Center for Veterinary Medicine Division of Surveillance Office of Surveillance and Compliance Dorothy McAdams, V.M.D. HF

1. Center for Veterinary MedicineDivision of Surveillance Office of Surveillance and Compliance Dorothy McAdams, V.M.D. HFV-216, Post Approval Review Team

2. Division of Surveillance Lynn Post, DVM, Ph.D., Director Vitolis Vengris, DVM, Ph.D., Deputy Director Medical Review and Pharmacovigilance Team John Baker, DVM Marketed Product Information Team Elizabeth Anne Grove, MS Post Approval Review Team Dorothy McAdams, VMD

3. Reporting Requirements • CFR Title 21: Food and Drugs PART 514—NEW ANIMAL DRUG APPLICATIONS 514.80   Records and reports concerning experience with approved new animal drugs.

4. Adverse Event Reporting • FDA’s routine monitoring of adverse events associated with a drug’s use enables ongoing assessment of the drug’s risks, including risks identified after a drug is approved • NADA/ANADA holders must report to the FDA adverse events reported to them • Serious and unexpected adverse events must be reported within 15 days • All other adverse events must be reported “periodically” – every 6 months for 2 years after approval, annually after 2 years • Professionals and consumers may voluntarily report adverse events to the FDA

5. An Adverse Drug Experience is any adverse reaction that occurs following the use of a drug product. ADEs can be mild (itching, sneezing) to severe (death). ADEs include complaints of ineffectiveness, product defects and human safety associated with the handling of animal drug products.

6. Post-approval Experience section for labels After a drug has been on the market for 1 to 2 years, the primary ADE reviewer analyzes the information to see if there are signs that need to be added to the Adverse Reaction section of the drug label.

7. How does CVM use ADE data? • Evaluate Trends and relative frequencies of clinical signs and lack of efficacy. • Initiate label revisions, formulation changes, product packaging alterations or further clinical studies for investigation • In rare circumstances this information may lead to removal of the drug from the market. • Monitor extra-label uses of products including food animal, wildlife and human exposures

8. Post Market Surveillanceof Promotional Materials • Drug safety & effectiveness is maximized when information about the drug is accurate, complete, and not misleading • A prescription drug is misbranded if its label, labeling, or advertising: • Is false or misleading, either because of what it says or what it fails to say • Fails to conspicuously include information required by the FDCA or its regulations

9. Post Market Surveillance of Promotional Materials Promotional Material Review Process Enforcement Examples Promotional Efforts & Concerns

10. 202.1   Prescription-drug advertisements • An advertisement for a prescription drug is false, lacking in fair balance, or otherwise misleading, or otherwise violative of section 502(n) of the act, among other reasons, if it:

11. (i) Contains a representation or suggestion, not approved or permitted for use in the labeling, that a drug is better, more effective, useful in a broader range of conditions or patients, safer, has fewer, or less incidence of, or less serious side effects or contraindications than has been demonstrated by substantial evidence or substantial clinical experience.

12. Fair Balance • (ii) It fails to present a fair balance between information relating to side effects and contraindications and information relating to effectiveness of the drug in that the information relating to effectiveness is presented in greater scope, depth, or detail than is required by section 502(n) of the act and this information is not fairly balanced by a presentation of a summary of true information relating to side effects and contraindications of the drug; Provided, however, That no advertisement shall be considered to be in violation of this section if the presentation of true information relating to side effects and contraindications is comparable in depth and detailwith the claims for effectiveness or safety.

13. Material facts • (iii) It fails to reveal facts material in the light of its representations or material with respect to consequences that may result from the use of the drug as recommended or suggested in the advertisement

14. Reminder Advertisements • Reminder advertisements are those which call attention to the name of the drug product but do not include indications or dosage recommendations for use of the drug product. These reminder advertisements shall contain only the proprietary name of the drug product, if any; the established name of the drug product, if any; the established name of each active ingredient in the drug product; and, optionally, information relating to quantitative ingredient statements, dosage form, quantity of package contents, price, the name and address of the manufacturer, packer, or distributor or other written, printed, or graphic matter containing no representation or suggestion relating to the advertised drug product.

15. Sources of Promotional Materials • Drug Experience Reports (Form 2301) • Professional and Trade Meetings • Internet • sponsor websites • veterinary list serves • Complaints • industry • consumers • animal owners • practicing veterinarians

16. Regulatory Process REVIEWER Team Leader Division Director Division of Compliance Regulatory Counsel Office of Chief Counsel (OCC) REGULATORY LETTER

17. Promotional Review Process • Reviewers are all veterinarians with practice experience • Products are assigned according to the individual reviewer’s expertise (i.e., small animal/large animal), interest and experience • Priority is given to promotional materials for products that may impact public health (i.e., residues, user safety)

18. Promotional Review Process cont’d • When violative pieces are identified, the reviewer works with the Regulatory Counsel to develop an action plan • Reviewers also work with the Adverse Event Review Team to identify emerging issues related to safety, off label use or medication errors and review promotional material with these concerns in mind

19. Basic requirements for promotional materials • Promotional materials should: • Be label driven • Reflect fair balance • Contain adequate safety and use information • Be truthful and not misleading

20. Types of Violations • Unsubstantiated Claims of Effectiveness • New Intended/Unapproved Use(s) • Omission of Risk/Minimization of Risk

21. CVM Enforcement ActionsFY 2009

22. Quest®(moxidectin)2% andQuest®Plus(moxidectin/praziquantal)Equine Oral Gel • Omission of Risk Information: • Power point presentations failed to include any risk information regarding possible side effects and contraindications • Indications: • Quest® (moxidectin) 2% Equine Oral Gel and Quest® Plus (moxidectin/praziquantal) Equine Oral Gel are approved for the treatment and control of gastrointestinal parasites of horses and ponies six months of age and older

23. Quest® / Quest® Plus • In the Warnings section of the package insert: Extreme caution should be used when administering the product to foals, young and miniature horses, as overdosage may result in serious adverse reactions.  Do not use in sick, debilitated, or underweight animals.  Not for horses or ponies intended for human consumption. • In the Precautions section of the package insert: [This product] has been formulated specifically for use in horses and ponies only.  This product should not be used in other animal species as severe adverse reactions, including fatalities in dogs, may result.

24. Banamine® (flunixin meglumine)Injectable Solution Banamine® (flunixin meglumine) is a potent, non-narcotic, nonsteroidal, analgesic agent with anti-inflammatory and antipyretic activity. • Indications for cattle: • Banamine Injectable Solution is indicated for the control of pyrexia associated with bovine respiratory disease, endotoxemia and acute bovine mastitis. Banamine Injectable Solution is also indicated for the control of inflammation in endotoxemia.

25. Banamine® (flunixin meglumine) • Unapproved Claims -“Banamine also significantly reduced lung consolidation in cattle suffering from BRD.” -“Banamine reduces fever and inflammation, controls endotoxemia in BRD cattle.” -“Banamine has been shown to reduce lung lesions associated with BRD which are associated with reduced weight gain….” -“The anti-inflammatory is “definitely” improving time to market that otherwise would be lost.”

26. Baytril® 100 (enrofloxacin) Injectable Solution Baytril®100 (enrofloxacin) Injectable Solution is abroad-spectrum fluoroquinolone antimicrobial agent indicated for use in cattle and swine for respiratory disease. It is not approved for use in female dairy cattle 20 months of age or older.

27. Baytril® 100 (enrofloxacin) Lack of substantial evidence to support claims of clinical speed of action. • Website • “Baytril 100 works fast and starts killing bacteria within a matter of minutes.” • “concentration dependent Baytril 100 Works Fast” and “…it achieves high drug levels at the site of infection to quickly kill bacteria.”  • “Unlike slower antibiotics that require days to achieve therapeutic results, Baytril 100 goes directly to the site of infection and starts killing respiratory disease causing bacteria in minutes, not days…”.

28. Promotional Concerns • Omission or minimization of risk information, especially pertaining to public health -user safety -food safety (drug residues) -antibiotic resistance • Extra label use in food producing animals -drug residues in milk/meat

29. Concerns Specific to Food Animal Drugs • Antibiotics and antiparasitics • Resistance • Tissue residues • Environmental effects • Misleading statements that might result in overuse or extra label use • Residue warnings & withdrawal times

30. THANK YOU CVM Web Site http://www.fda.gov/AnimalVeterinary