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PHARM

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  1. Placebo in Hypertension Adverse Reaction Meta-analysis PHARM A Collaborative Effort Effort Between: The Division of Cardio-Renal Drug Products IREF (Ischemia Research and Education Foundation) And Stephen Glasser Principals at FDA Albert DeFelice Jim Willard James Hung John Lawrence Principals at IREF Dennis Mangano All Companies were formally contacted And Formally gave permission to use the data And Agreed to retrieve & supply missing CRFs

  2. A Blinded (from original CRFs) Meta-Analysis of (Deaths & Dropouts), by study : 28 Years of Placebo-Controlled Antihypertensive Development Trials 540 Individual Protocols 86,137 Randomized Patients (21,699 P, 64,438 D) 12,657 Patient Years (3,221.5 P, 9,436 D) 42 Chemical Entities, 6 Drug Classes 9,636 Dropouts (3,056 P, 6,580 D) Mean age = 54.1 years Mean Sitting Blood Pressure - 157.6/102.4 mm HG Singular Primary End Point, RR (P/D) of Dropping Out RR = 1.33 (1.28, 1.39; p<10-15) RR (Mortality, Stroke, MI) = 1.03 (0.71, 1.47; p = 0.86)

  3. Angina, MI, CHF, Stroke, TIA, Death 4.4% Administrative Adverse Effects 31.9% 33.3% 30.4% Lack of Blood Pressure Control

  4. Administrative OT = OTher than medical Moved, Surgery, non-compliance, etc. Lack of Blood Pressure Control TF = Therapeutic Failure Investigator or Patient Judgment HE = Hypertensive Emergency Diastolic BP > 110 mm Hg, increase by >10 mm Hg and/or evidence of new end organ involvement Adverse Effects OC = Other Cardiac adverse events Angioedema, edema, low blood pressure, non-specific EKG changes OAE = Non-cardiac, Other Adverse events Laboratory abnormalities, headache, nausea/vomiting

  5. All Cause Mortality Death Non-Fatal Myocardial Infarction MI Non-Fatal Stroke CVA Transient Ischemic Attack TIA Congestive Heart Failure CHF Angina Pectoris AP Non-Fatal Arrhythmia AR Unscheduled Visits ER Hospitalization

  6. = Maximum Likelihood Estimation * Administrative DropOuts (OT) 3,081 Events (840 P, 2,241 D) *RR (placebo/Drug) = 1.09 (1.01, 1.18, p =0.031) Not a primary, 1 of many comparisons Therapeutic Failure (TF) 2,650 Events (1,266 P, 1,384 D) *RR = 2.53 (2.35, 2.73) p<10-15) Not a primary, 1 of many comparisons Together These Two Categories Account for 5,731 Events Or 62.3% of All Drop Outs

  7. 116 Events Total 5.00% Hosp 4.50% ER 4.00% 3.50% 3.00% Percent of DropOut Group with ER/Hosp 2.50% 22 Events Total 2.00% 1.50% 1.00% 0.50% 0.00% TF Placebo TF Drug OT Placebo OT Drug Unscheduled Visits

  8. = Maximum Likelihood Estimation * Other Adverse Events (OAE) 2,734 Events (653 P, 2,081 D) *RR (placebo/Drug) = 0.87 (0.79, 0.95, p =0.0017) Not a primary, 1 of many comparisons Other Cardiac Adverse Events (OC) 469 Events (52 P, 417 D) *RR = 0.33 (0.24, 0.44) P=<10-15) Not a primary, 1 of many comparisons Together These Two Categories Account for 3,203 Events Or 33.3% of All Drop Outs

  9. Other Adverse Events (OAE) Usually a combination of 2, 3 or more various kinds of signs, symptoms or laboratory abnormalities (that included skin rash, nausea and vomiting, headache, fatigue/drowsiness, etc. Rarely a single descriptor. Other Cardiac Adverse Events (OC) Hypotension was most prominent (140 D, 8 P) with 56% being postural hypotensive phenomena, non-specific EKG changes were next most frequent, then in decreasing frequency edema of extremities, non-descript chest pain.

  10. 14.00% Hosp 12.00% ER 10.00% 8.00% Percent of DropOut Group with ER/Hosp 6.00% 4.00% 2.00% 0.00% TF Drug OT Drug OC Drug OAE Drug TF Placebo OC Placebo OT Placebo OAE Placebo Unscheduled Visits 54 Events Total 222 Events Total 116 Events Total 22 Events Total

  11. Hypertensive Emergency (HE) 279 Events (134 P, 145 D) *RR = 2.75 (2.19, 3.57) p<10-15) Not a primary, 1 of many comparisons Less than 25% of the 279 patients in this category had clear “in words” new end organ organ involvement Meant to require new end organ damage with high blood pressure BUT Defined as New End Organ Damage OR Diastolic > 110 mm Hg Increase of Diastolic >10 mm Hg

  12. Baseline Cumulative Distribution Frequency Sitting Diastolic Blood Pressure All 9,636 drop outs (placebo & drug groups)

  13. Baseline Cumulative Distribution Frequency Supine Diastolic Blood Pressure All 9,636 drop outs (placebo & drug groups)

  14. Change From Baseline Cumulative Distribution Frequency Supine Diastolic Blood Pressure All 9,636 drop outs (placebo & drug groups)

  15. Change From Baseline Cumulative Distribution Frequency Sitting Diastolic Blood Pressure All 9,636 drop outs (placebo & drug groups)

  16. 25.00% Hosp ER 20.00% 15.00% Percent of DropOut Group with ER/Hosp 10.00% 5.00% 0.00% TF Drug OT Drug OC Drug HE Drug OAE Drug TF Placebo OT Placebo HE Placebo OC Placebo OAE Placebo Unscheduled Visits 52 Events Total 54 Events Total 222 Events Total 116 Events Total 22 Events Total

  17. 7.47% of the drop out population had an unscheduled visit. 120.00% Hosp 100.00% ER 80.00% Proportion of Drop Out Category With ER/HOSP 60.00% 40.00% * 20.00% * * 0.00% MI Drug TF Drug OT Drug OC Drug HE Drug AR Drug AP Drug TIA Drug CHF Drug CVA Drug OAE Drug MI Placebo HE Placebo Death Drug TF Placebo AR Placebo OT Placebo AP Placebo OC Placebo TIA Placebo CVA Placebo CHF Placebo OAE Placebo Death Placebo = Statistically Significant RR *

  18. There were 19 different analyses performed, Inferential p of 0.001 requires p<10-6 Relative Risk (Placebo/Drug) OT p=1.7X10-3 OAE p<10-15 TF p<10-15 OC p<10-15 HE AP AR MI CHF Death CVA TIA VT p<10-16 All dropout ER HOSP ER or HOSP CVA, MI, Death HE, AP, MI, CHF, CVA OC, AR, Death, VT 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo

  19. All Drop Outs Without OT and TF 40 SUM 30 AP 20 TIA RR=2.75 -15 p=<10 MI 10 CVA 0 Difference (Placebo - Drug) per 1,000 Patient Years CHF RR=0.87 -10 HE p=0.0017 Death -20 RR=0.89 p=0.001 AR RR=0.33 -30 -15 p<10 OC -40 OAE -50 Favor Placebo Favor Drug SUM

  20. All Drop Outs Without OT, TF and HE 10 SUM 0 AP RR=0.87 TIA p=0.017 -10 MI RR=0.80 -8 p<10 CVA Difference (Placebo - Drug) per 1,000 Patient Years -20 CHF RR=0.33 Death -15 p<10 -30 AR OC -40 OAE -50 Favor Placebo Favor Drug SUM

  21. Irreversible Harm 2 RR = 1.03 1.5 Sum p = 0.86 CVA 1 Difference per 1,000 patient years MI 0.5 Death 0 -0.5 Favor Placebo Favor Drug SUM

  22. Lewington et al Lancet 360:1903-1913, 20002

  23. Collins & MacMahon Brit Med Bul 50:272-298, 1994

  24. So, Where Does That Leave Us? In My Opinion: 30 years and 590 trials (12,657 patient years) have produced no evidence that there is an increase of irreversible harm produced by the utilization of placebo in short-term trials The population represented by PHARM appears to be like that of all published studies, but of relatively low absolute risk (low systolic blood pressure and low chronological age)

  25. Equipoise can be maintained (mainly because of the low absolute risk), such trials can continue; after another 30 to 50 years, one should check on the wisdom of continued equipoise The only meaningful discussion should relate to could these trials be made “safer” by limiting chronological age to Some arbitrary limit (say 50), and systolic Blood pressure to some arbitrary limit (say 145)

  26. Back-up Stuff, unorganized

  27. Sitting Diastolic Blood Pressure 15 15 Change (Base-Last) for Group * Diff (Drug - Placebo) 10 10 5 5 * Change From Baseline (mm Hg) for Event Group Difference (Drug-Placeebo) for the group (mm Hg) 0 0 * * -5 -5 * * * * * * -10 -10 * -15 -15 AP AR CVA CHF Death HE MI OT OAE OC TF TIA VT Drop Out Category

  28. Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63 By Patient Summary Entire Sessions All Measurements in a Session, 24 or more Hours Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug Placebo Drug 2 0 Dia Sys p = 0. 5 p = 0. 6 -2 -4 -6 Treatment Effect (Treatment - Baseline) mm Hg Dia -8 p < 0. 000000000 -10 p values are that Difference is = 0 Sys -12 p < 0. 000000000 1st Analysis, not to be trusted May 1999 From 12/98

  29. Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63 Morning By Patient Summary 6:00 A.M. to 9:59 A.M. Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug Placebo Drug 2 0 Dia Sys p = 0. 6 Value = -0.05 -2 p = 0. 9 -4 -6 Drug Effect (Treatment - Baseline) mm Hg Dia p < 0. 000000000 -8 -10 p values are that Difference Sys is = 0 p < 0. 000000000 -12 1st Analysis, not to be trusted May 1999 From 12/98

  30. Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63 DayTime By Patient Treatment Effect 10:00 A.M. to 5:59 P.M. Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug Placebo Drug 2 0 Sys Dia p = 0. 3 p = 0. 6 -2 -4 -6 Treatment Effect (Treatment - Baseline) mm Hg -8 Dia p < 0. 000000000 -10 -12 p values are that Difference Sys is = 0 p < 0. 000000000 -14 1st Analysis, not to be trusted May 1999 From 12/98

  31. Baseline >= -7 Days <= -1 Treatment >= 12 Days <= 63 By Patient Summary Entire Sessions All Measurements in a Session, 24 or more Hours Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug Placebo Drug 2 0 Dia Sys p = 0. 5 p = 0. 6 -2 -4 -6 Treatment Effect (Treatment - Baseline) mm Hg Dia -8 p < 0. 000000000 -10 p values are that Difference is = 0 Sys -12 p < 0. 000000000 1st Analysis, not to be trusted May 1999 From 12/98

  32. Preliminary Results from 9 Trials n = about700 for cuff, 250 for abpm diastolic systolic 2 0 SE -2 -4 -6 Mean Change From Baseline (mm Hg) -8 -10 -12 -14 placeboabp placebocuff Rx abp RX Cuff May 1999 From 12/98

  33. 160 2 150 1.8 140 1.6 130 1.4 120 1.2 Correlation Coefficient Blood Pressure (mm Hg) 110 1 100 0.8 90 0.6 80 0.4 70 0.2 60 0 5 min 10 min 30 min 60 min 120 min closest Standing Systolic abp Systolic Correlation Systolic Standing Diastolic Correlation Diastolic abp Diastolic Simultanious (?) ABPM and Cuff Blood Pressures May 1999 From 12/98