# Presentation: 211195

## Potential Conflicts of Interest

-       **IREF—Nonprofit***** (NIH; FDA; prior Industry)****** *****Personal Pharmaceutical Consulting—*****None ****** *****Personal Pharmaceutical Honoraria—*****None****** *****Personal Pharmaceutical Speakers Panel—*****None****** *****Personal [IREF] Pharmaceutical Stock—*****None****** *****IP***** *****/ License—*****EPI I, II, ******Adenosine Regulating Agents ******(acadesine; GP531)***

## PHARMPlacebo in Hypertension Adverse Reaction Meta-analysis

## PHARMPlacebo in Hypertension Adverse Reaction Meta-analysis

**FDA  *****Division of Cardio-Renal Drug Products***

**IREF  *****The Ischemia Research and Education Foundation***

***A Collaborative Investigation of the Safety of Placebo-Controlled Trials in Hypertension***

## 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**_

## When effective therapy exists: Placebo-control Trials are unsafe until proven otherwise.

_**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.***

## 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 Morbidity****** ******                                       ******2.  Cardiovascular Morbidity******	******                   ******3.  Neurologic Morbidity***** ****	****     ****●****   ****The adverse event ‘spheres’ are prospectively defined as:****                    *****Overall Morbidity = Cardiovascular Morbidity****** ***_***or***_*** ******Neurologic Morbidity******                                       ******                       ******Cardiovascular Morbidity = Angina****** ******[AP]****** ***_***or***_*** ******Arrhythmia****** ******[AR]****** ***_***or***_*** ******MI****** ***_***or***_*** ******CHF ******	******                       ******Neurologic Morbidity = Stroke****** ******[CVA]****** ***_***or***_*** ******TIA****** ***_***or***_*** ******Hypertensive 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%.*

## Methods

**	****           **** ****	*****	***

***As described by Dr. Lipicky.***

## Methods

**	****           **** ****	*****	***

***As described by Dr. Lipicky.***

***Overall Morbidity = Cardiovascular Morbidity ***_***or***_*** ******Neurologic Morbidity ******Cardiovascular Morbidity = Angina ***_***or***_*** Arrhythmia ***_***or***_*** MI ***_***or***_*** ******CHF ******Neurologic Morbidity = Stroke ***_***or***_*** TIA ***_***or***_*** Hypertensive Emergency***

_***Here, I will Focus on the Primary Outcomes***_***:***

## Methods

**	****           **** ****	*****	***

***As described by Dr. Lipicky.***

***Overall Morbidity = Cardiovascular Morbidity ***_***or***_*** ******Neurologic Morbidity ******Cardiovascular Morbidity = Angina ***_***or***_*** Arrhythmia ***_***or***_*** MI ***_***or***_*** ******CHF ******Neurologic Morbidity = Stroke ***_***or***_*** TIA ***_***or***_*** Hypertensive Emergency***

_***Here, I will Focus on the Primary Outcomes***_***:***

**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.***

_***And, on the Primary Aim / Hypothesis / Study-Inference***_***:***

## Results

**	****           **** ****	*****	***

_**OVERALL  FINDINGS**_**[86,137 Patients]**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**Consort Diagram of Study Patients**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**1973-2001**

**Consort Diagram of Study Patients**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**1973-2001**

**Consort Diagram of Study Patients**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**1973-2001**

**20 Companies**

**Consort Diagram of Study Patients**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**86,137 Patients enrolled**

**1973-2001**

**20 Companies**

**Consort Diagram of Study Patients**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**86,137 Patients enrolled**

**1973-2001**

**20 Companies**

**9,636 Patient Dropouts**
**(11.1%)**

**Consort Diagram of Study Patients**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**86,137 Patients enrolled**

**1973-2001**

**20 Companies**

**Consort Diagram of Study Patients**

**9,636 Patient Dropouts**
**(11.1%)**

**54 Years of Age**
**40% Women**
**30% Minority**
**159/102 BP ****[dropout]**

## Drop-Out Characteristics

**Women................40%**
**-------------------------------------------**
**Caucasian............70%**
**AA...................22%**
**Hispanic..............4% **
**Other.................4%**

**Sitting BP**

**Sitting**

**Supine BP**

**Drop-Out Characteristics**
**(9,363 Patients)**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**86,137 Patients enrolled**

**1973-2001**

**20 Companies**

_**PRIMARY AES:**_
_***Cardiovascular***_***	******                  ***_***Neurologic***_
**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%]**

**54 Years of Age**
**40% Women**
**30% Minority**
**159/102 BP [dropout****]**

**Consort Diagram of Study Patients**

**9,636 Patient Dropouts**
**(11.1%)**

## Primary Outcomes: Incidence(All Patients: 86,137)

**Primary Outcomes: Incidence****(All Patients: 86,137)**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**86,137 Patients enrolled**

**1973-2001**

**20 Companies**

**54 Years of Age**
**40% Women**
**30% Minority**
**159/102 BP [dropout****]**

**Consort Diagram of Study Patients**

_**PRIMARY AES:**_
_***Cardiovascular***_***	******               ***_***Neurologic***_
**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%]**

**9,636 Patient Dropouts**
**(11.1%)**

## Other Outcomes: Incidence(All Patients: 86,137)

**Other Outcomes: Incidence****(All Patients: 86,137)**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**86,137 Patients enrolled**

**Consort Diagram of Study Patients**

**21,699 **
**Placebo Patients**
** ****[25.2%]**

**64,438 **
**Drug Patients**
** ****[74.8%]**

## Consort Diagram of Study Patients

**93 **
**NDAs / SNDAs**

**540**
**RCTs**

**86,137 Patients enrolled**

**Consort Diagram of Study Patients**

**3,056 **
**Placebo Dropouts**
**(14.1%)**

**21,699 **
**Placebo Patients**
** ****(25.2%)**

**64,438 **
**Drug Patients**
** ****(74.8%)**

**6,580 **
**Drug Dropouts**
**(10.2%)***

## Primary Outcomes: Incidence

_**Note**_**:  **_**Three ‘Primary Outcomes’**_
** ****(1)  **_**Overall Morbidity**_** = Cardiovascular Morbidity  **_**or**_**  ****Neurologic Morbidity**
** ****(2)  **_**Cardiovascular Morbidity**_** = Angina  **_**or**_** **** Arrhythmia  **_**or**_**  MI  **_**or**_**  ****CHF     **
**(3)  **_**Neurologic Morbidity**_** = Stroke  **_**or**_**  TIA  **_**or**_**  Hypertensive Emergency     **

## Primary Outcomes: Incidence

**Primary Outcomes: Incidence**

## Primary Outcomes: Incidence

**Primary Outcomes: Incidence**

## Primary Outcomes: Relative Risk

**Primary Outcomes: Relative Risk**

## Primary Outcomes: Relative Risk

**Primary Outcomes: Relative Risk**

## Conclusions

**	****           **** ****	*****	***

## ‘Primary Conclusion’

***Overall Morbidity = Cardiovascular Morbidity ***_***or***_*** ******Neurologic Morbidity ******Cardiovascular Morbidity = Angina ***_***or***_*** Arrhythmia ***_***or***_*** MI ***_***or***_*** ******CHF ******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.***

**‘****Primary Conclusion’**

## ‘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.***

## A Secondary Consideration

**	****           **** ****	*****	***

***Counter-argument***

## Slide 34

## EQUIPOISE

**EQUIPOISE**

## EQUIPOISE

**EQUIPOISE**

## EQUIPOISE

**EQUIPOISE**

## EQUIPOISE

**EQUIPOISE**

## EQUIPOISE

**EQUIPOISE**

## EQUIPOISE

**EQUIPOISE**

## ?

**EQUIPOISE**
**?????**

**?**

## 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%

**	****           **** ****	*****	***

_***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%***_

## EQUIPOISE

**EQUIPOISE**

## Conclusion:  Equipoise

**	****           **** ****	*****	***

_***Conclusion***_***:  Equipoise***

## Conclusion:  EquipoiseBut #1........

**	****           **** ****	*****	***

_***Conclusion***_***:  Equipoise******But #1........***

## PRIMARY 

**PRIMARY **
**ENDPOINT **
**COMPONENT**

## Primary

**Primary**
**Endpoint**
**Components**

**‘****Protocol-Excluded’ [EP]**
**Components**

## Conclusion:  EquipoiseBut #2........

**	****           **** ****	*****	***

_***Conclusion***_***:  Equipoise******But #2........***

## ARITHMETIC

**ARITHMETIC**
**EQUIPOISE**

_**HE-OC Events**_** ****Drug = 0.82%  ****(526 / 64,438)**** Placebo= 0.86%  ****(186 / 21.6990**

## But......

**	****           **** ****	*****	***

***But......***

## But, are they Comparable???

**But, are they Comparable???**

## But......Are they comparable?

**	****           **** ****	*****	***

***But......Are they comparable?***

## But......Are they comparable?Certainly not ‘prospectively’.

**	****           **** ****	*****	***

***But......Are they comparable?******Certainly not ‘prospectively’.***

## But......Are they comparable?Certainly not ‘prospectively’. Even putting that aside, their severities may be different.

**	****           **** ****	*****	***

***But......Are they comparable?******Certainly not ‘prospectively’.****** Even putting that aside, ******their severities may be different.***

## HE and OC

## HE and OC

## HE and OC

## BACKGROUND

**Clearly, not all clinical events carry like severity, even when classified as adverse events, or serious adverse events (with WHO definitions).  **
**PHARMA analysis suggested that two discontinuation-related events distinguished the study groups:  (1) hypertensive emergencies; and (2) other cardiovascular events.  **
**Regarding the former—’Hypertensive Emergency’—the gravity of the events appears obvious; however, subjectivity in the interpretation of a "hypertensive emergency" may exist; and therefore, even these events should be subjected to a severity grading.**
**  **
**Regarding the latter—‘Other Cardiovascular Events’—it is clear that a broad spectrum of conditions may exist for this category, and that in certain circumstances, ‘Other Cardiovascular Events’ may be viewed as a "default category."  **
**Therefore, a grading system was constructed and applied blindly.   **

## Hypertensive Emergencies [HE]279 patients discontinued for HE. Patient identifiers & study group were redacted, & then each HE event was graded from 0 to 10:   0—No emergency and No hypertension;  1-4—No hypertension;  5—Hypertension (>200/100) + No s/s:  brain/eye/heart/kidney;  6—Hypertension (>200/100) + 1 Organ s/s [brain/eye/heart/kidney]   7—Hypertension (>200/100) + 2 Organs s/s [brain/eye/heart/kidney]   8—Hypertension (>200/100) + 3 Organ s/s [brain/eye/heart/kidney]   9—Hypertension (>200/100) + 4 Organ s/s [brain/eye/heart/kidney]     10—Hypertension (>200/100) + Death 

**Hypertensive Emergency: Severity Assessment**

## Other Cardiovascular Events [OCE]   469 patients discontinued for OCE. Patient identifiers & study group were redacted, & then each OCE event was graded from 0 to 10:      0—No event;           1—No ischemia of any organ;          2-5—Minor symptoms;          6—Myocardial Ischemia, Stupor, Loss of Consciousness;           7—Documented two-organ ischemia;          8—Documented MI or Stroke;         9—Documented MI or Stroke and second organ ischemia;        10—Death. 

**Other Cv Events: Severity Assessment**

## Hypertensive Emergency Events

|   N-ALL | 145  | 134 | P |
| --- | --- | --- | --- |
| % (x102) | 22.5  | 61.8 |  |
| R (P/D) |  | 2.74 | <0.001  |
| N>5 | 118  | 104 | P |
| % (x102) | 18.3 | 47.9 |  |
| R (P/D) |  | 2.62 | <0.001  |

**Drug**

**Placebo**

**Hypertensive Emergency Events**

## Hypertensive Emergency Events

|   N-ALL | 145  | 134 | P |
| --- | --- | --- | --- |
| % (x102) | 22.5  | 61.8 |  |
| R (P/D) |  | 2.74 | <0.001  |
| N>5 | 118  | 104 | P |
| % (x102) | 18.3 | 47.9 |  |
| R (P/D) |  | 2.62 | <0.001  |

**Drug**

**Placebo**

**Hypertensive Emergency Events**

## Other Cardiovascular Events

**Other Cardiovascular Events**

|   N-ALL | 417 | 52 | P |
| --- | --- | --- | --- |
| % (x102) | 64.7  | 24.0 |  |
| R (P/D) |  | 0.37 | <0.001  |
| N>5 | 18  | 15 | P |
| % (x102) | 2.8 | 6.9 |  |
| R (P/D) |  | 2.46 | 0.0140  |

**Drug**

**Placebo**

## Other Cardiovascular Events

**Other Cardiovascular Events**

|   N-ALL | 417 | 52 | P |
| --- | --- | --- | --- |
| % (x102) | 64.7  | 24.0 |  |
| R (P/D) |  | 0.37 | <0.001  |
| N>5 | 18  | 15 | P |
| % (x102) | 2.8 | 6.9 |  |
| R (P/D) |  | 2.46 | 0.0140  |

**Drug**

**Placebo**

## ‘Conclusions: HE versus OC’

## ‘Conclusions: HE versus OC’

** **

**‘****Conclusions: HE versus OC’**

## ‘Conclusions: HE versus OC’

** **
**   ****However, two arguments exist for discounting that inference.**
**         ****1.  The ‘arithmetic balance analysis’ is a secondary construct.**
**         **

**‘****Conclusions: HE versus OC’**

## ‘Conclusions: HE versus OC’

** **
**   ****However, two arguments exist for discounting that inference.**
**         ****1.****  ****The ‘arithmetic balance analysis’ is a secondary construct.**
**         ****2.  Given  that severe events  likely have greater short and long-term **
**	****  ****physical consequence, the findings for both severe  HE and severe OC **
**                ****support the hypothesis that harm is associated with PCT for HTN.**

**‘****Conclusions: HE versus OC’**

## ‘Conclusions: HE versus OC’

** **
**   ****However, two arguments exist for discounting that inference.**
**         ****1.  The ‘arithmetic balance analysis’ is a secondary construct.**
**         ****2.  Given  that severe events  likely have greater short and long-term **
**	****  ****physical consequence, the findings for both severe  HE and severe OC **
**                ****support the hypothesis that harm is associated with PCT for HTN.**
**   ****Given that the primary hypothesis was satisfied, namely that RR>1 for **
**     ****2/3 ‘spheres’ (neurologic morbidity and all morbidity), then I still conclude **
**                                                             ****that: **

**‘****Conclusions: HE versus OC’**

## ‘Conclusions: HE versus OC’

** **
**   ****However, two arguments exist for discounting that inference.**
**         ****1.  The ‘arithmetic balance analysis’ is a secondary construct.**
**         ****2.  Given  that severe events  likely have greater short and long-term **
**	****  ****physical consequence, the findings for both severe  HE and severe OC **
**                ****support the hypothesis that harm is associated with PCT for HTN.**
**   ****Given that the primary hypothesis was satisfied, namely that RR>1 for **
**     ****2/3 ‘spheres’ (neurologic morbidity and all morbidity), then I still conclude **
**                                                             ****that: **

**‘****Conclusions: HE versus OC’**

***Reassessment of placebo-controlled trials of anti-hypertensive drugs is indicated.***

## Thank You

## My Inferences forClinical Trial Design 

**	****           **** ****	*****	***

## CONTROVERSY

_**Considerations #1**_**:**** ****	****           ****●****   **_**Declaration of Helsinki**_**:****	****“The benefits, risks burdens, and effectiveness of a new method should be ****	****used against those of the best current prophylactic, diagnostic, and ****	****therapeutic methods.  This does not exclude the use of placebo, or no ****	****treatment, in studies where no proven prophylactic, diagnostic, and ****	****therapeutic method exists.“ **** ****●****   **_**International Conference for Harmonization**_**:****	****Considers use of PCT ethical, even if effective treatment is available for the ****	****condition under study, if withholding the treatment leads to no serious ****	****harm and if patients are fully informed about available therapies and ****	****consequences of no or delayed treatment.**

## CONTROVERSY

_**Considerations #2**_**:**** **_**Placebo Orthodoxy**_**—PCT are appropriate, even when an effective therapy exists.  ****         ****	****	****     No therapy should be approved unless it is clearly superior to ****	****	****	****     placebo / no therapy. ****            ****             **_**Strengths**_**: ****	****   a.  Methodologically rigorous.****                   b.  New therapy = standard therapy may still be clinically valuable.****             **_**Limitations**_**:****	****   a.  Criteria for ethical use of PCT are not always clearly stated.****	****   b.  Focus on irreversible physical harm. ****                                     (But, temporary, reversible conditions ******** permanent harm)****	****   c.   Permits intolerable suffering. **

## CONTROVERSY

_**Considerations #2**_**:**** ****	****           **_**Active-Control Orthodoxy**_**—PCT are not appropriate, when an effective therapy ****	****  ****	****	****	**** exists. ****	****	****	**** PCTs are inappropriate ******** the clinically relevant ****	****	****	****	**** question is not whether a new therapy is better than ****	****	****	****	**** nothing, but whether it is better than standard treatment. ****                  ****            **_**Strengths**_**: ****	****a.  Methodologically rigorous.****                b.  New therapy = standard therapy may still be clinically valuable.****            **_**Limitations**_**:****	****a.  Harm/discomfort associated with placebo-assignment may be non-****	**** ****	****       existent/ trivial.****	****b.  Power of the placebo response is underestimated (****↑****attention).****                c.   Active-control harm may > placebo-control harm (****↑****saes; equivalence ****↑****#.**

## CONTROVERSY

_**Considerations #3**_**:**** ****	****  ****●****   PCTs clearly unethical if withholding therapy********death, life-threat, serious harm. ****	****Ex.  PCT for TPA was not ethical (SK was effective).**** ****●****   PCTs clearly ethical if withholding therapy********minimal chance of harm/suffering. ****    ****                 Ex.  Rogain / allergic rhinitis.**** ****●****   PCT Orthodoxy < = > Active-control Orthodoxy****     Both views discount the ethical and methodologic complexities of clinical research.**** ****●     **** PCTs clearly ethical if withholding therapy********minimal chance of harm/suffering. ****    ****                                         Ex.  Rogain / allergic rhinitis.**

## CONTROVERSY

_**Considerations #4**_**:**** **_**Principle**_**:****     ****When effective therapies exist, there must be compelling methodological ****	****       reasons to conduct a PCT.**** **_**Methodological Criteria**_** ****                   ****	****     ****●****   High placebo response rate.****                     ****●****  Conditions wax & wane.****                     ****●****   Existing Txs are only partially effective, or have serious side-effects.****                     ****●****   Low frequency of condition (Equivalence)**_**Ethical Criteria**_**                     ****	****     ****●****   Placebo patients should not be more likely to:****                                           die****                                           suffer irreversible morbidity****                                           suffer reversible but serious harm****                                           experience severe discomfort****                    **** **