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

2. 2 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 A Blinded (from original CRFs) Meta-Analysis of (Deaths & Dropouts), by study : 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. 3 31.9% 30.4% 33.3% 4.4% Administrative Lack of Blood Pressure Control Adverse Effects Angina, MI, CHF, Stroke, TIA, Death

4. 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. 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. 6 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 * = Maximum Likelihood Estimation 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. 7 Unscheduled Visits

8. 8 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 * = Maximum Likelihood Estimation 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. 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. 10 TF Placebo TF Drug OT Placebo OT Drug OAE Placebo OAE Drug OC Placebo OC Drug 0.00% 2.00% 4.00% 6.00% 8.00% 10.00% 12.00% 14.00% Percent of DropOut Group with ER/Hosp ER Hosp Unscheduled Visits 116 Events Total 222 Events Total 54 Events Total 22 Events Total

11. 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 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 Less than 25% of the 279 patients in this category had clear “in words” new end organ organ involvement

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

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

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

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

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

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18. 18 Higher Risk on Treatment Higher Risk on Placebo Relative Risk (Placebo/Drug) 0.00.51.01.52.02.53.03.5 OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropout ER HOSP ER or HOSP CVA, MI, Death HE, AP, MI, CHF, CVA OC, AR, Death, VT p<10 -15 p<10 -16 p<10 -15 p=1.7X10 -3 There were 19 different analyses performed, Inferential p of 0.001 requires p<10 -6

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

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

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

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28. 28 Lewington et al Lancet 360:1903-1913, 20002

29. 29 Collins & MacMahon Brit Med Bul 50:272-298, 1994

30. 30 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)

31. 31 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)

32. 32 Back-up Stuff, unorganized

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34. 34 Baseline >= -7 Days = 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 PlaceboDrug -12 -10 -8 -6 -4 -2 0 2 Treatment Effect (Treatment - Baseline) mm Hg Sys Dia Sys Dia p < 0. 000000000 p = 0. 6 1st Analysis, not to be trusted p = 0. 5 p values are that Difference is = 0 May 1999 From 12/98

35. 35 Baseline >= -7 Days = 12 Days <= 63 Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug Morning By Patient Summary 6:00 A.M. to 9:59 A.M. PlaceboDrug -12 -10 -8 -6 -4 -2 0 2 Drug Effect (Treatment - Baseline) mm Hg Sys Dia Sys Dia p < 0. 000000000 p = 0. 9 1st Analysis, not to be trusted p = 0. 6 p values are that Difference is = 0 Value = -0.05 May 1999 From 12/98

36. 36 PlaceboDrug -14 -12 -10 -8 -6 -4 -2 0 2 Treatment Effect (Treatment - Baseline) mm Hg Baseline >= -7 Days = 12 Days <= 63 Error Bars are 1 SEM, n varies from 364 patients Placebo to 1050 patients Drug DayTime By Patient Treatment Effect 10:00 A.M. to 5:59 P.M. Sys Dia Sys Dia p < 0. 000000000 1st Analysis, not to be trusted p = 0. 6 p values are that Difference is = 0 p = 0. 3 May 1999 From 12/98

37. 37 Baseline >= -7 Days = 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 PlaceboDrug -12 -10 -8 -6 -4 -2 0 2 Treatment Effect (Treatment - Baseline) mm Hg Sys Dia Sys Dia p < 0. 000000000 p = 0. 6 1st Analysis, not to be trusted p = 0. 5 p values are that Difference is = 0 May 1999 From 12/98

38. 38 May 1999 From 12/98

39. 39 Simultanious (?) ABPM and Cuff Blood Pressures May 1999 From 12/98