national health policy conference, washington, dc february 6, 2006 1 drug safety challenges:...
TRANSCRIPT
National Health Policy Conference, Washington, DC February 6, 2006
1
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
National Health Policy Conference, Washington, DC February 6, 2006
2
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
National Health Policy Conference, Washington, DC February 6, 2006
3
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
National Health Policy Conference, Washington, DC February 6, 2006
4
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
National Health Policy Conference, Washington, DC February 6, 2006
5
Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
National Health Policy Conference, Washington, DC February 6, 2006
6
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
National Health Policy Conference, Washington, DC February 6, 2006
7
Post-marketing Drug Safety Risk Assessment:Identification of New Adverse Events
Pre-marketing Safety Data
Market Introduction
Post-marketing Period
? ? ?
National Health Policy Conference, Washington, DC February 6, 2006
8
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
National Health Policy Conference, Washington, DC February 6, 2006
9
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
National Health Policy Conference, Washington, DC February 6, 2006
10
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
National Health Policy Conference, Washington, DC February 6, 2006
11
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?
National Health Policy Conference, Washington, DC February 6, 2006
12
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
National Health Policy Conference, Washington, DC February 6, 2006
13
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
National Health Policy Conference, Washington, DC February 6, 2006
14
Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskClinical Trial
Random Allocation
Treatment of Interest
Control Treatment
Follow-up Period
National Health Policy Conference, Washington, DC February 6, 2006
15
Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskClinical Trial
Random Allocation
Treatment of Interest
Control Treatment
Follow-up Period
National Health Policy Conference, Washington, DC February 6, 2006
16
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
National Health Policy Conference, Washington, DC February 6, 2006
17
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
National Health Policy Conference, Washington, DC February 6, 2006
18
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)
National Health Policy Conference, Washington, DC February 6, 2006
19
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
National Health Policy Conference, Washington, DC February 6, 2006
20
Post-marketing Drug Safety Risk Assessment:Investigation of New Adverse Event RiskEpidemiological Study - Cohort Study
Start observation Time
Relative risk or hazard ratio
National Health Policy Conference, Washington, DC February 6, 2006
21
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
National Health Policy Conference, Washington, DC February 6, 2006
22
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
National Health Policy Conference, Washington, DC February 6, 2006
23
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)
National Health Policy Conference, Washington, DC February 6, 2006
24
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
National Health Policy Conference, Washington, DC February 6, 2006
25
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
National Health Policy Conference, Washington, DC February 6, 2006
26
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
National Health Policy Conference, Washington, DC February 6, 2006
27
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)
National Health Policy Conference, Washington, DC February 6, 2006
28
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
National Health Policy Conference, Washington, DC February 6, 2006
29
Active Surveillance
• Request for Information issued April 2005• Responses received June 2005• Responses currently under review• Agency will decide on next steps
National Health Policy Conference, Washington, DC February 6, 2006
30
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