National Health Policy Conference, Washington, DC February 6, 2006 1 Drug Safety Challenges: Considerations for Sources of Data Gerald J. Dal Pan, MD,

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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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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Market Introduction


? ? ?


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Market Introduction


Rare but serious adverse event

•Aplastic anemia

•Drug-induced liver injury


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Market Introduction


Also common in the population

•Myocardial infarction


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Market Introduction


Also a manifestation of the underlying disease

•Myocardial infarction


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Market Introduction


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


Market Introduction


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


Market Introduction


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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Random Allocation


Control Treatment

Follow-up Period


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Random Allocation


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

Documents

National Health Policy Conference, Washington, DC February 6, 2006 1 Drug Safety Challenges: Considerations for Sources of Data Gerald J. Dal Pan, MD,