Women’s Participation in Clinical TrialsAre we POWEREDto meet the Challenge?
Dr Sharon Walmsley
Professor of Medicine
University of Toronto, Canada
On behalf of the Score Card Working Group
Catherine Hankins Judith Currier
Supported by the team in the Office of the Chief Scientific AdvisorDiane AddisonTania LemayNicolai LohseAdam Trotta
Randomized Controlled Clinical Trials Most rigorous scientific means to evaluate
and compare therapies with respect to efficacy and side effects
Process of randomization and blinding eliminates bias
Requires large numbers of participants for diseases where there is established therapy
Randomized controlled clinical trials
To apply the results to clinical practice, the participants in the study must be similar to your population
Is sex an important variable for trials of antiretroviral drugs?
Why might there be sex differences in response to antiretrovirals Potential for differences in drug absorption, metabolism, excretion
Body size Body fat content Concentration of enzymes responsible for drug metabolism Hormonal effects
Gonadotropins and circulating steroids Hormone replacement therapy Pregnancy Oral contraceptives (drug interactions)
Attitudinal Adherence Delays in Initiation
What is the problem with the data in clinical trials of HIV therapies?
Women are under-represented Studies are under-powered for gender
comparison
Gender Bias in Clinical Trials
Cochrane Controlled Trials Register 1990-2000 n=49 studies: 15,612 participants Mean proportion of women 12.25% None analyzed by sex
Pardo, World AIDS, 2002, Abstract WePeB5964
Cohort studies of ARV
Confounders must be adjusted forAgeRaceEducationBaseline CD4, VLHepatitis C coinfectionAdherence
What would it take?Sample Size Calculations to Detect a 50% Reduction in 2-Year Failure Rates Between Women and Men
(1-beta=.8, alpha=.025)
Failure Rate in Women
0.50
3500
3000
2500
2000
1500
1000
500
00.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45
% accrual of women
10% accrual
15% accrual
20% accrualTotalSample
Size
J Currier et al., VIII Int Conference on AIDS, Amsterdam 1992, Abstract 4705
Complications of ARVIs it different by sex?
Sex Differences Noted
Rash
Fat Accumulation
and LipoatrophyPhenotype
Pancreatitis
Hepaticsteatosis andlactic acidosis
Higher in women
Lower riskof TG increaseHigher rates of
low HDL women
Sample Sizes Required to Detect 2-Fold Differences in Toxicity Rates Between Men and Women
Rate in Men Rate in Women Accural of Women Total Sample Size
5% 10% 10% 2353
5% 10% 15% 1689
5% 10% 20% 1367
10% 20% 10% 1095
10% 20% 15% 785
10% 20% 20% 879
20% 40% 10% 466
20% 40% 15% 333J Currier et al., VIII Int Conference on AIDS, Amsterdam 1992, Abstract 4705
Women’s ScorecardMethodology
Search of HIV treatment naive phase III clinical trials received by www.clinicaltrials.gov on or after 01/01/2000
Published data/abstracts for completed trials investigated for the inclusion of women/girls
Principal investigators contacted for ongoing studies
Women’s ScorecardMethodology Excluded
Pediatric only (<= 12 years)Only men or only women
Data collected
age, sex, enrolment number, study location, sponsors, contraception criteria, pregnancy exclusion criteria, year of study start
Women’s ScorecardMethodology Outcomes
Sex (% female participants)Adolescents ( % 13-18yr) (or 13-18yr Y/N? –
if too difficult to obtain the other information)Pregnancy exclusion (Y/N)
Women’s ScorecardResults 73 studies identified 14 excluded
8 studies only infants and children5 studies only women1 study only men
Women’s ScorecardResults Of the 59 remaining studies, data available so
far for 29
Number of participants in 29 studies n=18,620 Number of participants per study ( median 600,
IQR: 249-757) 37.9% woman participants (7060/18,620)
( range 5.9-79.2%)
Score Card Results
Enrollment of adolescents ( age 13-19) Per protocol: 8/59 studies One protocol adolescent only
Pregnancy exclusion 49/50
Score Card Results
Location of studies ( n=57)23 studies in high income countries only 15 in both high and low and middle income
countries19 in low and middle income countries only
Score Card Results
Sponsor22 public only33 private only4 cosponsor public and private
Score Card Results
Participation by womenHigh income (19%) vs low/middle income
countries (59%), p<.001Public (41%) vs private (28%) sponsored
studies, p<.001 vs cosponsored (70%)
Limitations of Score Card Data
Incomplete so far- biases in obtaining data
Women’s Scorecard
Next stepsContinue with current score cardMultivariate analysis to assess predicators of
woman participantsDevelop similar score cards for experienced
and management studiesPerform of meta-analysis of the naïve trials by
sex
Sex is Important
We need MORE POWER
for women
to fight this epidemic!