Women Representation in Clinical Trials

Philippe Généreux, MD

On Behalf of Roxana Mehran, MD

Disclosure Related to this Presentation

1) I am not Roxana Mehran

2) I am not a Woman

3) I love Women

Washington Post, 11 February 2015

“The lack of female representation in both preclinical studies and

clinical trials has put women at greater risk for adverse events from

medical interventions”

“The goal now is to ensure that every patient receives the correct

treatment and dose at the right time, with minimum adverse side effects. Women may have been neglected by medical research for a couple of decades but the march of technology is now bound to

take them forward as individuals”

U.S. Demographic Trends

U.S. Census Bureau

Changing Face of America

Women have heart attacks, too

½ of heart attack patients are

women

…but they are less likely to receive

appropriate treatment than men.

Ex: Beta blockers, ACE inhibitors, aspirin

Higher Death Risk in Women

25% Men

38% Women

Death within 1

year of first heart

attack

American Heart Association. Women and cardiovascular diseases—Statistics. Dallas (TX):

American Heart Association; 2004.

Women Undertreated and Underrepresented

in Clinical Trials

26%

Clinical Trial Representation

Lancet 2013; 382: 1879–88

33%

Yearly DES Procedure

Representation

Circulation 2013; 127: e6–e245.

0% 20% 40% 60% 80% 100%

ENDEAVOR

SIRIUS

SPIRIT III

TAXUS-IV

77%

71%

69%

72%

23%

29%

31%

28%MenWomen

Patients: N=596,000

National Hospital Discharge Survey/National Center for Health

Statistics, 2009 Estimates are based on a sample of inpatient

records from short-stay hospitals in the United States.

Heart Disease and Stroke Statistics-2012 Update. Circulation.

http://circ.ahajournals.org/content/125/1/e2

Einstein et al. 2009. “4-Year Follow-Up From the ENDEAVOR II

Trial.” JACC: Cardiovascular Interventions, 2(12): 1178-87.

Holmes et al. 2004. “Analysis of 1-Year Clinical Outcomes in the

SIRIUS Trial.” Circulation, 109:634-640.

Stone et. al. 2009. “Everolimus-and Paclitaxel-Eluting

Stents.” Circulation, 119:680-686.

Lansky et al. 2005. “Gender Differences After Paclitaxel-Eluting

Stents.” JACC, 45(8): 1180-5.

Morice, MC. 2008. “XIENCE V SPIRIT WOMEN clinical trial:

characterization of the female population undergoing stent

implantation. Women’s Health, 4(5):439-443.

Women comprise 30% of PCI procedures and

PCI clinical trial enrollment

Gender Representation in PCI Clinical Trials

Disparities in Clinical Practice are Mirrored

in Clinical Research

Coronary Stent Studies do not Reflect the

US Population People of color are projected to outnumber U.S. white population by

2042.

U.S. population 18–24 years old, by

race/ethnicity:

July 1990–99 and projections to 2050 0 50 100

Overall

White

Black

Latino

Asian

AI/AN

Pacific

Other

Male FemaleRegistry US

0.8 6

0.16 0.2

0.2 0.9

0.5 5

4 16

7.5 13

86 72

Composition (%)

N=5305

ION and LIBERTE PMS:

Pooled Patient Demographics

Sources: U.S. Bureau of the Census

U.S. Census Bureau, 2009 National Projections

supplement to the 2008 National Projections, August

14, 2008

Proportion of Women in CABG vs. PCI Trials

27 26

20

24

21 21

0

5

10

15

20

25

30

BARI EAST GABI ARTS ERACI SoS

Perc

an

tag

e o

f w

om

en

CABG vs. Medical Therapy: Proportion of Women in

3 Landmark Trials (ECSS, Veteran’s Study, CASS)

3.4

96.6

Females Males

76 women of 2,234 pts

%

%

Underrepresentation of Women, Elderly Patients, and Racial Minorities in the Randomized

Trials Used for Cardiovascular Guidelines

JAMA Intern Med. 2014;174(11):1868-1870. doi:10.1001/jamainternmed.2014.4758

Pati

en

t b

y s

ex

an

d e

thn

icit

y

Fem

ale

Pati

en

ts (

%)

Pati

en

ts b

y r

ace

an

d e

thn

icit

y (

%)

Unadjusted rates of female

enrollment in randomized

clinical trials by year of

publication of trial results.

Chiara Melloni et al. Circ Cardiovasc Qual Outcomes 2010

Representation of women overall

increased from 9% in 1970 to 41% in

2006.

Unadjusted rates of female enrollment by publication year of women in

government/foundation-funded and industry-funded trials (B) and in United

States–only and international trials (C).

Chiara Melloni et al. Circ Cardiovasc

Qual Outcomes 2010

• Trials performed

internationally enrolled more

women than those performed

in united states

• The percentage of women

enrolled in

government/foundation-

funded trials compared with

industry-funded trials was

comparable (31.9% versus

31.5%).

Unadjusted rates of female enrollment by publication year of women in

primary or secondary prevention trials

Primary prevention trials

enrolled more women than

secondary prevention trials

(42.6% versus 26.6%).

Why?

Higher-risk women could be less

willing to participate in trials

Physicians may have biases in

screening them for inclusion

Other social or medical reasons that

make their participation challenging

Percentage of women enrolled in randomized clinical trials overall and by

clinical indication.

Chiara Melloni et al. Circ Cardiovasc Qual Outcomes.

2010;3:135-142

Proportion of women in RCTs compared with the proportion of women among the population

with a given disease and proportion of women among deaths attributable to the disease.

Chiara Melloni et al. Circ Cardiovasc Qual Outcomes.

2010;3:135-142

Gender-based Inconsistencies • Despite improvements in therapies overall in the

past several years:

the sex gap persists

sex-associated risk factors contribute to excess risk in

women including:

• lower BMI

• lower creatinine clearance

• smaller vessel size

• sex-specific platelet biology

• Avoid bleeding in women using:

Bivalirudin

Closure devices

Radial artery access site

Further studies are required to identify any additional sex-associated risk

factors and adjust therapy accordingly in women

Temporal Trends in Bleeding and Vascular Complication

Rates Among Men and Women Undergoing PCI

Adapted from Ahmed et al. Circ Cardiovasc Interv. 2009;2:423–429.

From the Northern New England PCI Registry

Studies continue to highlight the higher risk of bleeding in women

Impact of Female Sex on Risk of Bleeding

Complications After PCI

Trial Author Female Sex-

Adjusted OR 95% CI

Multicenter Registries

ACC-NCDR Registry (1998-2003) Tavris et al 2.41 2.19-2.65

GRACE (1999-2002) Moscucci et al 1.43 1.23-1.66

NNE PCI Registry (2002-2007) Ahmed et al 2.60 1.74-3.91

Cath PCI Registry (2008-2011) Daugherty t al 1.96 1.91-2.02

Randomized Clinical Trials

REPLACE-2 (2001-2002) Feit et al 1.54 1.12-2.1

ACUITY (2004) Manoukian et al 1.92 1.61-2.29

TRITON-TIMI 38 (2007) Hochholzer et al 1.77 1.44-2.18

2,63

2,28

2,79

2,36 2,41 2,6

0

1

2

3

2002 2003 2004 2005 2006 2007

Od

ds

Rati

o (

95

% C

I) f

or

Va

sc

ula

r C

om

pli

ca

tio

ns

Adapted from Ahmed et al. Circ Cardiovasc Interv. 2009;2:423–429.

Adjusted risk of female sex predicting

bleeding and vascular complications

over a 6-year period

Female sex still

carries a 2.6-fold

increased risk of

bleeding with no

appreciable change

since 2002

Females are Predisposed to Bleeding

PCI Pharmacotherapy

Access-site

Anatomy

Platelet Biology

Body Mass Index

There is an overlapping

relationship among these sex-

specific differences which

contributes to the higher risk of

bleeding in women

Figure 5. Ahmed and Dauerman. Circulation. 2013;127:641-649.

Behavior

Patient Willingness

• Whites more willing to

have PCI or CABG

70%W v. 52% B,

76%W v. 65%B

p<0.05

Whites more familiar

with procedure 82%

v 62%, 63% v 31%

p<0.05

Blacks more likely to

refuse CABG (CASS)

Whittle et al J Gen Int Med 1997;12:267-273

Am J Publ Health 1986;76:1446

Physician Bias

• MD decision making , physician interpretation of clinical scenarios

Blacks 40% less likely to be referred for cath1

• Physician:patient race interactions- both black and white MDs referred blacks less2

1. Schulman et al NEJM 1999;340:618-26

2. Chen et al NEJM 2001;344:1443-9

Revascularization and Survival Duke Cath Database 11,127 White patients 1275 Black patients

Extension of Life

Expected by Bypass

Surgery

Risk of death at 5 years

Components of

Cox Model

Mortality

RR (95% CI)

Race Only 1.41(1.27-1.56)

Race + px factors 1.18(1.05-1.32)

Race+px + rxmemt 1.08(0.97-1.20)

Peterson et al. NEJM 1997;336:480-486

Adjusted OR for Revascularization

OR PTCA 0.87 (0.73-1.03)

OR CABG 0.68 (0.56-.082)

OR any Revasc. 0.65 (0.56-0.76)

How to improve

participation of women

in clinical trials?

The WIN-Her Initiative: Addressing Participation

Barriers

Women Opt-In for Heart Research

(WIN-Her)

• Boston Scientific is currently launching an

initiative focused on increasing female enrollment

in clinical trials to speed trial enrollment and to

improve the scientific robustness of the results

WIN-Her initiative (Women Opt-In for Heart Research)

Physician leads will be Dr. Jeanne Poole from the

University of Washington and Dr. Marye Gleva from

Washington University

• WIN-Her will be piloted in two upcoming

randomized IDE trials

MADIT-SICD (SICD)

ASAP-TOO (WATCHMAN)

WIN-Her Goals and Activities

• Project Goals

Understand how to overcome barriers to

enrollment of female patients, especially in

randomized trials

Develop and test new approaches to

increasing female enrollment

Partner with key stakeholders, including

FDA, to influence the dialog on this topic

Publish and share key learning from this

effort

WIN-Her Goals and Activities

• Key Activities

Conduct market research interviews with patients and physicians to identify better ways to engage with female patients

Develop and test educational materials and trial kick-off training materials

Increase focus on this topic within each trial via devoted time at trial kick-off meetings and during regular trial conference calls

Create formal processes to track progress, share best practices, and keep this topic visible with the investigators

Include screening log questions that will help to identify key reasons for female non-enrollment, time required to enroll female patients, etc.

How to fill the sex-specific

gap in medical knowledge?

Examples…

Women in Innovation and Drug-Eluting Stents

(WIN-DES) Collaborative Patient-Level Pooled Analysis

Stefanini, Baber et al – Lancet 2013

Cumulative event rates of death or myocardial infarction during 3 years of follow-up

• Patient-level data from 26

RCTs (N = 43.904)

including 11,557 women

(26.3%)

SAFE-PCI

SAFE-PCI

SAFE-PCI

WIN TAVI

Women’s International Transcatheter

Aortic Valve Implantation Registry

A registry designed to investigate the safety and efficacy of transcatheter

aortic valve implantation in women and investigate specific gender-related

factors that influence short- and long-term clinical outcomes.

1000 Women !!!

Total Enrollment & Enrollment by Site

0 10 20 30 40 50 60 70 80 90 100 110 120 130

Queen Elizabeth Hospital

Radboud University Nijmegen Medical Center

Elisabeth-Krankenhaus

Hospital Universitario Miguel Servet

Mount Sinai Hospital

Imperial College

Centro Cardiologico Monzino IRCCS

Mauriziano Hospital

University of Padova

Rangueil University Hospital

Erasmus Medical Center

University of Rome

University of Siena

University of Catania

Clinique Pasteur

Istituto Clinico Humanitas

University of Pisa

Institut Hospitalier Jacques Cartier

San Raffaele Hospital

University of Munich

1

4

11

14

16

19

23

24

27

33

34

55

57

61

70

71

79

90

102

123

Enrollment Completed

PLATINUM Diversity: Outcomes with the Promus PREMIERTM Stent in

Women and Minorities

PLATINUM Diversity Study Design

1500 patients / Up to 65 US Sites

≥ 1 PREMIER Stent &

one or more of the following:

• Female

• Black

• Hispanic/Latino

• Asian

• American Indian or Alaskan Native

• Observational

• Prospective

• Multicenter

• Open-label

• Single-arm

Follow-up (telephone):

• 30 days

• 6 months

• 1 year

Primary Endpoint:

• 12M Death/MI/TVR

• Demographic and socioeconomic status

• Adherence to DAPT

• Consistent with “Close the Gap” BSCI initiative

Study Objective: To compile acute procedural performance and clinical outcomes data for the Promus PREMIER

EES in understudied/underserved patient populations including women and minorities

Wayne Batchelor: Florida State College of Medicine, Tallahassee Research Institute, & Southern Medical Group, Tallahassee, FL

Roxana Mehran: Icahn School of Medicine at Mount Sinai Hospital, New York, NY

Co-Primary Investigators:

Enrollment:

Lewin Group analysis of the American Medical Association Masterfile

with adjustment for underreporting of retirements.

Rodgers GP et al. J Am Coll Cardiol. 2009;54(13):1195-1208.

Number of General Cardiologists by

Age and Sex, 2008

10%

Women

in 2012

Summary • >75% of clinical trials in Cardiology include less than

30% women. None have the power to show benefit or harm in this subset

• The inconsistent results of registries and post-hoc analyses from randomized trials do not give any guidance which revascularization or pharmacological strategies should be chosen for women

• Clinical trials should be designed with adequate power to detect hazards and benefits of treatments or strategies studied across minority groups

We need More Great Women like those!

Thanks For Your Devotion to our Field