Mitchell W. Krucoff, MD, FACC - Cardiac Safety Research ... · Mitchell W. Krucoff, MD, FACC...

[name of file], 1

Pre- and Post-Marketing Continuum Models for

Cardiovascular Safety with Diabetic Drugs:

Academic View

Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology

Duke University Medical Center

Director, Cardiovascular Devices Unit

Co-Director, CSRC

Duke Clinical Research Institute

Cardiac Safety

Research Consortium

Challenges Underlying The Premise

Shifting from:

Safety as a barrier to innovation to

facilitating innovation and improving

safety evaluation

Nice talk to pragmatic direction & traction

www.cardiac-safety.org

Facilitating Innovation & Ensuring Safety:

Managing (Mis)Perception

No effective therapy is perfectly safe

Upper confidence interval boundary more

important than point estimate

Dichotomous “safe or not” less informative

than continuum of unknown: “residual risk”*

Underpowered/unrepresented:

CV safety endpoints in DM trials

Patient subgroups

Duration of exposure

* GHTF SG 5 final documents: http://www.ghtf.org/sg5/sg5-final.html

ISO 14971: http://www.isosert.ru/isosert_iso_14971.pdf

Cardiac Safety

Research Consortium

Classical NME Clinical R&D:

Separate & Unequal

Pre-market RCT(s):

Well defined population

Emphasis on efficacy

endpoints

Statistically robust for

primary questions

Highly controlled

monitoring & quality

Independent adjudication

Expensive & logistically

challenging

Post-market surveillance:

• Registry/single arm designs

• Large numbers

• Real world mix

• More efficient, less

expensive

• Event reporting, monitoring

& quality ???

• SAP ???


Pre- & Post-market continuum:

gaps & bridges

Consensus definitions

Integrated trial designs

Enriched populations &

“all comer” designs

Efficient quality solutions

From selected patients to

real world cohorts

From RCTs to registries

From controlled settings to

practice of medicine

Cardiac Safety

Research Consortium

[name of file], 6

The Academic Research Consortium

(ARC)*

Consensus Definitions


Consistency is more important than perfection!

*Krucoff MW et al, JACC Intervention & EuroIntervention, in press

…ethical, clinical, and

logistical constraints must

be integrated into the

balance of how best to

encourage innovation and

brisk access to better

therapies with potential

safety concerns and their

evaluation…One of the most

fundamental barriers to

meaningful data aggregation

is the use of different

nomenclature and definitions

of key descriptors and

endpoints from one trial to

another, or from one

manufacturer to another.”

Krucoff MW et al, JACC Intervention & EuroIntervention, in press

Cardiac Safety

Research Consortium


ARC LAST:

>500 reported trials

Cypher

Cypher Select

Taxus

Taxus Liberte

Xience

Endeavor

Resolute

Costar

Nevo

Biomatrix

Biofreedom

Absorb

Valve ARC: VARC

Standardized Bleeding Definitions for Cardiovascular

Clinical Trials: A Consensus Report from the Bleeding

Academic Research Consortium (BARC)

Roxana Mehran, Sunil V. Rao, Deepak L. Bhatt, C. Michael Gibson,

Adriano Caixeta, John Eikelboom, Sanjay Kaul, Stephen D. Wiviott,

Venu Menon, Eugenia Nikolsky, Victor Serebruany, Marco Valgimigli,

Pascal Vranckx, David Taggart, Joseph Sabik, Donald E. Cutlip, Mitchell

W. Krucoff, E. Magnus Ohman, Philippe Gabriel Steg, and Harvey White

Short title: Standardized Bleeding Definitions

Word count: 3889

Abstract word count:221

Bleeding ARC (BARC)

Cardiac Safety

Research Consortium

Mehran R et al, Circulation in press

[name of file], 11

Integrated Clinical Trial

Designs:

Pivotal RCTs &COA Registries


Case Study: The Xience V Stent

New DES (EES) platform

RCTs (vs Taxus) at PMA filing:

SPIRIT II, III, IV: 3,000 pt exposures to EES

Clinical & angio: non-inferior & superior

Residual risk concerns:

LAST: (are bigger lumens bad?)

0.6% vs 1.2% ???

Real world populations

Cardiac Safety

Research Consortium

Registry (n = 2,700), RCT Diabetics 2:1 vs. TAXUS (n = 300) OUS

Registry (n = 1,550) RCT 2:1 vs. CYPHER® (n = 450) OUS

Integrated Pre-Approval and Post-Approval

Clinical Program (N > 16,000)

SPIRIT First RCT 1:1 XIENCE V vs. VISION (n = 60) OUS

SPIRIT II RCT 3:1 XIENCE V vs. TAXUS® (n = 300) OUS

SPIRIT III RCT 2:1 XIENCE V vs. TAXUS (n = 1,002) US

SPIRIT III 4.0 Registry 4.0 mm (n = 80) US

SPIRIT III Japan Registry (n = 88) Japan

SPIRIT IV RCT XIENCE V vs. TAXUS 2:1 Continued Access (n = 3,690) US

SPIRIT V

XIENCE V SPIRIT Women

XIENCE V USA Post-approval Registry – real world (n ~ 5,000) US

Ongoing and Planned Clinical Data

XIENCE India Post-approval Registry – real world (n ~ 1,000) OUS

Pre-approval Clinical Data

RCTs in

progressively

complex lesions

Registries in

progressively

complex patients

& lesions

SE2930040 Rev. A

Gregg Stone, SPIRIT IV 1 Year Results, TCT 2009

© 2009 Abbott Laboratories

SPIRIT IV Stent Thrombosis (ARC Def or Prob)

Number at risk

XIENCE V 2458 2426 2412 2388 2376

TAXUS 1229 1195 1184 1174 1166

1.06%

0.29%

Months

p=0.003

HR [95%CI] =

0.27 [0.11, 0.67]

Δ 0.77%

Ste

nt

thro

mb

osis

(%

) XIENCE V

TAXUS

FOR IMPORTANT SAFETY INFORMATION SEE FINAL SLIDE.

SE2930040 Rev. A

Gregg Stone, SPIRIT IV 1 Year Results, TCT 2009

© 2009 Abbott Laboratories

Group

EES

(%)

PES

(%)

Relative Risk

(95% CI)

Relative Risk

(95% CI)

P

interaction

All randomized (n=3687) 4.2 6.8 0.62 [0.46, 0.82] —

Single lesion treated (n=2710) 3.9 5.7 0.68 [0.48, 0.96] 0.34

Two or more lesions treated (n=901) 5.1 10.0 0.51 [0.32, 0.83]

RVD > 2.75 mm (n=1351) 3.9 4.7 0.83 [0.49, 1.41] 0.29

RVD ≤ 2.75 mm (n=1352) 3.9 6.8 0.57 [0.35, 0.91]

Lesion length > 13.3 mm (n=1346) 4.5 6.9 0.65 [0.41, 1.03] 0.79

Lesion length ≤ 13.3 mm (n=1349) 3.2 4.5 0.71 [0.41, 1.23]

Bailout stent required (n=221) 5.0 14.5 0.35 [0.14, 0.86] 0.19

No bailout stent required (n=3390) 4.1 6.4 0.65 [0.48, 0.87]

Diabetes (n=1140) 6.4 6.9 0.94 [0.59, 1.49] 0.02

No diabetes(n=2467) 3.1 6.7 0.47 [0.32, 0.68]

SPIRIT IV Subgroup Analysis: TLF at 1 Year

TLF = cardiac death, target vessel MI, or ischemia-driven TLR; 1 Year = 365

28 days

Single lesion treated data are used for RVD & lesion length subgroup analyses

0.1 1 10

EES better PES better

FOR IMPORTANT SAFETY INFORMATION SEE FINAL SLIDE.

N~2,952

N~1,080

N~800

N~2,000

N~300

~80%

~36%

~40%

~40%

~30%

3 vessel CAD: N=738

Real world (EU): N=1620

Diabetics: N=300

Gender specific N~1,200

Real world (US) N~3,000

Optimal DAP

Real world (India) N~700

~64%

~60%

~60%

~70%

~20%

SPIRIT/XIENCE V Integrated Post-Approval Strategy

Post-Approval Trials N=14,690; (Randomized: 4,440)

Adding Certainty

(On Label)

Advance Knowledge

(Real World)

3 vessel CAD: N=738

Real world (EU): N=1620

Diabetics: N=300

Gender specific N~1,200

Real world (US) N~3,000

Optimal DAP

Real world (India) N~700

~64%

~60%

~60%

~70%

~20% SPIRIT IV

N~3,690

SPIRIT V

N~3,000

SPIRIT Women

N~2,000

XIENCE V USA

N~5,000

XIENCE V INDIA

N~1,000

Integrated Trial Design:

Xience V USA (COA Registry) & SPIRIT IV

Objective: LAST

Identical descriptor and endpoints definitions

Elimination of exclusion criteria (“Off label” pts):

Renal failure

Low EFx

STEMI

Anatomic: Lmain, CTO, bifurcation, SVG

Etc

Prospective analysis plan:

Event rates in matched Xience V & SPIRIT IV pts

Objective: quality reliability of benchmark in off-label pts


SE2932151 Rev. A

1 Year ST Rate (ARC Def/Prob) Overall Population

0.44%

0.39%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

ST

(A

RC

Def/

Pro

b)

(%)

Early (< 30 Days) Late (30 Days - 1 Year)

18

XIENCE V USA

XIENCE V

0.84%

SE2932151 Rev. A

0.11%0.22%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

ST

(A

RC

Def/

Pro

b)

(%)


19

XIENCE V

0.34%

1-Year ST Rate (ARC Def/Prob) Standard Risk Cohort

*XIENCE V USA patients who have lesion length ≤ 28mm, RVD between 2.5mm and 4.25mm and do not have any one of the following: CTO, graft lesion, bifurcation

with side branch ≥ 2mm, ostial, LM, ISR, > 2 lesions stented in the same vessel, > 2 vessels treated, AMI, renal insufficiency, EF < 30%, staged procedure. †The

number of standard risk patients who have reached 1 year for ST analysis. Total number of standard risk cohort is 1,827, with 54 patients terminated before 1 year

without ST event and therefore excluded in this analysis.

XIENCE V USA

Standard Risk* (N = 1,773 †)

SE2932151 Rev. A

0.2%0.6%0.11% 0.2%

0.5%

0.22%0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

ST

(A

RC

Def/

Pro

b)

(%)


20

SPIRIT III & SPIRIT IV**

XIENCE V TAXUS XIENCE V

0.34% 0.4%

1.0%

p = 0.03

*XIENCE V USA patients who have lesion length ≤ 28mm, RVD between 2.5mm and 4.25mm and do not have any one of the following: CTO, graft lesion, bifurcation

with side branch ≥ 2mm, ostial, LM, ISR, > 2 lesions stented in the same vessel, > 2 vessels treated, AMI, renal insufficiency, EF < 30%, staged procedure. †The

number of standard risk patients who have reached 1 year for ST analysis. Total number of standard risk cohort is 1,827, with 54 patients terminated before 1 year

without ST event and therefore excluded in this analysis. ** Presented by Dr. James Hermiller at SCAI 2010

XIENCE V USA

Standard Risk* (N = 1,773 †)

1-Year ST Rate (ARC Def/Prob) Standard Risk Cohort

SE2932151 Rev. A

Late ST Rates (30 Days - 1 Year) After DAPT Interruption

Su

bseq

uen

t L

ate

ST

(A

RC

Def/

Pro

b)

(%)

No Interruption Interruption

After 30 Days*

13/3500 0/292

Interruption

After 180 Days*

2/435

Interruption

After 90 Days*

1/378

Overall

21

*Out to 1 year

SE2932151 Rev. A

Late ST Rates (30 Days - 1 Year) After DAPT Interruption

Su

bseq

uen

t L

ate

ST

(A

RC

Def/

Pro

b)

(%)

No Interruption Interruption

After 30 Days*

13/3500 0/292

Interruption

After 180 Days*

2/435

Interruption

After 90 Days*

1/378 2/1272 0/157 0/147 0/120

Overall

Standard Risk

22

*Out to 1 year

[name of file], 23

Integrated Clinical Trial

Designs: Sustainable

Registries & RCTs:

A “River of Information”


Registries in the Regulatory Landscape:

A “river” of information:

Large numbers

Real world pts

Logistically simple

Prospective SAP, quality controlled

Informative: Rare event safety

Real world safety

Indication extensions

Database: modelling platforms

Informed prior

OPC

Infrastructure for nested RCTs

Leverage RCT findings


Prospective Hypothesis Registry Designs &

Device Evaluation for Regulatory Applications

FDA Guidance: Bayesian Models

(http://www.fda.gov/MedicalDevices/DeviceRegulationandG

uidance/GuidanceDocuments/ucm071072.htm)

FDA Guidance: Adaptive Trial Designs

Post-market COA studies:

Endeavor (Medtronic)

Xience V (Abbott)

Collaborative PPP safety trials:

INTERMACS*

DAPT**

SAFARI***

TREAT*** * NIH/FDA/Advamed

** CSRC/FDA/Advamed/Pharma

*** CSRC/FDA/Advamed/Pharma/ACC/HRS

[name of file], 26

Study of Access site For Enhancing

Percutaneous Coronary Intervention

for Women

(SAFE-PCI for Women) A Randomized Trial of Radial vs. Femoral Approaches in

Women Undergoing Percutaneous Coronary Intervention

Sunil Rao MD, PI

Mitchell Krucoff MD, Study Chair


Cardiac Safety

Research Consortium

http://www.ncdr.com/webncdr/common/

[name of file], 28

National Cardiovascular Research

Infrastructure

(NCRI)

NIH/NHLBI grant (#: 1RC2HL101512-01)

PI: Robert Harrington MD

David F. Kong MD



EDC using NCRI* extraction from ACC-NCDR

Figure 1: NCRI Data Interface Strategy

NCRINCRI-only

Site

NCDR Site

Doing NCRI trial standard ACC process

Standard trial web data entry process

NCDR

NCDR d

ata

passed to

NCRI

trial d

atabase

* Tria

l spec

ific

data is

reporte

d

direct

ly

NCRINCRI-only

Site

NCDR Site

Doing NCRI trial standard ACC process

Standard trial web data entry process

NCDR

NCDR d

ata

passed to

NCRI

trial d

atabase

* Tria

l spec

ific

data is

reporte

d

direct

ly

* Trial specific data is data that is not included in NCDR data.


*NIH/NHLBI grant (#: 1RC2HL101512-01)

75% site based workload reduction

Part 11 compliant data structure

Pre- & Post-Market Continuum: Conclusions

Systematic approach to the pre- & post-

market as a continuum can both foster

innovation and improve safety information

“Residual risk” provides a useful,

continuous, quantitative construct to

support this continuum

Consistent use of consensus definitions,

integrated RCT & registry study designs and

integrated quality registries and RCT

infrastructure provide pragmatic tools with

which to build traction toward this end

[name of file], 31

Pre- and Post-Marketing Continuum Models for

Cardiovascular Safety with Diabetic Drugs:

Academic View

Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology


Director, Cardiovascular Devices Unit

Co-Director, CSRC


Cardiac Safety

Research Consortium

Date post:	17-May-2020
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