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Sex/Gender and Minority Inclusion in NIH Clinical

Research

What Investigators Need to Know!

Presenter: Miriam F. Kelty, PhD, National Institute on Aging, 2013

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Overview • Review and Rationale of Policy• Policy Updates

– Definition of Clinical Research– OMB Standards and Population Tracking– NIH-Defined Phase III Trials: Analyses

• Implementation– Applicants– Reviewers– NIH program and grant managers

• Progress and Trends• Resources and Getting Help

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NIH Policy on Inclusion of Women & Minorities in Clinical Research

Why does NIH have this policy?

• Mandated by Congress, 1993 PL 103-43• Ethical principle of justice and importance

of balancing research burdens and benefits

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Public Law PL 103-43• Women & Minorities must be included in all

clinical research studies.• Women & Minorities must be included in Phase III

clinical trials & the trial must be designed to permit valid analysis.

• Cost is NOT allowed as a reason for exclusion.• NIH must support outreach efforts to recruit &

retain women, minorities & their subpopulations in clinical studies.

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Updates to Inclusion Policy 2001

• NIH Definition of Clinical Research

• Updated OMB Standards for Data on Ethnicity & Race

• Clarified NIH-Defined Phase III Clinical Trials & Required Analyses

http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm

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NIH Definition of Clinical Research

(1a) Patient-oriented research.Research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual.

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NIH Definition of Clinical Research (continued)

(1b) Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, and (d) development of new technologies;

(2) Epidemiologic and behavioral studies; and

(3) Outcomes and health services research.

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OMB Directive 15:Racial/Ethnic Standards for Federal

Statistics & Administrative Reporting

• Collect data by self-report*– What is your ethnicity?– What is your race? (option to select more

than one race)

*Investigator, not subject, completes data tables

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OMB Directive 15• Ethnic Categories

– Hispanic or Latino– Not Hispanic or Latino

• Racial Categories– American Indian or Alaska Native– Asian– Black or African American– Native Hawaiian or Other Pacific Islander– White– More than one race

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NIH-Defined Phase III Clinical Trials

• Evidence must be reviewed to show whether clinically important sex/gender and race/ethnicity differences in intervention effect are expected

• Plans for valid analysis must be included in the design

• Results of analyses must be reported to NIH

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NIH-Defined Phase III Clinical Trials: Requirements

• If prior studies support significant differences*between subgroups, a plan for valid analyses to detect significant differences between sex/gender &/or racial/ethnic subgroups is required.

• If prior studies support no significant differences between subgroups, representation as subject selection criterion is not required; inclusion & analyses are encouraged.*Significant difference = a difference of clinical or public health

importance based on substantial scientific data. Not the same as statistically significant difference.

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NIH-Defined Phase III Clinical Trials: Requirements

• If prior studies neither support nor negatesignificant differences in intervention effect between subgroups, a plan to conduct valid analyses* of the intervention effect in sex/gender &/or racial/ethnic subgroups is required.

*For the purpose of this policy, Valid Analysis means an unbiased assessment that does not require high statistical power and should be conducted for both large and small studies.

NIH Policy for Inclusion of Children 1998

• Children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

• http://grants.nih.gov/grants/funding/children/pol_children_qu.htm#A

• No requirement to track children

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Implementation: Applicants• Instructions in SF424(R&R)/PHS 398

– Best source of information for investigators -http://grants.nih.gov/grants/forms.htm

– Create section on Human Subjects Research• Inclusion of Women

• Inclusion of Minorities

• Participation of Children

• Application will be returned without review if this section is omitted

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Implementation: Applicants

• Instructions in SF424(R&R)/PHS 398 (cont’d)– Inclusion of Women and Minorities Sections must

include:• Subject selection criteria & rationale• Rationale for exclusions• Enrollment dates (start & end)• Outreach plans for recruitment• Table showing proposed composition

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Implementation: Applicants

• Instructions in SF424(R&R)/PHS 398 (cont’d)– NIH-Defined Phase III Clinical Trials

• Evidence must be reviewed to show whether clinically important sex/gender and race/ethnicity differences in intervention effect are expected

• Plans for valid analysis must be included in the design

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Implementation: Applicants

• Annual Progress Reports must include cumulative enrollment (reported in the enrollment tables).

• Annual Progress Report for Phase III Clinical Trials must include:– Enrollment tables– Narrative statement about progress in data

analyses for sex/gender & racial/ethnicity/ effects.

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Implementation: Reviewers

• Reviewers evaluate inclusion planshttp://grants.nih.gov/grants/peer/hs_review_inst.pdf

• Unacceptable plans must be reflected in the summary notes & priority score

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Implementation: Reviewers

• For Phase III Clinical Trials:– Reviewers evaluate inclusion AND analysis plans.

• http://grants.nih.gov/grants/peer/hs_review_inst.pdf

– Unacceptable plans must be reflected in the summary notes & priority score.

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Implementation: NIH Managers

Applications with unacceptable plans cannot be funded

Applicants work with NIH program staff to revise plans

so that they are acceptable to NIH

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Complying with the NIH Inclusion Policy

• Principal Investigators• Review Staff and Reviewers• Program Staff• Grants Management Staff• NIH Tracking and Inclusion Committee• Congress• Public

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Monitoring Compliance with the NIH Inclusion Policy

Annual Comprehensive Report: Monitoring Adherence to the NIH Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research

http://orwh.od.nih.gov/inclusion/inclreports.html

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3B. ENROLLMENT REPORTED

Total All Clinical Studies*

Domestic Foreign

Number % Number %

Females Enrolled 11,439,143 10,748,744 94.0% 690,399 6.0%

% 59.8.% 59.8% 58.7%

Males Enrolled 7,570,646 7,093,702 93.7% 476,944 6.3%

% 39.6% 39.5% 40.6%

Sex of Subjects is Unknown 1128,949 120,433 93.4% 8,516 6.6%

% 0.7% 0.7% 0.7%

Total Subjects Enrolled 19,138,738 17,962,879 93.9% 1,175,859 6.1%

% 100.0% 100.0% 100.0%

1. The total "Enrollment Reported" in the NIH database in FY 2009 was 19,138,738subjects in 11,171 protocols with enrollment.

2. Females made up 59.8% (11.5M) of the total subjects enrolled, while Males made up 38.9% (7.57M), with 0.7% unknown.

3. The total Domestic Enrollment reported was 17,962,879 (93.9%)

4. Females made up 59.8% (10.7M) of the domestic subjects enrolled, while Males made up 39.5% (7M), with 0.7% (.0.2M) unknown.

NIH Extramural & Intramural Clinical Research: Sex/Gender Enrollment Reported for FY 2009

Planned Enrollment Report

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Cumulative Inclusion Enrollment Report

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1. Minorities made up 30.2% (5.7M) of total subjects enrolled in FY2009. 1-2% variation characterizes enrollment for FY2010. .

2. Minorities made up 27.8% (4.9M) of the Domestic Minority Enrollment and 66.8% (.78M) of the Foreign Minority Enrollment.

3. The Total Minority Enrollment was made up of 86.4% Domestic and 13.6% Foreign enrollment.

Total All Clinical Studies*

Domestic Foreign

Number % Number %

3B. Total Subjects Enrolled 19,138,738 17,962,879 93.9% 1,175,859 6.1%

3C. Minority Enrollment Reported 5,783,543 4,998,599 86.4 % 784,944 13.6%

30.2% 27.8% 66.8%

NIH Extramural & Intramural Clinical Research: Minority Enrollment Reported for FY 2009

Enrollment Trend by Sex/Gender & Minority

0.0%

20.0%

40.0%

60.0%

80.0%

1995 1997 1999 2001 2003 2005 2007 2009Year Reported

Percentage Comparison between Male and Female enrollment

FemaleMale

0.0%20.0%40.0%60.0%80.0%

100.0%

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Subtotal: All  SubjectsEnrolled by US MinorityCategories

Total Minority Enrollment Reported by Year

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Progress and Trends

• The number of clinical studies and total and minority enrollment have increased significantly over 15 years

• More Females have been reported than Males, although the F/M ratio is relatively constant

• The vast majority are domestic studies

• Domestic minority enrollment has varied between approximately 25% and 30%

What We Have Learned• Women’s Health Initiative (WHI):

– Long-term EP hormone therapy increased heart disease, stroke, clots,breast cancer & AD.

– Colon cancer & fractures decreased• FDA warning that menopausal hormone

therapy should not be used to prevent coronary heart disease.

• Knowledge led to change in practice.

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What We Have Learned• Women’s Ischemia Syndrome Evaluation

(WISE)– 50% of enrollees with symptoms had no blockages– impaired microvasculature function not detectable

by angiography• Different methods necessary to diagnose

cardiac ischemia in women than in men• Most common early symptoms in women are

sleep disturbance, fatigue, shortness of breath.• Sex differences in disease symptoms 30

What We Have Learned• Multi-ethnic Study of Atherosclerosis

– Women met LDL, SBP & aspirin adherence goals less than men

– African-American & Hispanic women had higher SBP and lower aspirin use than white women

• Sex & racial/ethnic differences in cardiovascular risk factor profiles

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What We Have Lerned

• Diabetes Prevention Program– Lifestyle changes reduce risk of diabetes in

men & women & in all ethnic/racial groups– Medication intervention effective but not

more effective than lifestyle changes in all groups.

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What We Have Learned

• Gender affects stroke risk in A-Fib Patients– Women have increased risk for stroke compared

to men– Women’s risk of stroke 14% greater independent

of warfarin use– Women over 75 are at greatest risk

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Summary/Conclusions• NIH has made progress in including

women & minorities in clinical research.• Need to analyze trial data for

sex/gender and racial/ethnic differences.

• Primary aim of policy is to collect scientific information leading to changes in standard of care.

• We have gained knowledge broadly applicable to health care.

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Resources and Getting Help

• SF424 (R&R)Instructionshttp://grants.nih.gov/grants/forms.htm

• PHS 2590 Instructionshttp://grants.nih.gov/grants/forms.htm

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Resources and Getting Help

• Inclusion of Women and Minorities – Implementation Page

http://grants.nih.gov/grants/funding/women_min/women_min.htm

• Inclusion of Childrenhttp://grants.nih.gov/grants/funding

/children/children.htm

• CONTACT IC PROGRAM STAFF!