sex inclusion in clinical trials · independent researcher. reproducibility is regarded as one of...
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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