1. Drug Control in Horse Racing in the U.S. Scot Waterman, DVM Executive Director Racing Medication & Testing Consortium

2. U.S. Regulatory Framework

3. State statute enables a state agency to govern pari-mutuel wagering State statute enables a state agency to govern pari-mutuel wagering Commission has power to write, enforce and adjudicate rules…executive, quasi-judicial, quasi-legislative Commission has power to write, enforce and adjudicate rules…executive, quasi-judicial, quasi-legislative Commissioners are usually appointed by the governor Commissioners are usually appointed by the governor No US federal government counterpart to the CPMA No US federal government counterpart to the CPMA

4. U.S. Regulatory Framework Makeup of commission varies state-by-state Makeup of commission varies state-by-state –Some states do not allow those involved in the industry day-to-day to serve as commissioners –Number of commissioners (as low as 1, as high as 13) Funding for operations varies state-by-state Funding for operations varies state-by-state –Majority of states funded through general funds but some based on revenue sources from handle Rulemaking process varies state-by-state Rulemaking process varies state-by-state –NJ, NY, CA from start to finish process can take over one year. Some states also have regulations encoded in statute…need to involve legislature to change

5. U.S. Regulatory Framework— Challenges Commission only quasi-legislative Commission only quasi-legislative –Generally some state legislature oversight which creates another potential hurdle for model rules Commission only quasi-judicial Commission only quasi-judicial –Violations appealed to state court which historically have reduced significant penalties Commission budgets always at risk Commission budgets always at risk Local politics more important than national politics Local politics more important than national politics

6. Racing Medication & Testing Consortium

7. RMTC History Formation: Formation: –Began with the AAEP Medication Summit, December 2001 –Summit designed to determine level of consensus on uniform medication policy –All organization that participated in original meeting are still involved nine years later –Organization has moved beyond rule uniformity as a singular goal Incorporated as a 501 (c) (3) charitable organization since 2003 Incorporated as a 501 (c) (3) charitable organization since 2003

8. RMTC Board Horsemen—THA, HBPA, CTT Horsemen—THA, HBPA, CTT Tracks-Magna, Churchill, Oak Tree, Del Mar, HTA, TRA, NYRA, Keeneland Tracks-Magna, Churchill, Oak Tree, Del Mar, HTA, TRA, NYRA, Keeneland Owners/Breeders—TOBA, TOC, KTA Owners/Breeders—TOBA, TOC, KTA Veterinarians—AAEP Veterinarians—AAEP Security—TRPB Security—TRPB Regulatory Association—RCI Regulatory Association—RCI Breed Registries/Other—AQHA, The Jockey Club, NTRA, USTA, Hambeltonian Society, Arabian Jockey Club Breed Registries/Other—AQHA, The Jockey Club, NTRA, USTA, Hambeltonian Society, Arabian Jockey Club Jockeys—Jockey’s Guild Jockeys—Jockey’s Guild

9. Goals and Objectives Uniform medication rules Uniform medication rules Uniform testing procedures and laboratory accreditation Uniform testing procedures and laboratory accreditation Uniform thresholds and withdrawal guidelines for therapeutic medications Uniform thresholds and withdrawal guidelines for therapeutic medications Unbiased source of information on medication issues for state racing commissions Unbiased source of information on medication issues for state racing commissions Develop intelligence on new threats to integrity Develop intelligence on new threats to integrity Better communication regarding medication issues Better communication regarding medication issues

10. RMTC Goals and Objectives Generally successful in the development of model medication policies and encouragement of adoption at state level Generally successful in the development of model medication policies and encouragement of adoption at state level –Large board viewed as an “industry consensus” once language is completed –Have been able to overcome some of the parochial issues as state level –Able represent RMTC in person at state commission meetings when requested –Development of a network of individuals within commissions to assist in the adoption process

11. RMTC Goals and Objectives US closer to uniformity than ever before US closer to uniformity than ever before Challenges still remain: Challenges still remain: –Penalties Difficult to get stewards/commissions to depart from status quo Difficult to get stewards/commissions to depart from status quo –How to make smaller states relevant, part of process –Commissions that want to look tougher than anyone else –Grinding process, impatient industry

12. RMTC Pharmacokinetic Program

13. Uniform thresholds and withdrawal times First step…create a priority list of drugs for study: First step…create a priority list of drugs for study: –AAEP was asked to put together a committee of veterinarians to identify “most essential” therapeutic medications –List was then prioritized based on the number of positive tests caused in the USA over a five year period and survey results of practitioners

14. Uniform thresholds and withdrawal times Second step…fund administration studies on each drug at relevant doses Second step…fund administration studies on each drug at relevant doses –FDA formula used for drug residues in milk used to calculate threshold at a given withdrawal period –Minimum of twenty horses used for each study to reduce the k factor of the formula –Withdrawal time based on end of pharmacologic activity when known

15. Study Design Test substance Test substance –Blood primary –Urine secondary Laboratory methods Laboratory methods –LC-MS at lowest attainable limit of detection (LOD) using latest instrumentation and methodology Drug Administrations Drug Administrations –Drugs were administered IV as single dose except for select drugs –Blood and urine samples were collected at specific times after drug administration – samples were sent to testing laboratories for analysis –“Cheater doses” studied when intelligence on dose/route/time is available

16. University of Florida Equine Performance Laboratory Director Director –Pat Colahan, DVM Horses Horses –Breeds Thoroughbred Thoroughbred Standardbred (specific studies) Standardbred (specific studies) –Gender Geldings and mares Geldings and mares –Age 3-10 years 3-10 years –Fitness Trained on treadmill and fitness assessed periodically Trained on treadmill and fitness assessed periodically

17. Equine Performance Laboratory Training and Fitness Assessment Training and Fitness Assessment –Exercised 3 times per week on high-speed treadmill Trot for 0.6 km at 4.0 m/s, gallop for 2 km at 8 m/s, and trot for 0.6 km at 4 m/s Trot for 0.6 km at 4.0 m/s, gallop for 2 km at 8 m/s, and trot for 0.6 km at 4 m/s Treadmill horizontal on Monday and inclined 6 degrees on Wednesday and Friday Treadmill horizontal on Monday and inclined 6 degrees on Wednesday and Friday –Incremental Exercise Test to Exhaustion Warm up on the treadmill at 4 m/s for 5 min before the start of the test; exercise for 1 min each at 9, 10, 11, 12, 13 and 14 m/s until they are unable to maintain the speed. Warm up on the treadmill at 4 m/s for 5 min before the start of the test; exercise for 1 min each at 9, 10, 11, 12, 13 and 14 m/s until they are unable to maintain the speed. Blood samples collected for lactate and pH Blood samples collected for lactate and pH –Require lactate > 20 mM and pH 20 mM and pH <6.95

18. Equine Performance Laboratory Sample collections Sample collections –Blood – individual venipuncture into lithium heparin tubes – plasma harvested and stored at – 70 °C –Urine – collected by free catch method – urine aliquotted and stored at – 70 °C Sample distribution Sample distribution –Samples are sent by overnight courier to participating laboratories

19. Process for sample analysis ISO 17025 accredited laboratories used ISO 17025 accredited laboratories used Instrumentation is LC-MS or LC-MS-MS. Instrumentation is LC-MS or LC-MS-MS. Develop and validate methods for each analyte before testing experimental samples. Develop and validate methods for each analyte before testing experimental samples. Schedule sample collection for a drug study after the proposed method has been suitably validated and approved for use in the study. Schedule sample collection for a drug study after the proposed method has been suitably validated and approved for use in the study.

20. Withdrawal Times Research Priority Group 1 Priority Group 1 –Acepromazine –Butorphanol –Detomidine –Glycopyrrolate –Lidocaine –Mepivacaine –Methocarbamol –Pyrilamine Priority Group 2 Priority Group 2 –Boldenone –Dantrolene –Firocoxib –Fluphenazine –Hydroxyzine –Nandrolone –Stanozolol –Testosterone

21. Glycopyrrolate Example Quaternary amine Quaternary amine Anti-cholinergic Anti-cholinergic FDA approved as a pre-anesthetic but used in racing as a respiratory “aid” due to bronchodilatory effect and reduction in airway secretions FDA approved as a pre-anesthetic but used in racing as a respiratory “aid” due to bronchodilatory effect and reduction in airway secretions Rapidly eliminated making detection more difficult Rapidly eliminated making detection more difficult 20-horse administration using 1 mg/horse IV and 10 mg/horse orally (n=6) 20-horse administration using 1 mg/horse IV and 10 mg/horse orally (n=6)

22. Plasma Threshold Time, hoursThreshold concentration based on 99/95 Tolerance Interval 243.5 pg/mL 482.0 pg/mL 720.5 pg/mL 960.33 pg/mL

23. Firocoxib Example Non-Steroidal Anti-Inflammatory Drug Non-Steroidal Anti-Inflammatory Drug FDA-approved for use in the horse as an oral paste FDA-approved for use in the horse as an oral paste Drug has an exceptionally long half life Drug has an exceptionally long half life Clinical effects compare favorably to phenylbutazone with fewer side effects Clinical effects compare favorably to phenylbutazone with fewer side effects 20-horse administration using 0.1 mg/kg orally for 7 days 20-horse administration using 0.1 mg/kg orally for 7 days Merial funded the research Merial funded the research

24. Firocoxib threshold considerations Plasma concentrations after a single dose are less than those after a multiple dosing regimen. Plasma concentrations after a single dose are less than those after a multiple dosing regimen. Clinical effects are likely during a single dose administration. Clinical effects are likely during a single dose administration. Therefore, a threshold must be able to detect single dose administration. Therefore, a threshold must be able to detect single dose administration. A threshold of 20-50 ng/mL would detect race day administration of a single dose. A threshold of 20-50 ng/mL would detect race day administration of a single dose. The withdrawal period after a multiple dosing regimen using a threshold of 40 ng/mL is one week. The withdrawal period after a multiple dosing regimen using a threshold of 40 ng/mL is one week.

25. Uniform thresholds and withdrawal times Other recommendations: Other recommendations: –Methocarbamol threshold of 1 ng/ml in plasma, withdrawal guideline of 48 hours based on single 15 mg/kg IV dose –Anabolic steroid screening and confirmatory limits Drugs complete by our next Board meeting Drugs complete by our next Board meeting –Acepromazine –Detomidine –Lidocaine –Mepivacaine –Pyrilamine SOPs and method validation data will be made available to all labs free of charge SOPs and method validation data will be made available to all labs free of charge

26. General Industry Challenges Funding for RMTC to continue research Funding for RMTC to continue research Funding from states for commissions to increase spending on testing, investigatory capabilities, adjudication Funding from states for commissions to increase spending on testing, investigatory capabilities, adjudication “Silver bullet” thinking on complex issues “Silver bullet” thinking on complex issues Dealing with issues that may be strictly based on perception and misinformation Dealing with issues that may be strictly based on perception and misinformation Culture of medication use Culture of medication use Competition for horses which encourages overnight extras instead of condition book races Competition for horses which encourages overnight extras instead of condition book races

27. RMTC: Contact Us www.rmtcnet.com www.rmtcnet.com www.rmtcnet.com