Components of Modified Kramer System 1. Previous Experience (-1, 0,+1) 2. Alternative Etiologic Candidate (-1, 0, +2) 3. Timing (-2, 0, +1) 4. Overdose (0, +1) 5. Dechallenge (-1, 0, +1) 6. Rechallenge (-1, 0, +1)
Interpretation of Range -6 to -1 0 to +2 +3 to +5 +6 to +7 Remotely drug related Possibly drug related Probably drug related Definitely drug related
Number of Reported Dog Deaths Heartworm Preventive Year of Initial Approval Number of Deaths, Approval to 9/1/04 Number of Deaths, 6/1/01 to 9/1/04 Ivermectin Products 1987 133 50 Milbemycin Products 1990 131 59 Selamectin 1999 171 110 Moxidectin Tablets (ProHeart) 1997 0 0 Subtotal 219 MoxidectinSustained Release (ProHeart 6) 2001 485 485
Anaphylaxis/Anaphylactoid Anaphylactoid Reactions Heartworm Preventive (year of initial approval) Assessments Approval to 9/1/04 Ivermectin Products (1987) Milbemycin Products (1990) Selamectin (1999) Moxidectin Tablets (Proheart)(1997) 16 36 45 0 Subtotal 97 Moxidectin Sustained Release (ProHeart 6) (2001) 1820
Onset Times of Anaphylaxis/ Anaphylactoid Reactions (ProHeart( 6) Number of Assessments 1000 800 600 400 200 0 <1 hr 1to<3 hr 3to<24 hr Total = 1820 <30 days unknown Time of Onset
Health Status of Dogs with Anaphylaxis/Anaphylactoid Anaphylactoid Reactions at Time of ProHeart 6 Administration GOOD 1,741 Fair 69 Poor 3 Unknown 7 Deaths: 54
Concomitant Status of Dogs with Anaphylaxis/Anaphylactoid Anaphylactoid Reactions at Time of ProHeart 6 Administration No concomitant 816 Concomitant 731 Unknown 273
Convulsions Heartworm Preventive (year of initial approval) Assessments Approval to 9/1/04 Ivermectin Products (1987) 131 Milbemycin Products (1990) 194 Selamectin (1999) 304 Moxidectin Tablets (ProHeart)(1997) 1 Subtotal 630 Moxidectin Sustained Release (ProHeart 6) (2001) 378
Onset Times of Convulsions Onset Times of Convulsions (ProHeart 6) 120 110 100 90 80 70 60 50 40 30 20 10 0 Number of Assessments <1 1 to<3 3 to<7 7 to<14 14 to<30 30 to<90 >90 Unknown Time of Onset (Days) Total = 378
Mean Serum Moxidectin Levels Following a Single Injection 6 Moxidectin Mean Serum Concentration (μg/l) 5 4 3 2 1 0 5 10 15 20 25 30 Days
Health Status of Dogs with Convulsions Following ProHeart 6 Administration GOOD 302 Fair 64 Poor 7 Unknown 5 Deaths: 61
Concomitant Status of Dogs with Convulsions Following ProHeart 6 Administration No concomitant 87 Concomitant 215 Unknown 76
Liver Problem Assessments Approval to 9/1/04 Heartworm Preventive (year of initial approval) SGPT/ALT Elevations Liver Lesions Ivermectin Products (1987) 38 9 Milbemycin Products (1990) 38 8 Selamectin (1999) 69 13 Moxidectin Tablets (ProHeart) (1997) 0 0 Subtotal 145 30 Moxidectin Sustained Release (ProHeart 6)(2001) 192 65
Health Status at Time of ProHeart 6 Injection for Dogs with Subsequent SGPT/ALT Elevations or Liver Lesions SGPT/ALT Elevations GOOD 149 Fair 36 Poor 6 Unknown 1 Liver Lesions GOOD 50 Fair 13 Unknown 2 Deaths: 38 Deaths: 47
Concomitant Status of Dogs with Elevated SGPT/ALT or Liver Lesions Following ProHeart 6 Administration SGPT/ALT Elevation No concomitant 50 Concomitant 112 Unknown 30 Liver Lesions No concomitant 13 Concomitant 44 Unknown 8
Onset Times of Elevated SGPT/ALT and Liver Lesions (ProHeart( 6) Number of Assessments 50 40 30 20 10 0 <1 1 to<3 3 to<7 7 to<14 14 to<30 Liver Lesions SGPT\ALT Time of Onset (Days) 30 to<90 >90 Total = 67 Total = 192 Unknown
Hematologic Assessments Approval to 9/1/04 Heartworm Preventive (year of initial approval) Low Platelets IMHA Ivermectin Products (1987) 10 20 Milbemycin Products (1990) Selamectin (1999) Moxidectin Tablets (Proheart) (1997) 26 50 0 16 15 0 Subtotal 86 51 Moxidectin Sustained Release (ProHeart 6) (2001) 124 67
Onset Times for Low Platelets and IMHA (ProHeart( 6) Number of Assessments 30 20 10 0 <1 1 to<3 3 to<7 7 to<14 14 to<30 Time of Onset (Days) Platelets Total = 124 IMHA Total = 67 30 to<90 >90 Unknown
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 IMHA GOOD 56 Fair 10 Poor 1 Deaths: 45 Deaths: 34
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
Number of ProHeart 6 ADE Reports Received by CVM, by Year (July 1, 2001 to June 30, 2004) Period Initial Reports Follow Up Reports Total Reports 7/1/01 to 6/30/02 1719 546 2265 7/1/02 to 6/30/03 1905 838 2743 7/1/03 to 6/30/04 1763 1076 2839
Number of Dogs with Reported ADEs and Number of Reported Dog Deaths ProHeart 6, by Year (July 1, 2001 to June 30, 2004) Period Number of Dogs Number of Deaths 7/1/01 to 6/30/02 1896 112 7/1/02 to 6/30/03 1814 148 7/1/03 to 6/30/04 1640 185
Number of Causality Assessments for Certain Reported Clinical Manifestations, ProHeart 6, by Year (July 1, 2001 to June 30, 2004) Period Anaphylactoid Reactions Convulsion SGPT/ALT Elevation Liver Lesions Low Platelets IMHA 7/1/01 to 6/30/02 7/1/02 to 6/30/03 7/1/03 to 6/30/04 704 110 23 9 26 14 544 126 52 15 28 24 487 118 92 37 52 26
Reasons for Post-Marketing Surveillance PRE-MARKETING Limited size Controlled population POST-MARKETING Larger size More diverse population
Post-Approval Concerns for 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
Additional Considerations ProHeart 6 is used with the intent of preventing disease Other alternatives exist fewer reported serious adverse effects
Analysis of ProHeart 6 Adverse Events by Fort Dodge Animal Health
Approximately 18 million doses of ProHeart 6 have been sold with more than 12 million doses administered -Fort Dodge Animal Health (page 31)
FDAH Allergy Event Reports per 10,000 doses sold (pages 37-38) 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
FDAH Non-Allergy Event Reports per 10,000 doses sold (pages 38-39) 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
The 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
Fort Dodge s s Causality Analysis of Medical Events by Selected Body Systems (page 39) Possible Unlikely Potential Probable Events classified as allergic excluded Neoplasia cases reviewed by expert Neurologic, hematologic, and hepatic cases reviewed by experts
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 ProHeart 6 HW Prev 1 HW Prev 2 No HW Treatment Vaccine N N A Rate N N A Rate N N A Rate N N A Rate Yes 483,064 6,292 130.3 246,131 2,804 113.9 11,975 120 100.2 1,489,032 17,406 116.9 No 252,590 2,253 89.2 164,951 1,469 89.1 6,430 45 70.0 4,144,984 120,529 290.8 Total 735,654 8,545 116.1 411,082 4,273 103.9 18,405 165 89.4 5,634,016 137,935 244.8