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!