Researched Abuse, Diversion, and Addiction-Related Surveillance Sidney H. Schnoll, M.D., Ph.D.

2 CONFIDENTIAL RADARS RADARS ® System Need for Surveillance System Increasing reports of abuse and diversion of OxyContin ® Lack of data to support or refute media reports National data sets (DAWN, NHSDA) reporting increasing problems with prescription opioids

3 CONFIDENTIAL Narcotic Analgesics ED Mentions as a Percent of Total Drug Abuse Mentions Drug Abuse Warning Network (DAWN),

4 CONFIDENTIAL National Household Survey of Drug Abuse Any Lifetime Use of Hydromorphone Lifetime Drug Use Behaviors: %Nonmedical Use of Multiple (2 or more) Prescription Analgesics (not hydromorphone) % Use of Cocaine % Use of Heroin % Use of Cocaine or Heroin % Nonmedical Use of Multiple Analgesics AND Cocaine or Heroin % Needle Use

5 CONFIDENTIAL RADARS RADARS ® System Need for Surveillance System National data sets reported data months after collection Those abusing and diverting were not necessarily patients Traditional drug safety/pharmacovigilance not the answer Needed rapid implementation

6 CONFIDENTIAL RADARS RADARS ® System Design Considerations Develop advisory board of experts in addiction, drug policy, law enforcement and epidemiology Use existing models if possible, i.e. tramadol independent steering committee Expand and use different models as needed Keep pipeline in mind

7 CONFIDENTIAL RADARS RADARS ® System External Advisory Board (EAB) Edgar Adams, Ph.D.Harris Interactive Cmdr. John BurkeNADDI Theodore Cicero, Ph.D.Washington Univ. Richard Dart, M.D.Rocky Mountain PCC Danna Droz, R.Ph., J.D.NASCSA Ann Geller, M.D.Columbia University James Inciardi, Ph.D.Univ. of Delaware Herbert Kleber, M.D.Columbia University Alvaro Muñoz, Ph.D.Johns Hopkins Univ. Mark Parrino, M.P.A.AATOD Edward Senay, M.D.Univ. of Chicago George Woody, M.D.Univ. of Pennsylvania

8 CONFIDENTIAL RADARS RADARS ® System Goals Prospectively study the nature and extent of abuse of scheduled prescription opioid medications Suggest interventions to reduce diversion and abuse that are related to problems identified

9 CONFIDENTIAL The RADARS System Drugs The RADARS ® System Drugs 1.buprenorphine 2.fentanyl 3.hydrocodone 4.hydromorphone 5.methadone 6.morphine 7.oxycodone

10 CONFIDENTIAL RADARS ® System Levels of Activity Other Purdue Signals Signal Detection Signal Verification Focused Studies Interventions Outcomes Relative Rate Determination

11 CONFIDENTIAL Signal Detection Components Rationale Serves as an early warning system Timely collection (quarterly) Geographically sensitive (3-digit ZIP code) –Calculation of local rates Useful for monitoring newly approved drugs

12 CONFIDENTIAL Our Early Detection System in Action The RADARS ® System Signal Detection Studies began picking up abuse and diversion of “generic OxyContin” one week after launch.

13 CONFIDENTIAL Signal Detection Studies Funded by Purdue Pharma L.P. Studies conducted at major research organizations and universities under direction of Principal Investigators Data independently housed Data reports presented to the EAB and Purdue on a quarterly basis

14 CONFIDENTIAL Denominator Candidates ProsCons 1.PopulationReadily availableUniform exposure assumed 2.Prescriptions filledReadily available; Easily understood One Rx  One person; no adjustment for dosage strength, days of therapy, quantity, acute vs. chronic use 3.Kg distributedReadily available; Easily understood No adjustment for potency; rate for high potency drugs will be over-estimated 4.Delivery unitsProvides closer estimate to drug available than prescriptions alone No adjustment for dosage strength 5.Patients dispensed medications Provides estimate of those benefiting from medication Based on projected figures that have high error rate in low population areas 6. Dosage unitsUsed by DEA and familiar to regulatory agencies Bases calculation on injectable dosages of buprenorphine and fentanyl, assumes incorrect minimum dosage strength for oxycodone 7. Minimum divertible dosage units Modifies DEA approach to correct for dosage units and delivery type Harder to understand, not intuitive; New metric

15 CONFIDENTIAL Comparison of Abuse Rates Using Different Denominators Rates based on median rate of abuse according to denominator total exposure using Poison Control Center data from 1Q03

16 CONFIDENTIAL Median National Rates by Signal Detection Study in ZIP Codes with Greater Than 100 Patients

17 CONFIDENTIAL Quarter3 Digit Zip Codes: state (Numerator, Denominator) 2002Q4 048: ME (1, 48.83) 246: VA (2, ) 597: MT (2, ) 403: KY (2, ) 811: CO (1, ) 2003Q1 408: KY (3, 71.07) 412: KY (2, 59.73) 416: KY (2, 98.10) 415: KY (2, ) 426: KY (1, ) 2003Q2 413: KY (1, 20.41) 408: KY (2, 61.23) 050: VT (1, 89.83) 229: VA (5, ) 426: KY (1, ) 2003Q3 418: KY (1, 20.99) 413: KY (1, 22.33) 408: KY (2, 59.83) 415:KY (2, ) 409: KY (4, ) 2003Q4 413: KY (2, 19.01) 412: KY (2, 35.64) 256: WV (4, 80.08) 408: KY (2, 47.13) 409: KY (6, ) 2004Q1 412: KY (2, 10.50) 408: KY (4, 42.82) 413: KY (1, 11.72) 248: WV (3, 37.17) 418: KY (1, 19.80) 2004Q2 048: ME (2, 33.05) 268: WV (1, 31.79) 246: VA (6, ) 247: WV (4, ) 808: CO (1, 45.17) 5 Highest Rates of Abuse for Oxycodone Extended- Release and the Corresponding 3 Digit Zip Codes

18 CONFIDENTIAL Drug Evaluation Network System (DENS) Thomas McLellan, PhD, Principal Investigator TRI & University of Pennsylvania Rationale Collect data on abuse of prescription drugs by those entering drug abuse treatment programs and track trends over time Objectives Gather data on prescription drug abuse in admissions to treatment programs Track trends in prescription drugs abused over time DENS has lost federal funding – no further data will be collected. TRI is not interested in collecting data for individual companies

19 CONFIDENTIAL Law Enforcement Drug Diversion James Inciardi, PhD, Principal Investigator University of Delaware Rationale Monitor diversion of RADARS ® System Drugs compared to other drugs in a specific geographic locale Objectives Monitor the extent of diversion from a national convenience sample of police diversion units Identify “signal sites” for these drugs over time Identify “epicenters of diversion” (3-digit zip code locations where a signal is detected > 1Q per year)

20 CONFIDENTIAL Key Informant Network Theodore Cicero, PhD, Principal Investigator Washington University Rationale Monitor an extensive network of specialists to proactively seek out documented cases of abuse Objectives U se key informants to proactively count the cases of abuse & addiction to RADARS ® System Drugs in specific geographic locations Monitor the number of cases of abuse and addiction of the RADARS ® System Drugs over time

21 CONFIDENTIAL Poison Control Centers (PCCs) Richard Dart, MD, PhD, Principal Investigator University of Colorado Rationale Monitor calls to PCCs regarding abuse of RADARS ® System Drugs Objectives Prospectively monitor exposure and information calls Monitor the changes in these calls over time

22 CONFIDENTIAL Opioid Abuse in Methadone Treatment Enrollees Mark Parrino, MPA and Andrew Rosenblum, Ph.D., Principal Investigators, AATOD and NDRI Rationale Collect admission data on new enrollees at 75 MTPs regarding abuse and addiction involving RADARS ® System Drugs Objectives Monitor drugs used by new admissions Monitor need for pain medication Monitor trends over time Pilot study completed February Full study implemented March 2005.

23 CONFIDENTIAL Field Research Structured Interview Process Law Enforcement Drug Treatment Center Physician Pharmacist Other –Indian Health Services –Hospital –Board of Pharmacy –State Agencies

24 CONFIDENTIAL Limitations and Concerns Not 100% coverage for all studies Not all sites report each quarter No universally accepted method defined for calculating rates/denominator issues Potential double counting No access to raw data Adverse event reporting

Researched Abuse, Diversion, and Addiction-Related Surveillance