PHARM FDA – IREF Potential Conflicts of Interest IREF—Nonprofit (NIH; FDA; prior Industry)...

PHARM FDA – IREF

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 FDA – IREF

PHARM

Placebo in Hypertension Adverse Reaction Meta-analysis

PHARM FDA – IREF

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

PHARM FDA – IREF

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

PHARM FDA – IREF

‘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.

PHARM FDA – IREF

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%.

PHARM FDA – IREF

Methods

As described by Dr. Lipicky.

PHARM FDA – IREF

Methods



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:

PHARM FDA – IREF

Methods





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:

PHARM FDA – IREF

Results

OVERALL FINDINGS

[86,137 Patients]

PHARM FDA – IREF

93 NDAs / SNDAs

Consort Diagram of Study Patients

PHARM FDA – IREF

93 NDAs / SNDAs

1973-2001


PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs

1973-2001


PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs

1973-2001

20 Companies


PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs

86,137 Patients enrolled

1973-2001

20 Companies


PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs


1973-2001

20 Companies

9,636 Patient Dropouts(11.1%)


PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs


1973-2001

20 Companies


9,636 Patient Dropouts(11.1%)54 Years of Age

40% Women

30% Minority

159/102 BP [dropout]

PHARM FDA – IREF

250

500

750

1000

Co

un

t

20 30 40 50 60 70 80 90

Age (Years)

Mean Age = 54.1 years

100110120130140150160170180190200210220230

70

80

90

100

110

120

130

Systolic =158 Diastolic =102

110120130140150160170180190

200210220230240250

70

80

90

100

110

120

130

Systolic =159 Diastolic =102

n

n

= 9,636

= 2,975

Women….............40%-------------------------------------------

Caucasian….........70%

AA……………….22%

Hispanic……....….4%

Other……………..4%

Sitting BP

Sitting

Supine BP

Drop-Out Characteristics(9,363 Patients)

PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs


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 Age40% Women30% Minority




PHARM FDA – IREF

Primary Outcome Incidence

35

81

41

0

25

50

75

100

SAE 'Sphere'

% x

100

.

All Patients

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

PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs


1973-2001

20 Companies

54 Years of Age40% Women30% Minority



PRIMARY AES:

Cardiovascular NeurologicAngina (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%]


PHARM FDA – IREF

Other Outcome Incidence

308

54

317

1

358

0

100

200

300

400

SAE Other

% x

100

.

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

PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs



21,699 Placebo Patients

[25.2%]

64,438 Drug Patients

[74.8%]

PHARM FDA – IREF

93 NDAs / SNDAs

540RCTs



3,056 Placebo Dropouts

(14.1%)

21,699 Placebo Patients

(25.2%)

64,438 Drug Patients

(74.8%)

6,580 Drug Dropouts

(10.2%)*

PHARM FDA – IREF

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

PHARM FDA – IREF

Primary Outcome Incidence

3423

30

6570

37

6271

108112

0

25

50

75

100

125

SAE 'Sphere'

% x

100

.

Drug

Placebo

Primary Outcomes: Incidence

PHARM FDA – IREF

Primary Outcomes; Relative Risk

1.1

0.7

1.1

1.5

1.10.8

1.4

2.3

0.9

1.71.4

2.9

0.0

1.0

2.0

3.0

SAE Sphere

Rela

tive R

isk [P/D

} .

Primary Outcomes: Relative Risk

PHARM FDA – IREF

Primary Outcomes; Relative Risk

1.1

0.7

1.1

1.5

1.1

0.8

1.4

2.3

0.9

1.7

1.4

2.9

0.0

1.0

2.0

3.0

SAE Sphere

Rela

tive R

isk [P/D

} .

Primary Outcomes: Relative Risk

PHARM FDA – IREF

Conclusions

PHARM FDA – IREF

Primary Outcomes

1.40

1.07

2.35

0.0

1.0

2.0

3.0

Cv | N | d CvM NM

SAE Sphere

Rel

ativ

e R

isk

[P/D

]




If the Relative Risk [P/D] is significantly > 1.0, in any of the three spheres,

then:


‘Primary Conclusion’

PHARM FDA – IREF

‘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.

PHARM FDA – IREF

A Secondary Consideration

Counter-argument

PHARM FDA – IREF

Higher Risk on Treatment Higher Risk on Placebo

Relative Risk (Placebo/Drug)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

OTOAETFOCHEAPARMI

CHFDeathCVATIAVT

All dropouts

PHARM FDA – IREF



0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

OTOAETFOCHEAPARMI

CHFDeathCVATIAVT

All dropouts

EQUIPOISE

PHARM FDA – IREF



0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

OTOAETFOCHEAPARMI

CHFDeathCVATIAVT

All dropouts

EQUIPOISE?????

?

PHARM FDA – IREF

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%

PHARM FDA – IREF



0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

OTOAETFOCHEAPARMI

CHFDeathCVATIAVT

All dropouts

EQUIPOISE

PHARM FDA – IREF

Conclusion: Equipoise

PHARM FDA – IREF


But #1……..

PHARM FDA – IREF



0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

OTOAETFOCHEAPARMI

CHFDeathCVATIAVT

All dropouts

PRIMARY ENDPOINT

COMPONENT

PHARM FDA – IREF



0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

OTOAETFOCHEAPARMI

CHFDeathCVATIAVT

All dropouts

PrimaryEndpoint

Components

‘Protocol-Excluded’ [EP]Components

PHARM FDA – IREF


But #2……..

PHARM FDA – IREF



0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

OTOAETFOCHEAPARMI

CHFDeathCVATIAVT

All dropouts

ARITHMETICEQUIPOISE HE-OC Events

Drug = 0.82% (526 / 64,438)

Placebo= 0.86% (186 / 21.6990

PHARM FDA – IREF

But……

PHARM FDA – IREF



0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

OTOAETFOCHEAPARMI

CHFDeathCVATIAVT

All dropouts

But, are they Comparable???

PHARM FDA – IREF

But……Are they comparable?

PHARM FDA – IREF


Certainly not ‘prospectively’.

PHARM FDA – IREF


Certainly not ‘prospectively’.

Even putting that aside,

their severities may be different.

PHARM FDA – IREF

HE and OC

PHARM FDA – IREF

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.

PHARM FDA – IREF

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]



10—Hypertension (>200/100) + Death

Hypertensive Emergency: Severity Assessment

PHARM FDA – IREF

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

PHARM FDA – IREF

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

PHARM FDA – IREF

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

PHARM FDA – IREF

‘Conclusions: HE versus OC’

PHARM FDA – IREF

• The arithmetic balance between OC and HE events argues for equipoise.


PHARM FDA – IREF


• However, two arguments exist for discounting that inference.

1. The ‘arithmetic balance analysis’ is a secondary construct.


PHARM FDA – IREF




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.


PHARM FDA – IREF







• 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:


PHARM FDA – IREF

Thank You

PHARM FDA – IREF

My Inferences

for

Clinical Trial Design

PHARM FDA – IREF

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.

PHARM FDA – IREF

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.

PHARM FDA – IREF

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 ↑#.

PHARM FDA – IREF

CONTROVERSY

Considerations #3:

● PCTs clearly unethical if withholding therapydeath, life-threat, serious harm.

Ex. PCT for TPA was not ethical (SK was effective).

● PCTs clearly ethical if withholding therapyminimal 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 therapyminimal chance of harm/suffering. Ex. Rogain / allergic rhinitis.

PHARM FDA – IREF

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

PHARM FDA – IREF Potential Conflicts of Interest IREF—Nonprofit (NIH; FDA; prior Industry)...

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