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
OBJECTIVES
 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
GENERALIZABILITY
The accuracy with which results or
findings can be transferred to
situations or people other than those
originally studied.
REPRODUCIBILITY
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.
DESIGNING THE STUDY
The Hypothesis
Literature Search
Study Population
Inclusion/Exclusion Criteria
The Analysis
Power
Primary endpoints
Secondary endpoints
Subgroup Analysis
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
men and
congestiveheart
heartfailure
failureinpatients
women
LITERATURE
SEARCH
RESEARCH RESOURCES
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
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
HOMOGENEITY
GENERALIZABILITY
REPRODUCIBILITY
WHAT IF THE QUESTION IS
SEX EXCLUSIVE
The effect of estrogen on
cardiovascular disease
1960
2000’s
Estrogen in
CVD study
in
Men
Women’s
Health
Initiative
WHAT IF THE QUESTION IS
NOT SEX EXCLUSIVE
Aspirin as primary prevention in
cardiovascular disease
1982
Physician’s
Health Study
2007
Women’s
Aspirin Study
ASPIRIN RESULTS IN MEN
VS
WOMEN
MYTHBUSTER
SEX-BIASED RESEARCH
IS NOT GENERALIZABLE
INCLUSION/
EXCLUSION
CRITERIA
INCLUSION CRITERIA
Desired characteristics
of the study population.
If present,
allows a subject to participate
in the proposed study.
NARROW INCLUSION
CRITERIA
NARROW
INCLUSION CRITERIA
HOMOGENEITY
GENERALIZABILITY
EXCLUSION CRITERIA
Undesirable characteristics of the
study population
If present,
prohibits a subject from participation
in the proposed study
BROAD
EXCLUSION CRITERIA
HOMOGENEITY
GENERALIZABILITY
SEX DIFFERENCES CAN
INFLUENCE STUDY CRITERIA
 Congestive heart failure
 Preserved EF
 Acute Coronary Syndrome
 Chest pain
 Level of troponins
 Baseline EKG changes
 Age
 Childbearing potential
 Co-morbidities
 Lung capacity
 eGFR
STATISTICS
Subpopulations
SUBPOPULATIONS
Subpopulations
Age
Sex
Male
Race/Ethnicity
Female
Premenopausal
Postmenopausal
Geographical
Socio-Econimic
GENERAL ASSUMPTIONS
THERAPEUTIC EFFECT IN CLINICAL TRIALS
 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
SUBGROUP ANALYSIS
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 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)
SUBGROUP ANALYSIS
Pros
Hypothesisgenerating
Defined subgroups
can be analyzed
Lead to a metaanalysis
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
RECOMMENDATIONS
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
(Wang et al NEJM 2007 357;21)
CARDIAC RESYNCHRONIZATION
THERAPY IN WOMEN: US FOOD
AND DRUG ADMINISTRATION
META-ANALYSIS OF PATIENTLEVEL DATA
( Z U ST ER Z EEL R ., ET AL . J AM A IN T ER N M ED .
2 0 1 4 ;17 4(8): 13 40-1 348 )
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
REPORTING SUBGROUP ANALYSIS
 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
GLOBAL POPULATION
52% Women
48% Men
The Research Pipeline
Male/Sex Not
Reported
80%
CellBased
Male
75%
Men
67%
AnimalBased
Human
Trials
Women
75%
Clinical
Care
Not Knowing The Difference Doesn’t Mean
There Is No Difference
MYTH BUSTERS
WOMEN WILL NOT PARTICIPATE IN
CLINICAL TRIALS
MYTHBUSTER
SUBJECTS BY GENDER IN MAJOR OSTEOPOROSIS
TRIALS
139,647
subjects
♂
♀
9,550
120,096
J Clin Endocrinol Metab. 2012 Jun;97(6):1871-80
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
http://grants.nih.gov/reproducibility/index.htm
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.
BENCH TO BEDSIDE
Discovery of Target
Safety and efficacy
Animal models
Safety and Efficacy
Patients
PHASES OF A CLINICAL TRIAL
DRUG WITHDRAWN FROM
THE US MARKET 1997-2000
Drug
Type of Drug
Primary Health Risk
Prescription Drugs with Evidence of Greater Health Risks in
Women
Pondimin
Appetite
Valvular heart disease
suppressant
Redux
Appetite
Valvular heart disease
suppressant
Rezulin
Diabetic
Liver failure
Lotronex Gastrointestinal
Ischemic colitis
a
Seldane
Antihistamine
Torsades de Pointes
Lowered heart rate in elderly women and
Posicor
Cardiovascular
adverse interactions with 26 other drugs
Hismanal
Propulsidb
Antihistamine
Gastrointestinal
Torsades de Pointes
Torsades de Pointes
Prescription Drugs Without Evidence of Greater Health Risks in
Women
Raxar
Antibiotic
Torsades de Pointes
Duract
Analgesic and
Liver failure
anesthetic
Office of Women’s Health
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
How Does Research Save Lives?
Sex-Inclusive
Research
Evidence-Based
Healthcare Education
Clinical
Care
CONSIDERATION OF SEX & GENDER
IN PLANNING CLINICAL RESEARCH
Literature
Review
Approach
What aspects are
being studied
Prior studies that point
to a sex or gender
difference
Is this an oversight?
Research
Methods
To what extent?
Well-defined
Research
Hypothesis
Will sample
capture sex and/or
gender factors
Inclusion/Exclusion
Criteria
Are sex and gender
differences
represented
Is subgroup
analysis planned
Consider sex and/or
gender differences
Confirmatory or
exploratory analysis