Transcript 200806_walsmley_en

Women’s Participation in
Clinical Trials
Are we POWERED
to 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 Advisor
 Diane Addison
 Tania
Lemay
 Nicolai Lohse
 Adam 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



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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 for
 Age
 Race
 Education
 Baseline
CD4, VL
 Hepatitis C coinfection
 Adherence
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)
% accrual of women
Total
Sample
Size
3500
10% accrual
3000
15% accrual
2500
20% accrual
2000
1500
1000
500
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
Failure Rate in Women
J Currier et al., VIII Int Conference on AIDS, Amsterdam 1992, Abstract 4705
0.50
Complications of ARV
Is it different by sex?
Sex Differences Noted
Pancreatitis
Lower risk
of TG increase
Higher rates of low
HDL women
Rash
Hepatic
steatosis and
lactic acidosis
Higher in
women
Fat
Accumulation
and
Lipoatrophy
Phenotype
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%
333
J Currier et al., VIII Int Conference on AIDS, Amsterdam 1992, Abstract 4705
Women’s Scorecard
Methodology
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 Scorecard
Methodology

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 Scorecard
Methodology

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 Scorecard
Results
73 studies identified
 14 excluded

8
studies only infants and children
 5 studies only women
 1 study only men
Women’s Scorecard
Results

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)
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
(
range 5.9-79.2%)
Score Card Results
Enrollment of adolescents ( age 13-19)
 Per protocol: 8/59 studies
 One protocol adolescent only
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
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
countries
 19 in low and middle income countries only
Score Card Results

Sponsor
 22
public only
 33 private only
 4 cosponsor public and private
Score Card Results

Participation by women
 High
income (19%) vs low/middle income
countries (59%), p<.001
 Public (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
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Next steps
 Continue
with current score card
 Multivariate analysis to assess predicators of
woman participants
 Develop similar score cards for experienced
and management studies
 Perform of meta-analysis of the naïve trials by
sex
Sex is Important
We need MORE POWER
for women
to fight this epidemic!