Databases or Registries? Points to Consider Mary Lou Skovron, DrPH Group Director, Global Epidemiology Bristol-Myers Squibb FDA/Industry Statistics Workshop September 29, 2006

Overview Claims databases Registries Examples Conclusions Types Advantages Limitations Registries Examples Conclusions

Claims Databases

Claims Databases Types Open-Plan eg UHC, PharMetrics Pharmacy-based Practice-based Hospital-based HMO, eg Kaiser-Permanente Government eg Medicare, Medicaid

Claims Databases: Advantages Already exist, accruing patient information…useful when a relatively quick answer is needed Potentially large populations from which to draw treated patient and comparison samples…statistical power not usually an issue May include subgroups not included in clinical trials…expand knowledge

Claims Databases: Limitations ICD-9 coding… potential for misclassification Limited sensitivity/specificity Coding affected by reimbursement Short ‘residence’ in the database Clinical, lab, imaging data not usually present Rare events in rare diseases require huge “electronic” populations to identify adequate numbers treated May not represent important sub-populations Surveillance bias and channeling bias Inpatient drug exposures not usually recorded

Claims Databases: Application Acute events (short-term events) Events that come to medical attention, eg CVA Validated algorithm to identify indication and event of interest OR medical record review to verify events Statistical approaches for confounders (eg propensity scores, instrumental variables, risk factor scores, multivariate analyses)

Registries

Registries “A systematic collection of defined events or product exposures in a defined patient population for a defined period of time”1 “A registry per se is not a study. It is an organized collection of data in humans within a particular disease group or other special group…”2 1Arlett P, Moseley J, Seligman PJ p 119 in Pharmacoepidemiology Fourth Edition, Strom BL, ed 2005 2 CIOMS V Section II.h.

Registries: Types Drug/Device Registry: Includes subjects receiving the drug or device regardless of indication Disease Registry: Includes patients with the disease regardless of drug or device exposure

Registries: Strengths Richer data than in electronic databases: Patient SES, history, treatment, clinical data can be collected Define encounter frequency and follow-up duration Event ascertainment does not depend on ICD-9 coding Can address additional questions in the data

Registries: Limitations Accrual can be slow if insufficient sites engaged Generalizability must be established Practical limits on number of patients followed

Registries: Application Long-term outcomes Rare diseases Potential confounders important Multiple objectives

Usefulness of Registries Characteristics of patients in the target population for the new drug Clinical course of the disease Treatment patterns, health care utilization Frequency of adverse events

Registry Lifecycle Early: Describe patient demographics, clinical characteristics, practice patterns (usually cross-sectional analyses); incidence of AEs with short lag times Intermediate: Analyze relationships pf patient characteristics, treatment with outcomes; incidence of less common AEs, AEs with longer lag times; assess risk factors for AE incidence Advanced: Evaluate changes in practice patterns; impact on outcomes and AE incidence; assess rare AE incidence

Registry Quality DeCIDE Network currently developing a reference document on developing, conducting and evaluating registries Sponsored by AHRQ Document in draft, Outline available on the web Report currently in draft

Examples

Example: Cox-2 Inhibitors and Cardiac Events Cox-2 use frequent in population Primary care drug Cardiac events not rare in target population Short-term (< 2 years) events Clinical history important

One Solution Cox-2 Inhibitors and Cardiac Events Claims database analysis1 Advantages: Data already accrued when study need identified Large population Limitation offset Multivariate regression to control confounding Verified cardiac events by chart review Remaining limitations Under-represented > 65 yo 1Velentgas P et al 2006

Key Feature of the Solution Numbers readily available: Exposure: ~ 425,000 eligible subjects available for study at least one dispensing of the 5 study medications during preceding 18-month period first dispensing after minimum of six months without any of the medications Endpoint: ~ 725 confirmed MI/ACS Verification of endpoints Medial record review applying accepted criteria

Example: Thrombolytics And Bleeding Important focus: subpopulations eg ethnicity, gender, age Short-term event Benefit and risk Hospital-based treatment

Solution Thrombolytics and Bleeding Registry approach: National Registry of Myocardial Infarctions Salient strengths: Clinical and lab data ascertained Data from medical records Limitation Offset Validated completeness against another data source Large number of hospitals to assure adequate subpopulations Remaining limitations Short-term data cannot answer long-term questions

Key Feature of the Solution Large number of hospitals participate order to gather data on~200,000 MIs per year Rich patient, clinical, treatment and outcome information Answered the question about safety in subgroups under-represented in the clinical trials In its > 10 year lifecycle has contributed to broad understanding and improvement of medical practice External investigators can propose research; external advisory group reviews and approves all research

Example: Safety of Orencia®, a New Biological for RA Short-term (infections) and longer-term (NHL and other malignancies) events Low general population prevalence of RA candidates for biologics treatment RA a specialty-treated disorder Proactive approach

Solution: Complementary Approaches Claims database study in UHC data Event validation Large pool of potential comparators Population treatment patterns Infections, other possible short-term events Registry building on the independently conducted National databank for Rheumatic Diseases Large pool of participating rheumatologists 5,000 Orencia® initiators comparison to >=15,000 initiators/switchers of other treatments Patient self-report and event verification Enrollment and retention enhancements Short and long-term events

Key Features of the Solution External scientific advisory group Individual protocols Statistical analysis plans Interpretation of results including approaches to integration

Conclusions

Conclusions One size does not fit all: evaluate options Registries: a useful alternative to electronic databases Consider complementary approaches

Useful References Strom BL, ed; Pharmacoepidemiology 4th Edition; UK; John Wiley and Sons Ltd;2005 AHRQ DeCIDE Network upcoming publication http://effectivehealthcare.ahrq.gov/decide/

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