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The Registration of Veterinary Pharmaceuticals

The Registration of Veterinary Pharmaceuticals. John W. Hallberg, D.V.M., Ph.D. Director, US Regulatory Affairs Pharmacia Animal Health. Curriculum Vitae John W. Hallberg. Director, US Animal Health Regulatory Affairs EDUCATION

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The Registration of Veterinary Pharmaceuticals

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  1. The Registration of Veterinary Pharmaceuticals John W. Hallberg, D.V.M., Ph.D. Director, US Regulatory Affairs Pharmacia Animal Health

  2. Curriculum VitaeJohn W. Hallberg • Director, US Animal Health Regulatory Affairs • EDUCATION • Bachelor of Science, Animal Science, Iowa State University, 1976 • Masters of Science, Meat Science, ISU, 1978 • Thesis: Creatine Phosphokinase Isoenzymes in Stress-Susceptible and Stress-Resistant Pigs • Doctor of Veterinary Medicine, ISU, 1982 • Doctor of Philosophy, ISU, 1984 • Dissertation: Neural and Pulmonary Aspects of the Porcine Stress Syndrome • Licensed veterinarian in the states of Iowa and Michigan

  3. Curriculum Vitae John W. Hallberg • EMPLOYMENT HISTORY • 1974-1976: Meat Lab Employee and Foreman, Iowa State University (ISU) • 1976-1977: Meat Lab Manager, ISU • 1976-1978: Graduate Research Assistant, ISU • 1978-1981: Graduate Research Assistant (summers), ISU • 1982-1983: Veterinarian, General Food Animal Practice with Dr. McGory, Cascade,IA • 1983-1990: Veterinarian, General Food Animal Practice at Drs. White, Jedlicka and Hallberg, PC, Cascade, IA • 1990-1997: Clinical Research Scientist II, The Upjohn Company, Kalamazoo, MI • 1998-1999: Clinical Research Scientist III, Pharmacia and Upjohn Animal Health • 2000-2001: Manager, US Animal Health Regulatory Affairs, Pharmacia Animal Health • 2001-Present: Director, US Animal Health Regulatory Affairs, Pharmacia Animal Health

  4. Development of Pharmaceutics • The Law: • Pure Food and Drugs Act of 1906 • Prevented interstate commerce in misbranded or adulterated drugs • Federal Food, Drug and Cosmetic Act of 1938 (FFDAC) • Drugs must be proven safe • Strict liability statute

  5. Development of Pharmaceutics • The Law: FFDCA • 1962 Amendments • “Safe and Effective” • Orphan Drug Act 1983 • Minor Use • Hatch-Waxman Act 1984 • “Generic Drugs” • Food and Drug Administration Modernization Act of 1997

  6. Development of Pharmaceutics • Animal Medicinal Drug Clarification Act (AMDUCA) of 1994 • Allow extra-label drug use • Codifies responsibility • Animal Drug Availability Act of 1996 (ADAA) • Vet. Feed Directive: 21CFR 207, 225, 510, 514, 558 • Efficacy: 21 CFR 514.111, 415.117 • Minor Species: draft proposal • Drug Combinations: pending

  7. Development of Pharmaceutics • Key Definitions from the “Act” • Drug • Articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals. • New Drug • A drug that is not generally regarded as safe and effective under the conditions prescribed and recommended or suggested in the labeling.

  8. Development of Pharmaceutics • Key Definitions from the “Act” • Adulterated • Something is wrong with the product: Contaminated, wrong ingredients, missing ingredients, incorrect proportions, not made under cGMP • Misbranded • Something is wrong with the label: false and misleading in any particular

  9. Development of Pharmaceutics • Violations of the FFDCA • Misdemeanors – no criminal intent < 1 year in prison, fine $100,000 for person, $200,000 for corporation • Felony – repeat offender, not more that 3 years in prison, fine $250,000 for person, $500,000 for corporation

  10. Development of Pharmaceutics • The Regulations: • The Code of Federal Regulations - 21 CFR • Further expands on the act and the previous four definitions

  11. Development of Pharmaceutics • The Guidelines: • Help the Sponsor interpret the “Code” • Many of these by activity and species

  12. Development of Pharmaceutics • Investigational New Animal Drug Application • New Animal Drug Application

  13. Development of Pharmaceutics • Safe • Target Animal Safety • Human Food Safety • Environmental Safety • Effective • Target Animal

  14. Development of Pharmaceutics • The Project Team at Pharmacia • Microbiology: S. Salmon, MS • Pharmaceutic Development: A. Cooper, Ph.D.; B. Re • Manufacturing: B. Burleigh, E. Behie, R. Blalock • Drug Safety: B. Seaman, D.V.M. • Residue Metabolism: R. Hornish, Ph.D; J. Caputo, Ph.D.; S. Brown, D.V.M., Ph.D. • Regulatory: J. Hallberg, D.V.M., Ph.D.; C. Donovan, MS; M. Steele • Information Management/Biostatistics: K. Dame, T. Chester, Ph.D. • Clinical Development: Mike Moseley, Ph.D. (Project Leader); H. Deluyker, D.V.M., Ph.D., M. Wachowski • Marketing: D. Ricke, C. Roeder, J. Luchsinger, D.V.M. • Technical Service: B. Beachnau, D.V.M.; A. Belschner, D.V.M.; G. Neubauer, D.V.M.; J. Ver Steeg, D.V.M.; R. Saltman, D.V.M.; J. Olson, D.V.M.

  15. Development of Pharmaceutics • Example of Pirlimycin Hydrochloride • Lincosaminide antibiotic • “Upjohn” discovery • Replacement for clindamycin on the human side

  16. Development of Pharmaceutics Pirlimycin, continued • 1980: Formed Project Team • 1981: Established product criteria for efficacy, milk discard, and product stability • 1982: Formulation development • 1983: Established an INAD • 1984: Initial field efficacy study • 1986-1987: Field dose determination and confirmation

  17. Development of Pharmaceutics Pirlimycin, continued • 1988: Initiated pivotal metabolism, toxicology and environmental safety studies • 1989: Phased review submissions for Tox, EA, Target Animal Safety and Efficacy • 1990-1992: Phased review submissions for residue metabolism, residue decline, residue method, label, Freedom of Information Summary

  18. Development of Pharmaceutics Pirlimycin, continued • Tox Studies: • 90 Day Rat and Dog Studies • Segment II Teratology • Two Generation Repro Study in Rats • Genotox • Unscheduled DNA Synthesis • Ames Test • CHO Mammalian Cell Forward Mutation Assay • Micro Nucleus Test

  19. Development of Pharmaceutics Pirlimycin, continued • Tox Studies Results • NOEL = 10 mg/kg/day • ADI = 0.01 mg/kg/day, 0.6 mg pirlimycin per day for a 60 kg adult • Safe Concentration • Muscle = 1.2 ppm • Fat = 4.8 ppm • Liver = 2.4 ppm • Kidney = 3.6 ppm • Milk = 0.4 ppm

  20. Development of Pharmaceutics Pirlimycin, continued • Residue/Metabolism Studies • C14 Rat metabolism study • 2- C14 metabolism studies in the cow • 3 cold tissue residue declines studies • 4 cold milk residue decline studies • Residue method validation • Tolerances for pirlimycin in milk 0.40 ppm and liver (0.50 ppm)

  21. Development of Pharmaceutics Pirlimycin, continued • Residue/Metabolism Studies • Results: • Tolerances in Milk (0.40 ppm) and Liver (0.50 ppm) • Approved Residue Methods • Determination of Milk Discard Period (36 hours) • Determination of Pre-Slaughter Withdrawal Period (28 days)

  22. Development of Pharmaceutics Pirlimycin, continued • Efficacy Studies • Multi-location field efficacy study • Staph. aureus model efficacy study • Results: Indication • PIRSUEAqueous Gel (pirlimycin hydrochloride) is indicated for the treatment of clinical and subclinical mastitis in lactating dairy cattle. PIRSUE has been proven effective only against Staphylococcus species such as Staphylococcus aureus and Streptococcus species such as Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis.

  23. Development of Pharmaceutics Pirlimycin, continued • Target Animal Safety • Two pivotal GLP udder irritation studies • Results: The formulation was safe and non-irritating • Environmental Assessment • Studies on environmental degradation • Studies on adverse effects on algae, fish, earthworms, and plants • Results: A finding of “No Significant Impact”

  24. Development of Pharmaceutics Pirlimycin, continued • 1990: CVM accepts Tox, Efficacy, TAS and Metabolism • 1991: CVM accepts 36 hour milk discard • 1992: CVM accepts residue methods • 1993: CVM accepts EA and CMC section

  25. Development of Pharmaceutics Pirlimycin, continued • 1993: P&U submits summary NADA • 10 September 1993: CVM Approval • Activities to present: worldwide approvals for Pirsue Aqueous Gel, upgrade to a sterile product

  26. Development of Pharmaceutics Pirlimycin, continued • Necessary Activities for Sterile • Submission of the MRL document in the EU • CMC: New formulation, package, manufacturing facility • Bioequivalence study, new udder irritation study, new milk and tissue residue decline study, two new efficacy studies for the EU, new EA studies for EU

  27. Development of Pharmaceutics Pirlimycin, continued • EU Approval of the MRL 1999 • US Sterile Approval 7 September 2000 • EU Sterile Approval January 2001 • Total Time Summary Inception to Completion 20 Years

  28. Development of Pharmaceutics • What’s New • www.cvm.fda.gov “Important News”

  29. Development of Biologics • Regulation: Vaccine-Serum-Toxins Act • USDA regulates through APHIS with the CFR, Veterinary Service Memos and Veterinary Service Notices • USDA Vaccine Groups • Veterinary Biologics Staff - Hyattsville, MD • National Veterinary Services Lab - Ames, IA • Veterinary Biologics Field Office - Ames, IA

  30. Development of Biologics • Product Licensure: • Purity, Safety, Potency and Efficacy

  31. Development of Pharmaceutics and Biologics • Conclusion • Thank you • Questions

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