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U.S. Food and Drug Administration

U.S. Food and Drug Administration. Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated. . Components of Modified Kramer System.

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U.S. Food and Drug Administration

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  1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

  2. Components of Modified Kramer System • Previous Experience (-1, 0,+1) • Alternative Etiologic Candidate (-1, 0, +2) • Timing (-2, 0, +1) • Overdose (0, +1) • Dechallenge (-1, 0, +1) • Rechallenge (-1, 0, +1)

  3. Interpretation of Range • -6 to -1 Remotely drug related • 0 to +2 Possibly drug related • +3 to +5 Probably drug related • +6 to +7 Definitely drug related

  4. Number of Reported Dog Deaths

  5. Anaphylaxis/Anaphylactoid Reactions

  6. Onset Times of Anaphylaxis/ Anaphylactoid Reactions (ProHeart 6)

  7. Health Status of Dogs with Anaphylaxis/Anaphylactoid Reactions at Time of ProHeart 6 Administration • GOOD 1,741 • Fair 69 • Poor 3 • Unknown 7 Deaths: 54

  8. Concomitant Status of Dogs with Anaphylaxis/Anaphylactoid Reactions at Time of ProHeart 6 Administration • No concomitant 816 • Concomitant 731 • Unknown 273

  9. Convulsions

  10. Onset Times of Convulsions (ProHeart 6)

  11. Mean Serum Moxidectin Levels Following a Single Injection

  12. Health Status of Dogs with Convulsions Following ProHeart 6 Administration • GOOD 302 • Fair 64 • Poor 7 • Unknown 5 Deaths: 61

  13. Concomitant Status of Dogs with Convulsions Following ProHeart 6 Administration • No concomitant 87 • Concomitant 215 • Unknown 76

  14. Liver Problem Assessments Approval to 9/1/04

  15. SGPT/ALT Elevations GOOD 149 Fair 36 Poor 6 Unknown 1 Deaths: 38 Liver Lesions GOOD 50 Fair 13 Unknown 2 Deaths: 47 Health Status at Time of ProHeart 6 Injection for Dogs with Subsequent SGPT/ALT Elevations or Liver Lesions

  16. SGPT/ALT Elevation No concomitant 50 Concomitant 112 Unknown 30 Liver Lesions No concomitant 13 Concomitant 44 Unknown 8 Concomitant Status of Dogs with Elevated SGPT/ALT or Liver Lesions Following ProHeart 6 Administration

  17. Onset Times of Elevated SGPT/ALT and Liver Lesions (ProHeart 6)

  18. Hematologic Assessments Approval to 9/1/04

  19. Onset Times for Low Platelets and IMHA (ProHeart 6)

  20. Health Status at Time of ProHeart 6 Injection for Dogs with Low Platelets or IMHA LOW PLATELETS • GOOD 91 • Fair 28 • Poor 4 • Unknown 1 Deaths: 45 IMHA • GOOD 56 • Fair 10 • Poor 1 Deaths: 34

  21. Concomitant Status of Dogs with Low Platelets or IMHA Following ProHeart 6 Administration LOW PLATELETS • No concomitant 26 • Concomitant 76 • Unknown 22 IMHA • No concomitant 19 • Concomitant 34 • Unknown 14

  22. Number of ProHeart 6 ADE Reports Received by CVM, by Year (July 1, 2001 to June 30, 2004)

  23. Number of Dogs with Reported ADEs and Number of Reported Dog Deaths ProHeart 6, by Year (July 1, 2001 to June 30, 2004)

  24. Number of Causality Assessments for Certain Reported Clinical Manifestations, ProHeart 6, by Year (July 1, 2001 to June 30, 2004)

  25. PRE-MARKETING Limited size Controlled population POST-MARKETING Larger size More diverse population Reasons for Post-Marketing Surveillance

  26. Post-Approval Concernsfor Drug Safety • Frequency of events • Severity of events • Temporal association with administration • Correlation with rising or peak serum levels • Ongoing serious events despite regulatory measures

  27. Additional Considerations • ProHeart 6 is used with the intent of preventing disease • Other alternatives exist • fewer reported serious adverse effects

  28. Analysis of ProHeart 6 Adverse Events by Fort Dodge Animal Health

  29. “Approximately 18 million doses of ProHeart 6 have been sold with more than 12 million doses administered” -Fort Dodge Animal Health (page 31)

  30. FDAH Allergy Event Reports per 10,000 doses sold (pages 37-38) • ProHeart 6: 1.26 • Duramune Max 5/4L vaccine: 0.4 • Rabvac 3 vaccine: 0.5 Allergy event reporting rate for ProHeart 6 is 2.5 to 3.1 times higher than for Fort Dodge vaccines

  31. FDAH Non-Allergy Event Reportsper 10,000 doses sold (pages 38-39) • ProHeart 6: 1.19 • Duramune Max 5/4L vaccine: 0.3 • Rabvac 3 vaccine: 0.35 Non-allergy event reporting rate for ProHeart 6 is 3.4 to 4.0 times higher than for Fort Dodge vaccines

  32. “The adverse event case fatality rate associated with ProHeart 6 reports is lower than many FDAH pharmaceuticals and similar to case fatality rates for the FDAH canine vaccine product lines including Duramune Max 5/4L. Thus the incidence of death does not appear to be causally related to ProHeart 6 usage.” Fort Dodge Animal Health, Page 36

  33. Fort Dodge’s Causality Analysis of Medical Events by Selected Body Systems (page 39) Possible Unlikely Events classified as allergic excluded Potential Probable Neoplasia cases reviewed by expert Neurologic, hematologic, and hepatic cases reviewed by experts

  34. Analysis of Banfield Data Limitations • Selection bias • Information bias Table 4.4.2-1. Rate per 10,000 of Any Adverse Event by Treatment Category

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