Transcript The Registration of Veterinary Pharmaceuticals and Biologics

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
– 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
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
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
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
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)
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Vet. Feed Directive: 21CFR 207, 225, 510, 514, 558
Efficacy: 21 CFR 514.111, 415.117
Minor Species: draft proposal
Drug Combinations: pending
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.
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
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
Development of Pharmaceutics
• The Regulations:
– The Code of Federal Regulations 21 CFR
• Further expands on the act and the previous
four definitions
Development of Pharmaceutics
• The Guidelines:
– Help the Sponsor interpret the “Code”
– Many of these by activity and species
Development of Pharmaceutics
• Investigational New Animal Drug
Application
• New Animal Drug Application
Development of Pharmaceutics
• Safe
– Target Animal Safety
– Human Food Safety
– Environmental Safety
• Effective
– Target Animal
Development of Pharmaceutics
• The Project Team at Pharmacia
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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.
Development of Pharmaceutics
• Example of Pirlimycin Hydrochloride
– Lincosaminide antibiotic
– “Upjohn” discovery
– Replacement for clindamycin on the human
side
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
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
Development of Pharmaceutics
Pirlimycin, continued
• Tox Studies:
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90 Day Rat and Dog Studies
Segment II Teratology
Two Generation Repro Study in Rats
Genotox
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Unscheduled DNA Synthesis
Ames Test
CHO Mammalian Cell Forward Mutation Assay
Micro Nucleus Test
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
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Muscle = 1.2 ppm
Fat = 4.8 ppm
Liver = 2.4 ppm
Kidney = 3.6 ppm
Milk = 0.4 ppm
Development of Pharmaceutics
Pirlimycin, continued
• Residue/Metabolism Studies
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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)
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)
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.
Development of Pharmaceutics
Pirlimycin, continued
• Target Animal Safety
– Two pivotal GLP udder irritation studies
– Results: The formulation was safe and nonirritating
• Environmental Assessment
– Studies on environmental degradation
– Studies on adverse effects on algae, fish,
earthworms, and plants
– Results: A finding of “No Significant Impact”
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
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
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
Development of Pharmaceutics
Pirlimycin, continued
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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
Development of Pharmaceutics
• What’s New
– www.cvm.fda.gov “Important News”
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
Development of Biologics
• Product Licensure:
– Purity, Safety, Potency and Efficacy
Development of Pharmaceutics and
Biologics
• Conclusion
• Thank you
• Questions