safety programs
• Must account for many different types of risk
• Must account for many potentially confounding factors
• Must account for time course of events
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Post-marketing Drug Safety Risk Assessment:What Pre-marketing Safety Data Tell Us
Pre-clinicalPharmacology
And Toxicology
ClinicalPharmacology
Clinical Safety DataOpen-label Studies
Clinical Safety DataControlled Studies
Pre-MarketingSafety Data
Product Label
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
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How post-marketing adverse event reports get to FDA
Patients, consumer, and healthcare professionals
FDA MedWatch
Manufacturer
FDA
FDA’s Adverse Event Reporting System (AERS) database
voluntary
voluntary
regulatory requirements
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
? ? ?
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Rare but serious adverse event
•Aplastic anemia
•Drug-induced liver injury
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Also common in the population
•Myocardial infarction
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Also a manifestation of the underlying disease
•Myocardial infarction
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Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
How do we separate a potential signal from the background?
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Rare but serious adverse event
Intensive case evaluation
Look back at pre-marketing safety database
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event Risk
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
Common in the population OR
Manifestation of the underlying disease
Intensive case
evaluation
Look back at pre-marketing
safety databaseStill hard to establish
and quantify risk
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskClinical Trial
Random Allocation
Treatment of Interest
Control Treatment
Follow-up Period
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskClinical Trial
Random Allocation
Treatment of Interest
Control Treatment
Follow-up Period
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskClinical Trial
Random Allocation
Treatment of Interest
Control Treatment
Follow-up Period
Excess Risk
Risk Ratio
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Alternative Sources of Information
• Large health care utilization databases
• Electronic medical record systems
• Registries
• Can be used for active surveillance or to answer specific drug safety questions
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Heath Care Utilization Databases• Large, population-based, integrated pharmacy
and medical claims databases– filled prescriptions– professional services– hospitalizations
• Can capture real-world practice patterns, in the context of the system that gives rise to the data (in US, generally within a given health insurance plan or set of plans)
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Heath Care Utilization Databases• Strengths
– size– based on actual care– data already collected
• Limitations– specific clinical data not present– lack of some important health-related
information (eg, smoking status)– only captures what is billed for– frequent patient turnover as insurance changes
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskEpidemiological Study - Cohort Study
Start observation Time
Relative risk or hazard ratio
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Example of a cohort study:Statins and hospitalized rhabdomyolysis
Cohort: Drug-specific inception cohorts of statin and fibrate users, based on data from 11 US health plans using automated claims covering prescription drugs, outpatient care, hospitalizations, and medical procedures
Exposure: Algorithm developed to calculate person-time on drug for each patient based on prescription claims. Separate classifications for monotherapy and statin-fibrate combination therapy
Outcome: Medical record review of all patients based on hospitalization claims with at least one ICD-9-CM code suggestive of severe muscle injury, followed by a blinded review to determine cases of rhabdomyolysis.
Source: Graham D et al. JAMA 2004;292:25885-2590
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Example of a cohort study:Statins and hospitalized rhabdomyolysisAnalysis: Relative risk estimates of rhabdomyolysis, adjusted for age, sex, and diabetes mellitus were calculated using Poisson regression. Incidence rates per 10,000 person-years of treatment, with 95% CIs, were calculated.
Results:Rhabdoymyolysis per 10,000 Person-Years of Therapy With Lipid-Lowering Drugs Used asMonotherapy or as Combination Therapy With Another Drug
Combination Therapy
DrugMonotherapy Incidence
Rates (95% CI) CombinationIncidence Rates
(95% CI)Atorvastatin 0.54 (0.22-1.12) Atorvastatin + fenofibrate 22.45 (0.57-125)Cerivastatin 5.34 (1.46-13.68) Cerivastatin + gemfibrozil 1035 (369-2117)Pravastatin 0 (0-1.11) No cases 0 (0-67.71)Simvastatin 0.49 (0.06-1.76) Simvastin + gemfibrozil 18.73 (0.47-104)Fenofibrate 0 (0-14.58) Fenofibrate + atorvastatin 16.86 (0.43-93.60)Gemfibrozil 3.70 (0.76-10.82) Gemfibrozil + cerivastatin 789 (166-2138)
Source: Graham D et al. JAMA 2004;292:25885-2590
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Electronic Medical Records• Contain more information than claims
databases:– medications prescribed– detail clinical information (eg, symptoms and signs)– physical examination results– results of diagnostic tests
• Example: General Practitioner Research Database (GPRD)
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskRegistry
Case-control studies
Estimate magnitude of problem
Study natural history or survival
Persons with disease of interest
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Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskRegistry
Risk factors for exposure
Estimate magnitude of exposure
Outcome of exposure
Persons with exposure of interest
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Use of a Postmarketing Registry:Antiepileptic Drugs and Teratogenicity
Pregnant women with epilepsy on valproic acid
Enrollment 7 monthsBirth
PostpartumOutcome
ascertainment
149 VPA-exposed, 16 with major malformations (10.7%, 95% CI: 6.3-16.9)
Internal comparator rate: 2.9% (95% CI: 2.0-4.1)
External comparator rate: 1.62%Source: Wyszynski DF et al. Neurology 2005;64:961-965
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New Database Acquisitions• Four organizations with linked pharmacy-medical claims
databases• Contracts signed September 2005• Allows for collaborations between FDA epidemiologists and
experts at these organizations• Four organizations:
– HMO Research Network/Harvard Pilgrim Health
– Kaiser Family Foundation
– Vanderbilt University
– Ingenix (i3Drug Safety)
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New Database Acquisitions• Four organizations:
– Harvard Pilgrim Health/HMO Research Network• Eight geographically diverse health plans with 3.2 million members
• Electronic medical records available for 6 of 8 sites
– Kaiser Family Foundation• 6.1 current members in northern and southern California
• Fully integrated databases, linked to vital statistics and cancer registries
• Unique formulary limited to selected drugs and indications
– Vanderbilt University• Two state Medicaid populations (Tennessee and Washington)
• 2.2 millions members, some at high medical risk (eg, the poor, nursing home residents)
– Ingenix• Geographically diverse insured population of 12 million members
• Some laboratory data also available
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Active Surveillance
• Request for Information issued April 2005• Responses received June 2005• Responses currently under review• Agency will decide on next steps
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CMS Interactions
• ODS epidemiogists are working with CMS and AHRQ staff to understand better the nature of CMS data
• Current efforts focused on using Part B data for a pilot drug safety study
• Still in learning/exploratory stages