SEX INCLUSION in

CLINICAL TRIALS MARJORIE R. JENKINS, MD MEHP FACP PROFESSOR OF MEDICINE

CHIEF SCIENTIFIC OFFICER

RUSH ENDOWED CHAIR FOR EXCELLENCE IN

RESEARCH

LAURA W. BUSH INSTITUTE FOR WOMEN’S HEALTH

TEXAS TECH UNIVERSITY HSC

Responsive to the influence of sex

within clinical research design

Recognize the limitations of subgroup

analysis by sex

Understand the clinical implications

of sex-biased research

OBJECTIVES

The accuracy with which results or findings can be transferred to

situations or people other than those originally studied.

GENERALIZABILITY

The ability for the research to be duplicated (achieving the same results)

either by the same researcher or an independent researcher.

Reproducibility is regarded as one of the foundations of

the entire scientific method.

REPRODUCIBILITY

The Hypothesis

Literature Search

Study Population

Inclusion/Exclusion Criteria

The Analysis

Power

Primary endpoints

Secondary endpoints

Subgroup Analysis

DESIGNING THE STUDY

HYPOTHESIS

Hypothesis can be supported or rejected on the basis of data gleaned from the study population and lead to better understanding, decision-making, and treatment choice. (Lazare 1976)

Moderate to severe vasomotor symptoms increase risk of

cardiovascular events

Osteoporotic wrist fractures increase mortality

Drug A will lower mortality in congestive heart failure patients

Drug A will lower mortality in congestive heart failure in men and

women

LITERATURE

SEARCH

GenderMed Database:

www.gendermeddb.charite.de/?site=home&la

ng=eng

Texas Tech University Health Sciences

Center

www.sexandgenderhealth.com

NIH OWRH CME Modules:

orwh.od.nih.gov/resources/cme.asp

RESEARCH RESOURCES

www.sexandgenderhealth.com

Song MM, Simonsen CK, Wilson JD, Jenkins MR. “Development of a PubMed search tool for identifying sex and

gender specific literature.” J Womens Health (Larchmt). DOI: 10.1089/jwh.2015.5217.

STUDY POPULATION

GENERALIZABILITY

REPRODUCIBILITY

HOMOGENEITY

The effect of estrogen on cardiovascular disease

WHAT IF THE QUESTION IS SEX EXCLUSIVE

1960 2000’s

Estrogen in

CVD study

in

Men

Women’s

Health

Initiative

Aspirin as primary prevention in cardiovascular disease

WHAT IF THE QUESTION IS NOT SEX EXCLUSIVE

1982 2007

Physician’s

Health Study

Women’s

Aspirin Study

ASPIRIN RESULTS IN MEN V S WOMEN

SEX-BIASED RESEARCH IS NOT GENERALIZABLE

MYTHBUSTER

INCLUSION/

EXCLUSION

CRITERIA

Desired characteristics of the study population.

If present, allows a subject to participate

in the proposed study.

INCLUSION CRITERIA

NARROW INCLUSION

CRITERIA

HOMOGENEITY

NARROW INCLUSION CRITERIA

GENERALIZABILITY

Undesirable characteristics of the study population

If present, prohibits a subject from participation

in the proposed study

EXCLUSION CRITERIA

HOMOGENEITY

BROAD EXCLUSION CRITERIA

GENERALIZABILITY

Congestive heart failure

Preserved EF

Acute Coronary Syndrome

Chest pain

Level of troponins

Baseline EKG changes

Age

Childbearing potential

Co-morbidities

Lung capacity

eGFR

SEX DIFFERENCES CAN

INFLUENCE STUDY CRITERIA

STATISTICS

Subpopulations

Age Sex

Male Female

Premenopausal Postmenopausal

Race/Ethnicity Geographical Socio-Econimic

Subpopulations SUBPOPULATIONS

Treatment effect is assumed to be similar across the global treatment groups

Direction, but not magnitude, of effect is the same across subgroups

No assumption of magnitude of effect across subgroups

GENERAL ASSUMPTIONS THERAPEUTIC EFFECT IN CLINICAL TRIALS

Any evaluation of treatment effects for a specific endpoint in subgroups of patients defined by

baseline characteristics

Wang M.S. et al NEJM 2007 357;21

SUBGROUP ANALYSIS

Subgroup analysis after the fact is “dangerous useful and often done”

(Goode, 1983)

July 2005-June 2006

59/97 trials reported subgroup analysis (Wang et al NEJM 2007 357;21)

Pros

Hypothesis- generating

Defined subgroups can be analyzed

Lead to a meta-analysis

Support consistency across trial subpopulations

Cons

Increase Type I error – false positives

Decrease power Increase Type II error

Can be overstated

Lead to misleading results

SUBGROUP ANALYSIS

Perform an a priori calculation

Disclose methods and findings transparently

Clarify upfront whether analyses are confirmatory or exploratory

Well-powered studies

Reduces data-mining

Make study materials and raw data available

Work collaboratively to increase power and replicate findings

RECOMMENDATIONS

(Wang et al NEJM 2007 357;21)

CARDIAC RESYNCHRONIZATION

THERAPY IN WOMEN: US FOOD

AND DRUG ADMINISTRATION

META-ANALYSIS OF PATIENT-

LEVEL DATA (ZUSTERZEEL R., ET AL. JAMA INTERN MED.

2014;174(8):1340-1348)

Cardiac Resynchronization Therapy

CRT-D TO ICD HRS FOR OUTCOMES

BY SEX IN THE TOTAL POPULATION

CRT-D indicates cardiac resynchronization therapy; HR, hazard ratio;

ICD, implantable cardioverter defibrillator; LBBB, left bundle branch

block; ms, milliseconds. P values represent sex-by-treatment

interactions.

Results

• Overall, women benefited more than men. • Marked difference patients with LBBB and a

QRS of 130 to 149 milliseconds. • Neither group benefited with LBBB and QRS

of <130 milliseconds. • The majority benefited from LBBB with QRS

of >150 milliseconds.

Results

LBBB and QRS 130-149 milliseconds

Women had a 76 percent reduction in heart

failure (absolute difference 23%) or death

and a 76 percent reduction in death alone

(absolute difference 9%), but there was no

significant benefit in men.

Impact

Recent guidelines limit the Class I indication for

CRT-D to patients with LBBB and QRS of 150 milliseconds or longer.

Women are less likely to receive

the benefits CRT-D

REPORTING

In the Abstract

Only if pre-specified

In the Methods section

Indicated how many subgroup analysis were performed

Indicate how many were reported

Indicate the potential effect on type I errors (false positives)

Either through formal adjustments due to multiplicity

Informally through description of analysis and approach

Discussion

Avoid over interpretation of subgroup differences

Acknowledge the limitations

Provide supporting or contradictory data from other studies

REPORTING SUBGROUP ANALYSIS

52% Women 48% Men

GLOBAL POPULATION

The Research Pipeline

Cell-Based

Animal-Based

Human Trials

Clinical Care

Male/Sex Not Reported

80%

Male 75%

Men 67%

Women 75%

Not Knowing The Difference Doesn’t Mean

There Is No Difference

MYTH BUSTERS

WOMEN WILL NOT PARTICIPATE IN CLINICAL TRIALS

SUBJECTS BY GENDER IN MAJOR OSTEOPOROSIS TRIALS

139,647

subjects

♂ 9,550

♀ 120,096

J Clin Endocrinol Metab. 2012 Jun;97(6):1871-80

MYTHBUSTER

Outcomes in men

serve as adequate

proxies for outcomes in

women…

INVESTMENT

PHILANTHROPIC GIVING IN AMERICA

2011

Source: Giving USA 2011, a publication of Giving USA Foundation

NIH expects that sex as a biological variable will be

factored into research designs, analyses, and

reporting in vertebrate animal and human studies.

Strong justification from the scientific literature,

preliminary data or other relevant considerations

must be provided for applications proposing to

study only one sex.

http://grants.nih.gov/reproducibility/index.htm

BENCH TO BEDSIDE

Discovery of Target Safety and efficacy

Animal models Safety and Efficacy

Patients

PHASES OF A CLINICAL TRIAL

Drug Type of Drug Primary Health Risk

Prescription Drugs with Evidence of Greater Health Risks in

Women

Pondimin Appetite

suppressant

Valvular heart disease

Redux Appetite

suppressant

Valvular heart disease

Rezulin Diabetic Liver failure

Lotronex Gastrointestinal Ischemic colitis

Seldanea Antihistamine Torsades de Pointes

Posicor Cardiovascular Lowered heart rate in elderly women and

adverse interactions with 26 other drugs

Hismanal Antihistamine Torsades de Pointes

Propulsidb Gastrointestinal Torsades de Pointes

Prescription Drugs Without Evidence of Greater Health Risks in

Women

Raxar Antibiotic Torsades de Pointes

Duract Analgesic and

anesthetic

Liver failure

Office of Women’s Health

DRUG WITHDRAWN FROM

THE US MARKET 1997-2000

Source: GAO analysis(Drugs Withdrawn From Market) in GAO-01-286R

TZD’S AND BONE LOSS

Thiazolidinediones (TZDs), rosiglitazone, and pioglitazone have negative skeletal consequences. Increased fracture risk in women, but not men, was reported for both TZDs, based on analyses of adverse event reports from clinical trials.

IMPACT

THE PRACTICE

OF MEDICINE

IS BASED

ON SCIENTIFIC

EVIDENCE

Sex-Inclusive

Research

Evidence-Based

Healthcare Education

Clinical

Care

How Does Research Save Lives?

Approach

What aspects are being studied

Well-defined

Is this an oversight?

Research

Hypothesis

Consider sex and/or gender differences

Literature

Review

Prior studies that point to a sex or gender

difference

To what extent?

Research

Methods

Will sample capture sex and/or

gender factors

Inclusion/Exclusion Criteria

Are sex and gender differences represented

Is subgroup analysis planned

Confirmatory or exploratory analysis

CONSIDERATION OF SEX & GENDER

IN PLANNING CLINICAL RESEARCH