Imaging Biomarkers:utilisation for the purposes of registration

EMEA-EFPIA Workshop on Biomarkers15 December 2006

2

Vascular Imaging Technologies

QCA-% stenosisIVUS-PAVCarotid Ultrasound-IMT

3

ICH E 9 Guidance for Industry (II.2.2.6)statistical principles for clinical trials

IVUS

Clinical Trial Evidencetreatment effects on the surrogate

correspond to clinical outcomes

Epidemiologic Dataprognostic value of the surrogate

for clinical outcome

Biological Plausibilitye.g., pathophysiology suggests a

relationship between the surrogate and a clinical outcome

CIMTQCA

ICH, E9, Step 45 Feb 1998

Evidence to establish surrogacy

4

First accepted imaging surrogate of clinical efficacy

Set the standard for the field when placebo control groups were still acceptable

Measures lumen diameter (mm) or percent stenosis

Quantitative Coronary Angiography (QCA)

5

Imaging measurements and clinical events with cholesterol lowering therapies

QCA meta-analyses (Rossouw)

0.0 0.5 1.0 1.5 2.00.0 0.5 1.0 1.5 2.0

=Less progression Lower odds of coronary events

Odds Ratio of Progression Odds Ratio of Clinical Event

Lifestyle

Resins

Statins

Combx

All Drug

Surgery

All

Lifestyle

Resins

Statins

Combx

All Drug

Surgery

All

QCA progression and clinical events

Rossouw J E. Am J Cardiol. 1995;76:86C-92C.

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Limitations

QCA can only measure “luminal atherosclerosis” (i.e., advanced disease that impinges the lumen)

Most events occur in non-stenotic vessels

Digital QCA loses spatial resolution- Not sufficient resolution for active control studies

QCA Limitations

01020304050607080 <50% 50-70% >70%

Diameter Stenosis% P

atie

nts

with

MI

(n =

195

) Smith. Circulation. 1996;93:2205-2211(data from four studies)

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Vascular Ultrasound

AdvantagesCoronary and carotid ultrasound permit direct visualisation of vascular diseaseDetects latent disease not visible to angiography

atheroma

De Franco AC, Nissen SE, Am J Cardiol 2001;88:7M-20M

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Carotid Ultrasound

Measures of intima-media thickness

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Evidence that Carotid IMT PredictsClinical Disease

Epidemiological DataRotterdam Study

CLAS (Cholesterol Lowering Atherosclerosis Study) post-treatment long-term outcomes follow-up

CHS (Cardiovascular Health Study)

1.43 (OR)1.46 (OR)0.2 mm SDCHS

2.2 (RR)0.03 mm/yrCLAS

1.41 (OR)1.43 (OR)0.163 mm SDRotterdamrisk of Strokerisk of MI∆ in CIMTStudy

Bots ML, Hoes AW, Koudstaal PJ, et al. Circulation 1997;96:1432-1437 (Rotterdam)Hodis HN, Mack WJ, LaBree L, et al Ann Int Med 1998;128:262-269 (CLAS)O’Leary DH, Polak JF, Kronman RA, et al N Eng J Med 1999;340:14-22 (CHS)

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Cardiovascular Health Study: Baseline CIMT Predictive of Stroke and MI

4,476 subject without CHD at baselineMedian follow-up 6.2 yrsRR of stroke or MI for highest vs. lowest CIMT quintile was 3.87

O’Leary et al, N Engl J Med. 1999;340:14-22.

0 1 2 3 4 5 6 7

1st Quintile

Cu

mu

lati

ve E

ven

t-fr

ee R

ate

(%)

Years

70

75

80

85

90

95

100

2nd Quintile

3rd Quintile

4th Quintile

5th Quintile

0.89 mm

0.96 mm

1.13 mm

1.36 mm

1.50 mm

Mean CIMT*

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Evidence that changes in CIMT Predict Clinical Disease:Lipid intervention studies: meta-analysisClinical trials involving HMG-CoA reductase inhibitors that reported both Carotid IMT and Cardiovascular Event Outcomes

Relative Impact on Reported Cardiovascular Endpoints: Odds Ratio [95% CI]

0.48 [0.30, 0.78]-0.012 [-0.016, -0.007]**Pooled Estimate

0.32 [0.10, 1.06]CVD Death, MISignificant Benefit (p <0.001)PravastatinFAST(50) (N=164)

0.64 [-0.24, 1.66]CVD Death, MI, Stroke-0.008 [-0.013, -0.003] (p=0.002)FluvastatinBCAPS(49) (N=793)

0.51 [0.24, 1.07]Clinical Events-0.030 [-0.056, -0.004] (p=0.002)PravastatinREGRESS(28) (N=255)

1.02 [0.14, 7.33]CVD Death, MI-0.014 [-0.021, -0.005] (p=0.0007)PravastatinCAIUS(48) (N=305)

0.37 [0.11, 1.24]Clinical Coronary Events-0.009 [-0.031, 0.013] (p=0.44)PravastatinPLAC-II(47) (N=151)

0.57 [0.22, 1.47]CVD Death, MI, Stroke-0.014 [-0.022, -0.006] (p=0.005)PravastatinKAPS(26) (N=447)

0.34 [0.12, 0.69]CVD Death, MI, Stroke-0.015 [-0.023, -0.007] (p=0.001)LovastatinACAPS(25) (N=919)

OddsRatio

AbstractedCVD Event

Relative Impact on IMT Progression of Primary Outcome (mm/yr): Mean

[95% CI] (Reported p-Value)StatinClinical Trial (N*)

*Arms used in meta-analysis; ** Excludes FAST.Espeland MA et al. Current Controlled Trials in Cardiovasc Med. 2005;6:3-6.

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Difference(µm/y, 95% CIs)

Baseline IMT(µm)nTrial

Control:ActiveControl:ActiveMigdalis 680:70120:20PART2 790:800309:308SECURE 2.5 mg 1146:1148227:232SECURE 10 mg 1146:1160227:234Hosomi 700:70050:48PREVEND 770:770323:319All ACEIs 929:1161Heterogeneity:X2=18.1, P=0.003

BCAPS 893:912390:393ELVA 897:89444:35All BBs 434:428Heterogeneity: X2=3.7, P=0.05

PREVENT

Change/y(µm)

Control:Active103:30

5:822:1822:1420:1011:8

8:712: −12

11: −41258:1259186:191All trials 1549:1780Heterogeneity:X2=25.9, P=0.001

−7 (−12 to −2)P=0.01

−10 (−33 to 13)P=0.41

−6 (−12 to 0.4)P=0.07

−100 −50 0 50 100Favors ControlFavors Active Treatment

Wang et al. Stroke 2006;37:1933-40

Change in CIMT in Blood Pressure Lowering Trials: meta-analysis

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CIMT as surrogate for CV events: Summary Of LDL and BP Trials

IMT change produces parallel estimates of risk and benefit. Changes in events are deductible from observed changes in the surrogate

0.71 [0.55, 0.92]**-0.007 [−0.012, −0.002]BP RCTs

0.48 [0.30, 0.78]*-0.012 [−0.016, −0.007]Statin RCTs

CV event effectCIMT effect (mm/yr)

* Espeland et al. Curr Control Trials Cardiovasc Med 2005;6:3** Wang et al. Stroke 2006;37:1933-40

RCT = randomized control trial

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Atherosclerosis Imaging: QCA and IMTCurrent cardiovascular imaging supported USA and/or CAN Labeling1

slow progression or promote regression of CAD

QCA: CLAS, FATSQCA: global change score,

% stenosis

Niacin (Niaspan ®, 1997) + resin

slow progression of CADQCA: LCASQCA: MLDFluvastatin(Lescol ®, 1997)

slow progression of coronary atherosclerosis; reduce new lesions and total occlusions (Canada)

QCA: MAASQCA: MLDSimvastatin(Zocor ®, 1996)

slow progression of CADQCA:

PLAC I; REGRESS

CIMT: PLAC II, REGRESS, KAPS

QCA: MLD

CIMT

Pravastatin(Pravachol ®, 1996)

slow progression of CADQCA: CCAIT, MARS, FATS

CIMT: ACAPS

QCA: MLD,

% stenosis

CIMT

Lovastatin (Mevacor ®, 1995)

Imaging IndicationSupporting StudiesImaging type: endpointsCompound

1. lovastatin NDA 19-643/Supp #034,1995; pravastatin NDA 19-898/Supp # 013,1996; fluvastatin NDA 02-026/Supp #012,1997; Niaspan NDA 20-381, 1997.

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Epidemiological DataCHD patients (Von Birgelen et al)

Correlation with change in left main coronary artery atheroma cross sectional area (CSA) with

Risk factorsRisk scoresClinical events

Coronary Ultrasound:Evidence that IVUS Predicts Clinical Disease

IVUS-PAVVon Birgelen C, Hartmann M, Mintz G, et al. Circulation. 2004;110:1579-1585.

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Coronary Ultrasound:Evidence that IVUS Predicts Clinical Disease

0 5 10 15 20 25 30

Total Cholesterol ≥204 mg/dl (n=31)Total Cholesterol <204 mg/dl (n=25)

LDL-Cholesterol ≥125 mg/dl (n=28)LDL-Cholesterol <125 mg/dl (n=28)

HDL-Cholesterol ≤46 mg/dl (n=28)HDL-Cholesterol >46 mg/dl (n=28)

Total-C/HDL-C-Ratio ≥4 (n=39)Total-C/HDL-C-Ratio <4 (n=17)

Triglycerides ≥118 mg/dl (n=28)Triglycerides <118 mg/dl (n=28)

Systolic Blood Pressure ≥140 mmHg (n=34)Systolic Blood Pressure <140 mmHg (n=22)

Age ≥59 Years (n=30)Age <59 Years (n=26)

Family History (n=10)No Family History (n=46)

Diabetes Mellitus (n=10)No Diabetes Mellitus (n=46)

Smoker (n=16)No Smoker (n=40) 6.6 ± 17.0

24.7 ± 17.5

10.4 ± 19.518.3 ± 15.2

10.9 ± 17.815.8 ± 23.9

10.6 ± 18.713.2 ± 19.5

10.2 ± 19.314.3 ± 18.4

9.4 ± 14.614.2 ± 22.4

3.7 ± 15.515.3 ± 19.3

2.4 ± 14.221.2 ± 18.5

3.8 ± 15.219.8 ± 19.1

6.1 ± 16.516.6 ± 19.5

p <0.002

p=0.2

p=0.6

p=0.6

p=0.4

p=0.4

p <0.02

p <0.001

p <0.001

p <0.05

Von Birgelen C, Hartmann M, Mintz G, et al. Circulation. 2004;110:1579-1585.

Plaque & Media Changes / Year (%)

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Mean LDL Cholesterol Levels and Median Change in Percent Atheroma Volume for Several Intravascular Ultrasound Trials

Adapted from Nissen, S. E. et al. JAMA 2006;0:295.13.jpc60002-10.

ACTIVATEPlacebo

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0.54

0.56

0.58

0.60

0.62

0.64

0.66

0.68

0.70

-0.4†

2.7*

-1

0

1

2

3

4

Pravastatin 40 mgSignificant

atherosclerotic progression

from baseline

Atorvastatin 80 mgNo significant change

from baseline; atherosclerotic

progression was stopped

Cha

nge

in T

AV

(%)

P=0.02

PROVE-IT

Indirect Evidence that CIMT and IVUS Predict Clinical Events: Pravastatin/Atorvastatin Studies

ARBITER (CIMT) REVERSAL (IVUS)

Pravastatin Atorvastatin

Mea

n C

IMT

+/–

2 SE

M

Baseline6 Months12 Months

05

1015202530

Dea

th o

r Maj

or

Car

diov

ascu

lar

Even

t (%

)

Months of Follow-up0 3 6 9 12 15 18 21 24 27 30

P=0.005

80 mg of Atorvastatin40 mg of Pravastatin

No. at RiskPravastatinAtorvastatin

20632099

16881736

15361591

14231485

810842

138133

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Combination therapies have the potential to reduce cardiovascular risk further than mono-therapy

Risk of Coronary Heart Disease and Lipid Levels

0

1

2

3

25 Increased Risk

Increased Risk

55 85

LDL-Cholesterol

(mg/dl or mmol/L)

100 160 220

HDL-Cholesterol (mg/dl or mmol/L)

Rel

ativ

e R

isk

In 4

Yea

rs

Framingham Study; Am J Cardiol. 2000.

5.74.12.62.21.40.7

An example

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Scientific objectiveDemonstrate the incremental benefit of novel therapy combined with LDL-C lowering therapy over standard of care alone in slowing the progression of atherosclerosis

Clinical DevelopmentOngoing Vascular Imaging Trials: a case study

?

√

√

IVUS

√√Clinical Trial Evidence

treatment effects on the surrogate correspond to clinical outcomes

√√Epidemiologic Data

prognostic value of the surrogate for clinical outcome

√√Biological Plausibility

e.g., pathophysiology suggests a relationship between the surrogate and a clinical outcome

CIMTQCA

ICH, E9, 5 Feb 1998

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Atherosclerosis Imaging 2006Questions

Does the EMEA consider that carotid ultrasound now meets the criteria of ICH E9 for a surrogate variable, in consideration of the wealth of pathophysiologic, epidemiologic, and clinical trial data published since the guidance was issued? If not, why not?

Does the EMEA concur that atherosclerosis is a systemic disorder and that IVUS measures of wall thickness represent a higher resolution image of IMT than that detected by carotid ultrasound? If not, why not?

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Atherosclerosis Imaging 2006Questions

What are the EMEA comments on the fact that vessel wall thickness is an integrated marker of cardiovascular risk and that IVUS, as an example does not attempt to assess vulnerable plaque, but as is the case with carotid IMT, is an assessment of the patient’s potential for future CV events?

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Backup

Carotid IMT Subject Populations:• Heterozygous FH• mixed hyperlipidemia, TG > 150• eligible for statin treatment

SCREENING

B-mode US

* Same as statin dose at the end of the titration period.24 months D-B/ randomized Tx

statin alone*

B-mode US / 6 months

• Core labs for central reading• multi-country, multi-center

Example of a Phase 3 Imaging Program

statin dose titration

target: LDL-C to CV risk goal

Coronary IVUS Subject Population:• Angio. proven CAD (> 20% stenosis)• Eligible for statin treatment

Coronary IVUSCoronary IVUS

Carotid ultrasound

Carotid ultrasound

IVUS

technology

∆ IMT (mm)/year~ 800Heterozygous FH

∆ IMT (mm)/year~ 800Mixed dyslipidemia

Nominal ∆ PAV~ 1000CHD

EndpointNumber of subjectsTarget population

novel agent and statin