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Potential Conflicts of Interest

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  1. IREF—Nonprofit (NIH; FDA; prior Industry)Personal Pharmaceutical Consulting—None Personal Pharmaceutical Honoraria—NonePersonal Pharmaceutical Speakers Panel—NonePersonal [IREF] Pharmaceutical Stock—NoneIP/ License—EPI I, II, Adenosine Regulating Agents (acadesine; GP531) Potential Conflicts of Interest

  2. PHARMPlacebo in Hypertension Adverse Reaction Meta-analysis

  3. PHARMPlacebo in Hypertension Adverse Reaction Meta-analysis A Collaborative Investigation of the Safety of Placebo-Controlled Trials in Hypertension FDA Division of Cardio-Renal Drug Products IREF The Ischemia Research and Education Foundation

  4. Principal Investigators:Raymond Lipicky, M.D.(FDA) & Dennis T. Mangano, Ph.D., M.D. (IREF)Co-Investigators:A. DeFelice / R. Fenichel / J. Girton / S. Glasser / M. Gordan / J. Hung / A. Karkowsky / J. Lawrence / T. Sherpa / B. Stertz / S. Targum / D. Throckmorton / J. Willard Industry Contribution:93 NDAs (SNDAs) MOU:Collaborative Relationship / Data Access / Publication / Data Sharing / …… IREF:$875,000 Grant to PHARM (2 fulltime employees x 8.5 years) / $102,000 Internal IREF Costs COLLABORATIVE STRUCTURE

  5. ‘MINORITY PRESENTATION’ Emphasis:Literal Per-Protocol-Specified Interpretation Evidence Weight:● Primary Analysis (nearly 100% weight)--Basis for conclusion ● Secondary Analyses (minimal weight, but may provide insight) Philosophy: ● Neither Placebo-control Orthodoxy, nor Active-control Orthodoxy(Both views discount the ethical and methodologic complexities of clinical research.)● Risk-averse:When effective therapies exist, there must be compelling methodological reasons to conduct a PCT.● When an effective therapy exists, The placebo-control trial may be considered if – and only if –placebo-treated patients are not be more likely to: (1) die, (2) suffer irreversible morbidity, (3) suffer reversible but serious harm, or (4) experience severe discomfort. When effective therapy exists: Placebo-control Trials are unsafe until proven otherwise.

  6. PROTOCOL Specific Aim:●To determine the relative risk of adverse clinical events among patients receiving placebo versus those receiving anti-hypertensive therapy. ●The relative risk will be determined for three* adverse event ‘spheres’:1. Overall Morbidity2. Cardiovascular Morbidity3. Neurologic Morbidity●The adverse event ‘spheres’ are prospectively defined as:Overall Morbidity = Cardiovascular MorbidityorNeurologic MorbidityCardiovascular Morbidity = Angina[AP]orArrhythmia[AR]orMIorCHF Neurologic Morbidity = Stroke[CVA]orTIAorHypertensive Emergency[HE] If the Relative Risk [P/D] is significantly > 1.0, in any of the three spheres, then:Reassessment of the of placebo-controlled trials of anti-hypertensive drugs is indicated. * Death also will be assessed independently; however, the power to discern difference (placebo versus drug) is < 50%.

  7. Methods As described by Dr. Lipicky.

  8. Methods As described by Dr. Lipicky. Here, I will Focus on the Primary Outcomes: Overall Morbidity = Cardiovascular Morbidity orNeurologic Morbidity Cardiovascular Morbidity = Angina or Arrhythmia or MI orCHF Neurologic Morbidity = Stroke or TIA or Hypertensive Emergency

  9. Methods As described by Dr. Lipicky. Here, I will Focus on the Primary Outcomes: Overall Morbidity = Cardiovascular Morbidity orNeurologic Morbidity Cardiovascular Morbidity = Angina or Arrhythmia or MI orCHF Neurologic Morbidity = Stroke or TIA or Hypertensive Emergency And, on the Primary Aim / Hypothesis / Study-Inference: If the Relative Risk [P/D] is significantly > 1.0, in any of the three spheres, then: Reassessment of placebo-controlled trials of anti-hypertensive drugs is indicated.

  10. Results OVERALL FINDINGS[86,137 Patients]

  11. Consort Diagram of Study Patients 93 NDAs / SNDAs

  12. Consort Diagram of Study Patients 93 NDAs / SNDAs 1973-2001

  13. Consort Diagram of Study Patients 93 NDAs / SNDAs 1973-2001 540 RCTs

  14. Consort Diagram of Study Patients 93 NDAs / SNDAs 1973-2001 540 RCTs 20 Companies

  15. Consort Diagram of Study Patients 93 NDAs / SNDAs 1973-2001 540 RCTs 20 Companies 86,137 Patients enrolled

  16. Consort Diagram of Study Patients 93 NDAs / SNDAs 1973-2001 540 RCTs 20 Companies 86,137 Patients enrolled 9,636 Patient Dropouts (11.1%)

  17. Consort Diagram of Study Patients 93 NDAs / SNDAs 1973-2001 540 RCTs 20 Companies 86,137 Patients enrolled 9,636 Patient Dropouts (11.1%) 54 Years of Age 40% Women 30% Minority 159/102 BP [dropout]

  18. Diastolic =102 Systolic =158 Mean Age = 54.1 years 230 220 210 1000 = 9,636 200 n 190 750 180 130 Count 170 500 120 160 150 250 110 140 130 20 30 40 50 60 70 80 90 100 120 Age (Years) Diastolic =102 Systolic =159 110 90 100 250 80 130 240 230 120 70 220 210 110 200 190 n = 2,975 100 180 170 160 90 150 140 80 130 120 70 110 Drop-Out Characteristics (9,363 Patients) Sitting BP Sitting Supine BP Women….............40% ------------------------------------------- Caucasian….........70% AA……………….22% Hispanic……....….4% Other……………..4%

  19. Consort Diagram of Study Patients 93 NDAs / SNDAs 1973-2001 540 RCTs 20 Companies 86,137 Patients enrolled 54 Years of Age 40% Women 30% Minority 159/102 BP [dropout] 9,636 Patient Dropouts (11.1%) PRIMARY AES: CardiovascularNeurologic Angina (AP)—99 [0.11%]TIA—30 [0.03%] Arrhythmia (AR)—82 [0.10%] Stroke (CVA)—40 [0.05%] MI—77 [0.09%] Hypertensive Emergency (HE)—279 [0.32%] CHF—44 [0.05%] Death—43 [0.01%]

  20. Primary Outcomes: Incidence(All Patients: 86,137)

  21. Consort Diagram of Study Patients 93 NDAs / SNDAs 1973-2001 540 RCTs 20 Companies 86,137 Patients enrolled 54 Years of Age 40% Women 30% Minority 159/102 BP [dropout] 9,636 Patient Dropouts (11.1%) PRIMARY AES: CardiovascularNeurologic Angina (AP)—99 [0.11%] TIA—30 [0.03%] Arrhythmia (AR)—82 [0.10%] Stroke (CVA)—40 [0.05%] MI—77 [0.09%] Hypertensive Emergency (HE)—279 [0.32%] CHF—44 [0.05%] Death—43 [0.01%] OTHER AES: Other Cv (OC)—489 [5.4%] VT—8 [0.00%] Tx Failure (TF)—2650 [3.08%] Other AE (OAE)—2734 [3.17%] Admin (OT)—3081 [3.58%]

  22. Other Outcomes: Incidence(All Patients: 86,137)

  23. Consort Diagram of Study Patients 93 NDAs / SNDAs 540 RCTs 64,438 Drug Patients [74.8%] 21,699 Placebo Patients [25.2%] 86,137 Patients enrolled

  24. Consort Diagram of Study Patients 93 NDAs / SNDAs 540 RCTs 21,699 Placebo Patients (25.2%) 64,438 Drug Patients (74.8%) 86,137 Patients enrolled 3,056 Placebo Dropouts (14.1%) 6,580 Drug Dropouts (10.2%)*

  25. Primary Outcomes: Incidence Note: Three ‘Primary Outcomes’ (1) Overall Morbidity = Cardiovascular Morbidity orNeurologic Morbidity (2) Cardiovascular Morbidity = Angina or Arrhythmia or MI orCHF (3) Neurologic Morbidity = Stroke or TIA or Hypertensive Emergency

  26. Primary Outcomes: Incidence

  27. Primary Outcomes: Incidence

  28. Primary Outcomes: Relative Risk

  29. Primary Outcomes: Relative Risk

  30. Conclusions

  31. ‘Primary Conclusion’ Overall Morbidity = Cardiovascular Morbidity orNeurologic Morbidity Cardiovascular Morbidity = Angina or Arrhythmia or MI orCHF Neurologic Morbidity = Stroke or TIA or Hypertensive Emergency If the Relative Risk [P/D] is significantly > 1.0, in any of the three spheres, then: Reassessment of placebo-controlled trials of anti-hypertensive drugs is indicated.

  32. ‘Primary Conclusion’ The Relative Risk [P/D] is significantly > 1.0, in two of the three spheres, therefore: Reassessment of placebo-controlled trials of anti-hypertensive drugs is indicated.

  33. A Secondary Consideration Counter-argument

  34. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo

  35. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo EQUIPOISE

  36. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo EQUIPOISE

  37. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo EQUIPOISE

  38. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo EQUIPOISE

  39. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo EQUIPOISE

  40. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo EQUIPOISE

  41. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo EQUIPOISE ????? ?

  42. HE & OC Balance:Drug HE-OC Events: 145+417 = 526 /64,438 = 0.82%Placebo HE-OC Events: 134+52 = 186 / 21,699 = 0.86%

  43. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo EQUIPOISE

  44. Conclusion: Equipoise

  45. Conclusion: EquipoiseBut #1……..

  46. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo PRIMARY ENDPOINT COMPONENT

  47. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo ‘Protocol-Excluded’ [EP] Components Primary Endpoint Components

  48. Conclusion: EquipoiseBut #2……..

  49. Relative Risk (Placebo/Drug) OT OAE TF OC HE AP AR MI CHF Death CVA TIA VT All dropouts 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Higher Risk on Treatment Higher Risk on Placebo ARITHMETIC EQUIPOISE HE-OC EventsDrug = 0.82% (526 / 64,438) Placebo= 0.86% (186 / 21.6990

  50. But……