Imaging Biomarkers: utilisation for the purposes of registration EMEA-EFPIA Workshop on Biomarkers 15 December 2006
Imaging Biomarkers:utilisation for the purposes of registration
EMEA-EFPIA Workshop on Biomarkers15 December 2006
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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