Reliable Evaluation of Benefit-to-Risk in T2DM:

Reliable Evaluation of Benefit-to-Risk in T2DM:

Some Statistical Considerations

July 1, 2008

Thomas R. Fleming, Ph.D.Professor, Dept of Biostatistics

University of [email protected]

CV Risk Assessment for T2DM Therapies

Reliable Evaluation of Benefit-to-Risk

• Surrogate Endpoints

• Validation of Surrogates

• Evaluation of Safety

• Conclusions

Biomarkers (Surrogates) in Diabetes

Treatment effects on Biomarkers ~ HbA1c , C-Peptide

• Establish Biological Activity

• But not necessarily overall Clinical Efficacy ~ Retinopathy, Nephropathy, CVD, Stroke, MI ~ Major hypoglycemic events: Coma/Seizure

HbA1c End-Organ Glycemic Control Diabetic Complications

Intervention

Disease

End-Organ DiabeticComplications HbA1c

Glycemic Control

Disease

Intervention

Multiple Pathways of the Disease Process

What magnitude and what duration is needed?

HbA1c End Organ Glycemic Control Diabetic Complications

• Unintended negative effectse.g., Hypoglycemic Events

• Alternative beneficial effects

Disease

Intervention

Interventions having Mechanisms of Action Independent of the Disease Process

Recent Experiences: Misleading Surrogates

Strategy for HbA1c 6.0 vs. 7-7.9 Target: ACCORD ↓ HbA1c vs. Suggested ↑ Mortality

Erythropoietin : Renal, Oncology ↑ Hemoglobin vs. ↑ Thrombosis & ↑

Mortality

Troglitazone : T2DM Prevention Program (DPP) ↓ HbA1c vs. ↑ Serious Hepatic Risks

Torcetrapid / Atorvastatin in CHD: ILLUMINATE ↑ HDL ↓ LDL vs. ↑ Death & ↑ CHD

Death/MI/Stroke

Muraglitazar & Rosiglitazone : Type 2 Diabetes↓ HbA1c vs. Suggested ↑ Death / Stroke / MI or ↑

MI

End Stage Renal Disease

Standard Dose Epogen Hematocrit 30%

High Dose Epogen Hematocrit 42%R

Goal: Normalize Hematocrit Values

reduce Death and MI

Patient Distribution & Percent Deaths by Hematocrit %

27-30 30-33 33-36 36-39 39-42

STANDARD DOSE EPOGEN

60%

45%

30%

15%

0%


27-30 30-33 33-36 36-39 39-42


HIGH DOSE EPOGEN

• 30% death RR

for 10 pt in hem.

60%

45%

30%

15%

0%

60%

45%

30%

15%

0%

27-30 30-33 33-36 36-39 39-42


27-30 30-33 33-36 36-39 39-42


HIGH DOSE EPOGEN

• 30% death RR

for 10 pt in hem.

60%

45%

30%

15%

0%

60%

45%

30%

15%

0%

27-30 30-33 33-36 36-39 39-42


27-30 30-33 33-36 36-39 39-42


HIGH DOSE EPOGEN

• 30% death RR

for 10 pt in hem.

• in hematocrit

60%

45%

30%

15%

0%

60%

45%

30%

15%

0%

27-30 30-33 33-36 36-39 39-42


27-30 30-33 33-36 36-39 39-42


HIGH DOSE EPOGEN

• 30% death RR

for 10 pt in hem.

• in hematocrit

• 30% in death RR

60%

45%

30%

15%

0%

60%

45%

30%

15%

0%

27-30 30-33 33-36 36-39 39-42

End Stage Renal Disease

Standard Dose EPOGEN

High Dose EPOGEN

Results (Interim at 1/2 planned endpoints)

n Death/MI Death

Standard Dose 615 164 160High Dose 618 202 195

Death / MI relative risk: 1.30 (0.94, 1.79)

Besarab et al, NEJM 339:584-590, 1998: “ in incidence of thrombosis of vascular access sites”

R

Recent Experiences: Misleading Surrogates

Strategy for HbA1c 6.0 vs. 7-7.9 Target: ACCORD ↓ HbA1c vs. Suggested ↑ Mortality

Erythropoietin : Renal, Oncology ↑ Hemoglobin vs. ↑ Thrombosis & ↑ Mortality

Troglitazone : T2DM Prevention Program (DPP) ↓ HbA1c vs. ↑ Serious Hepatic Risks

Torcetrapid / Atorvastatin in CHD: ILLUMINATE ↑ HDL ↓ LDL vs. ↑ Death & ↑ CHD

Death/MI/Stroke

Muraglitazar & Rosiglitazone : Type 2 Diabetes↓ HbA1c vs. Suggested ↑ Death / Stroke / MI or ↑

MI

Surrogate True Clinical Endpoint Endpoint

• Unintended negative effects


Disease

Intervention

Reliability of Surrogate Endpoints





• Conclusions

Validation of Surrogate Endpoints

Property of a Valid Surrogate

Effect of the Intervention on the Clinical Endpoint

is reliably predicted by the

Effect of the Intervention on the Surrogate Endpoint

Z = 0 : target 7-7.9; Z = 1 : target 6.0S(t) : HbA1c at time t

is the CVD / MI / Stroke rate

(t | Z) = 0(t) e

In ACCORD, to detect e = 0.85 with 89% power when preserving 0.025 false pos error rate,

the trial requires L = 1540 events.In turn, this requires approximately 10,000 patients, followed for approximately 5-6 years.

i.e., 1(t) = 0(t) e

Prentice’s Sufficient Conditionsto Validate a Surrogate Endpoint

1. The surrogate endpointmust be correlated with

the clinical outcome

2. The surrogate endpointmust fully capture

the net effect of treatmenton the clinical outcome


is the CVD / MI / Stroke rate

(t | Z) = 0(t) e

(t | Z, S(t) ) = 0(t) eZ + S(t)

Proportion of net treatment effectexplained by the surrogate endpoint:

p = 1 -

Meta-analysesare required to explore

the validityof surrogate endpoints


(t | Z) = 0(t) e

(t | Z, S(t) ) = 0(t) eZ + S(t)


DeGruttola et al, J Infectious Diseases 175:237-246, 1997

p = 1 -

HbA1c Major Clinical Glycemic Control Events

• Unintended negative effectse.g., Hypoglycemic Events


Disease

Intervention


Z = 0 : target 7-7.9; Z = 1 : target 6.0S(t) : Hypoglycemic Event at time t

(t | Z) = 0(t) e

(t | Z, S(t) ) = 0(t) eZ + S(t)


DeGruttola et al, J Infectious Diseases 175:237-246, 1997

p = 1 -


Statistical Meta-analyses of clinical trials data

Clinical Comprehensive understanding of the

~ Causal pathways of the disease process ~ Intervention’s intended and unintended

mechanisms of action

Effects on HbA1c vs. Effects on CVD / Stroke / MI

Hypothetical Illustration

Validation across multiple Clinical Outcomes

T2DM (For an array of interventions)

• Effects on HbA1c predicting effects on:

Microvascular composite outcomes Macrovascular composite outcomes Other composites of clinical efficacy measures

Anti-Hypertensives (>500,000 patients from rand trials)FDA Cardio-Renal Advisory Committee: June 15, 2005

• Effects on Blood Pressure predicting effects on each of the following, considered individually:

Stroke, MI, CVD, Overall Mortality, Heart Failure

Odds Ratio for CV Events and Systolic BP Difference: Recent and Older Trials

Staessen et al. Staessen et al. J HypertensJ Hypertens. 2003;21:1055-1076.. 2003;21:1055-1076.

Odd

s R

atio

(ex

peri

men

tal/

refe

renc

e)O

dds

Rat

io (

expe

rim

enta

l/re

fere

nce)

1.501.50

1.251.25

1.001.00

0.750.75

0.500.50

0.250.25

-5-5 00 55 1010 1515 2020 2525

PP<.0001<.0001

Difference (reference minus experimental) Difference (reference minus experimental) in Systolic BP (mm Hg)in Systolic BP (mm Hg)

Recent trialsRecent trials

Older trials placeboOlder trials placebo

STONESTONE

UKPDS L vs. HUKPDS L vs. H

PROGRESSION/ComPROGRESSION/Com

STOP 1STOP 1

RCT70-80RCT70-80

EWPHEEWPHEHEPHEP

MRC2MRC2

SHEPSHEP

Syst-EurSyst-Eur

PART2/SCATPART2/SCAT

HOPEHOPE

STOP2/ACEIsSTOP2/ACEIs

ALLHAT/DoxALLHAT/Dox

UKPDS C vs. AUKPDS C vs. A

MIDAS/NICS/VHASMIDAS/NICS/VHAS

STOP2/CCBsSTOP2/CCBs

HOT M vs. HHOT M vs. HINSIGHTINSIGHT

HOTHOT

PROGRESS/PerPROGRESS/PerPATSPATS

RENAALRENAAL

L vs. HL vs. HMRCMRC

ATMHATMH

Syst-ChinaSyst-China

OlderOlderRecentRecentAASK L vs. HAASK L vs. HABCD/NT L vs. HABCD/NT L vs. H

ALLHAT/Lis BlacksALLHAT/Lis BlacksALLHAT/Lis ALLHAT/Lis 6565ALLHAT/LisALLHAT/LisALLHAT/AmlALLHAT/Aml

CONVINCECONVINCEDIABHYCARDIABHYCAR

ANBP2ANBP2

LIFE/ALLLIFE/ALL

ELSAELSA

LIFE/DMLIFE/DMNICOLENICOLEPREVENTPREVENT

IDNT2IDNT2

SCOPESCOPE

Older trials activeOlder trials active

Slide: Henry Black’s lecture





• Conclusions

Class of Agents

and

Example members

Safety Event

and

Clinical Setting

Bkgd

Rate

/1K

Relative ↑ In Safety

Risk, RR

Attrib

Risk,

#/1K

PY

Cox 2 inhibitors

Celebrex, Vioxx, Bextra

CV Death / Stroke / MI

RA, OA and Alzheimers

10 1.5 5

Long Acting β-Agonists Salmeterol, serevant

Asthma-related Death

Severe Asthma

0.5 4 1.5

Anti-psychotics

Ziprasidone

QTc related CV Events

Schizophrenia

? ? ?

Tysabri Progressive Multifocal Leukoenceph

Multiple Sclerosis & Crohn’s Disease

<0.001? 1000 1

Rotavirus Vaccine Intussusception

High Risk for Rotavirus

0.1 >10 >1

Muraglitazar

Rosiglitazone


Type 2 Diabetes

20 1.5 - 2 10-20

Erythropoietin Death

Renal Disease, Oncology

? 1.1-1.15 ?

ADHD Psychostimulants

Adderall, Ritalin in Adults

ADHD Drugs in Pediatrics


ADHD Adult Setting

ADHDPediatric Setting

10

0.12

2.5

2.5

15

0.2

Primary Goal

Identifying effective interventions that are safe An important objective: Obtaining a Timely & Reliable Assessment

of Benefit-to-Risk

… Detecting long & short term risks… … Detecting rare & frequent risks…

Enabling one to rule outunacceptable increases in safety risks

Approaches to Pre- and Post-MarketingEvaluation of Safety

I Passive Surveillance Systems

II Active Surveillance Systems

III Large Randomized Clinical Trials

Surveillance for new safety signals

Exploration of existing signals

“Post Marketing” Passive Surveillance Systems

AERS: A single system for collection & analysis of reports on all serious AEs

(based on voluntary submission of MedWatch forms for AEs that caregivers believe might be drug related)

… for Safety Rare events: < 1/1000

“signal detection” … hypothesis generation requires

Large RR, or Temporal relationship

Passive Surveillance Systems

+ Timely information

+ Uniformity of reporting procedure

– Not randomized; no comparator group

– Lack of denominator

– Voluntary submission underreporting

“Post Marketing” Active Surveillance Systems

Large Prospective Cohorts & Large Linked Databases

Linking Automated Databases from HMOs 500,000 patients (e.g., Northern California Kaiser)

… for Safety• Rare events: < 1/1000

Active Surveillance Systems

+ Information on a defined population

+ Complete numerators & denominators

+ Fast & inexpensive

– Not randomized– Confounder information often unavailable– Outcome specificity

… is stated event truly an event?– Outcome sensitivity

Class of Agents

and

Example members

Safety Event

and

Clinical Setting

Bkgd

Rate

/1K


Risk, RR

Attrib

Risk,

#/1K

PY

Cox 2 inhibitors




10 1.5 5



Severe Asthma

0.5 4 1.5

Anti-psychotics

Ziprasidone


Schizophrenia

? ? ?


Multiple Sclerosis & Crohn’s Dis.

<0.001? 1000 1



0.1 >10 >1

Muraglitazar

Rosiglitazone


Type 2 Diabetes

20 1.5 - 2 10-20



? 1.1-1.15 ?





ADHD Adult Setting

ADHD Pediatric Setting

10

0.12

2.5

2.5

15

0.2

Class of Agents

and

Example members

Safety Event

and

Clinical Setting

Bkgd

Rate

/1K


Risk, RR

Attrib

Risk,

#/1K

PY

Cox 2 inhibitors




10 1.5 5



Severe Asthma

0.5 4 1.5

Anti-psychotics

Ziprasidone


Schizophrenia

? ? ?



<0.001? 1000 1



0.1 >10 >1

Muraglitazar

Rosiglitazone


Type 2 Diabetes

20 1.5 - 2 10-20



? 1.1-1.15 ?


Adderall, Ritalin (Adults)



ADHD Adult Setting


10

0.12

2.5

2.5

15

0.2

Safety Assessments: Advantages provided by Randomized Prospective Cohorts

• Randomization removes systematically occurring imbalances in baseline characteristics

~ Pts/caregivers don’t start/stop treatments “at random” ~ Known & recorded covariates are the “tip of iceburg”

• Need to conduct an ITT evaluation Need ability to define a time 0 cohort

~ Assess risk over specified time interval, even if intervention is stopped earlier in time

~ Risk cannot be assumed to be independent of duration of exposure

Safety Assessments: Advantages provided by (Randomized) Prospective Cohorts

• Sensitivity & Specificity ~ Systematic and reliable capture of all events ~ Timely adjudication, (esp. in open label settings)

• Retention ~ Maintaining follow-up for targeted durations

• Adherence ~ Achieving proper dose and duration of use

Typically Sized (2N = 1K – 20K) “Pre- & Post-Marketing” Randomized Trials

Moderate term & moderate/high frequency

Annual Rate of Events 10 vs. 30 /1,000 2N = 2K p.y.* 1 vs. 3 /1,000 2N = 20K p.y.*

10 vs. 15 /1,000 2N = 20K p.y.* Cox 2 Inhibitors, ADHD adults

20 vs. 25 /1,000 2N = 40K p.y.* Type 2 Diabetes

+ Causal Inference

* 90% power to rule out targeted ↑; = 0.025

Class of Agents

and

Example members

Safety Event

and

Clinical Setting

Bkgd

Rate

/1K


Risk, RR

Attrib

Risk,

#/1K

PY

Cox 2 inhibitors




10 1.5 5



Severe Asthma

0.5 4 1.5

Anti-psychotics

Ziprasidone


Schizophrenia

? ? ?



<0.001? 1000 1



0.1 >10 >1

Muraglitazar

Rosiglitazone


Type 2 Diabetes

20 1.5 - 2 10-20



? 1.1-1.15 ?





ADHD Adult Setting


10

0.12

2.5

2.5

15

0.2

The PRECISION Trial:Ruling out Excess Rates of


Pain Medications in Patients withOsteoarthritis & Rheumatoid Arthritis

With or at Hi Risk for CV Disease

CelecoxibIbuprofenNaproxen

R

Using the Proportional Hazards Model for the rate of “CV Death/Stroke/MI”

Naproxen : Celecoxib :

If one sets

with 1α=0.025 & power 0.90,

then L=508 events are required.

)(0 t ett )()( 01

1100 :: HH

PRECISION Trial

0:333.1ln: 10 HH

“CV Death / MI / Stroke” Events

0.84 1.00 1.12 1.19 1.333

Celecoxib better

Celecoxib compared with Naproxen

Naproxen better

Hazard Ratio (Celecoxib / Naproxen) Based on analysis at L=508 Events

A

B

C

D

CEL: superior

CEL: ruling out unacceptably inferior

CEL: neither ruling out to be unacceptably inferior, nor establishing as inferior

CEL: inferior

Performance Standards in Non-inferiority Safety Trials

Enrollment Rate need timely result

Target Population / Ineligibility Rate / Event Rate need to address settings where excess risk is most plausible need sufficiently high risk to achieve targeted number of events

Adherence must at least match adherence in prior trials with safety signal include frequency/timing of withdrawal from rand. treatment

Cross-ins minimize by: careful screening; educating caregivers & patients

…Very challenging in a post-marketing setting… Retention

critical to maintaining integrity of randomization





• Conclusions

Consequences of Reliance on Surrogate Endpoints For Accelerated or Full Regulatory Approval

Less reliable evidence regarding Efficacy

Less reliable evidence regarding Safety

…The stronger the efficacy evidence , the greater the resilience regarding uncertainties about safety…

Recent Experiences:

• Tysabri : PML in Crohns Disease & Multiple Sclerosis

• Erythropoiesis Stimulating Agents : Chemo-Induced Amemia & Hemodialysis in

CHF

• Muraglitazar & Rosiglitazone : Type 2 Diabetes

Goals in Development of Interventions in Diabetes

• Achieving an efficient evaluation of experimental interventions… possibly with the use of biomarkers

• Achieving reliable as well as timely evaluation of both safety and efficacy

of new interventions

• Providing patients and care-givers not only a choice, but an informed choice

Documents

Reliable Evaluation of Benefit-to-Risk in T2DM: