SEX INCLUSION in CLINICAL TRIALS

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 heart failure in patients men and 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 2007 Physician s Health Study 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 Race/Ethnicity Geographical Socio-Econimic Male Female Premenopausal Postmenopausal

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 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

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% Male 75% Men 67% Women 75% Cell- Based Animal- Based Human Trials 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 Seldane a Antihistamine Torsades de Pointes Posicor Cardiovascular Lowered heart rate in elderly women and adverse interactions with 26 other drugs Hismanal Antihistamine Torsades de Pointes Propulsid b 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 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

Evidence-Based Healthcare Education How Does Research Save Lives? Sex-Inclusive Research Clinical Care

CONSIDERATION OF SEX & GENDER IN PLANNING CLINICAL RESEARCH Approach Literature Review What aspects are being studied Is this an oversight? Prior studies that point to a sex or gender difference To what extent? Research Methods 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