Inclusion of Women in Clinical Inclusion of Women in Clinical Trials & Drug DevelopmentTrials & Drug Development

Regulatory PerspectiveRegulatory Perspective

Ameeta Parekh, Ph.D.Ameeta Parekh, Ph.D.

R&D DirectorR&D Director

Office of Women’s Health

Food & Drug Administration

November 10, 2009November 10, 2009

American Association of Pharmaceutical Scientists Annual MeetingAmerican Association of Pharmaceutical Scientists Annual Meeting

Los AngelesLos Angeles

OVERVIEWOVERVIEW

Historical framework Historical framework – Women in clinical studiesWomen in clinical studies

Regulatory frameworkRegulatory framework– Regulations, guidances, practicesRegulations, guidances, practices

– Regulatory Initiatives: Bio-informaticsRegulatory Initiatives: Bio-informatics

SUBSTANTIATION OF GAPSSUBSTANTIATION OF GAPS

Numerous reports:Numerous reports:

1.1. Government - NIH, AHRQ, GAO, Government - NIH, AHRQ, GAO, FDAFDAunder-representation, analysisunder-representation, analysis

2.2. Institute of Medicine (IOM) ReportInstitute of Medicine (IOM) Reportcontribution of sex as a biological variablecontribution of sex as a biological variable

3.3. Peer-reviewed PublicationsPeer-reviewed Publications

A LOOK BACK IN TIMEA LOOK BACK IN TIME

19851985 US Public Health Task Force Reported that US Public Health Task Force Reported that historical lack of focushistorical lack of focus on women’s health issues on women’s health issues deprived women of proper health care and health deprived women of proper health care and health informationinformation

1986 1986 NIH established NIH established voluntaryvoluntary policy to include policy to include women in clinical researchwomen in clinical research

19901990 GAO report GAO report criticizing implementation of criticizing implementation of 1986 policy1986 policy

19901990 NIH Office of Research on Women’s Health NIH Office of Research on Women’s Health establishedestablished

AHRQ Publication No. 03-E035

May 2003

Peer Reviewed Literature

•Research in the last 20 years … excluded women entirely or included only limited numbers of women and minorities

•Often findings specific to findings specific to women are NOT provided women are NOT provided

•~~20 percent20 percent of the articles of the articles provided provided separate findings for separate findings for womenwomen

•Many Many tests and therapiestests and therapies used clinically are used clinically are based on based on studiesstudies conducted conducted predominantly predominantly in menin men

Excluded women of Excluded women of childbearing potentialchildbearing potential from participation in from participation in earlyearly studies of drugsstudies of drugs

1977 REGULATION: General Considerations for the

Clinical Evaluation of Drugs

SOCIETY RESPONDSSOCIETY RESPONDS

Critics of 1977 guidelineCritics of 1977 guideline– Precludes a female’s ability to make a decisionPrecludes a female’s ability to make a decision– Violates principle of autonomy (informed consent)Violates principle of autonomy (informed consent)

Advocacy GroupsAdvocacy Groups– Females denied access to important and innovative Females denied access to important and innovative

therapiestherapies

Congress RespondsCongress Responds

The public including many women’s groups lobby The public including many women’s groups lobby CongressCongress

1994 - Created by Congressional mandate1994 - Created by Congressional mandate ““...Establish an Office of Women’s Health..”...Establish an Office of Women’s Health..” at FDA at FDA

– ““Correct gender disparities in FDA drug, device, Correct gender disparities in FDA drug, device, biologics testing and regulation policy”biologics testing and regulation policy”

– ““Oversee the implementation of revised clinical trial Oversee the implementation of revised clinical trial guidelines with respect to representation of guidelines with respect to representation of women…”women…”

– ““Coordinate PHS women’s health policy with the Coordinate PHS women’s health policy with the PHS Office of Women’s Health and other PHS PHS Office of Women’s Health and other PHS agency offices…”agency offices…”

1993 GUIDELINE:1993 GUIDELINE:Study and Evaluation of Gender Differences in the Study and Evaluation of Gender Differences in the

Clinical Evaluation of DrugsClinical Evaluation of Drugs

Reversed the 1977 PolicyReversed the 1977 Policy Collection and analysis of data on sex Collection and analysis of data on sex

differencesdifferences– EffectivenessEffectiveness– Adverse effectsAdverse effects– Pharmacokinetics (PK)Pharmacokinetics (PK)

Can reduce risk of fetal exposure through Can reduce risk of fetal exposure through protocol designprotocol design

Women were NOT ADEQUATELY INCLUDED in clinical studies

60% of drugs – representation of women less than prevalence with disease

Data NOT analyzed for SEX differences

Lack of understanding of sex/gender differences

FDA OWH: 1994

1992 GAO Report1992 GAO Report

REPORT ON FDA

NDA SUBMISSIONS:

• Requires information on: • Trial participation• Safety• Effectiveness

• Data evaluated by:• “Gender” (sex)• Age• Race

1998 REGULATION: Investigational New Drug Applications (INDs)

and New Drug Applications (NDAs)( “Demographic Rule”) 21 CFR 314.50 and 21 CFR 312.33

1998 REGULATION (cont)IND Annual Reports

IND ANNUAL REPORTS: Requires tabulation of the number of participants according to:

• “Gender” (sex)• Age• Race

2000 REGULATION (amendment):

Clinical Hold Regulations for Products Intended for Life-Threatening Diseases

•Permits FDA to stop studies under an IND for treatment of a life-threatening disease if women are excluded due to reproductive potential

2001 GAO Report2001 GAO Report

Appropriate numbersAppropriate numbers of of women in NDAswomen in NDAsAnalysis by sexAnalysis by sex waswas NOTNOT consistently consistently presentpresent

Participation of women Participation of women is similar to that of men is similar to that of men except:except:

•Earliest phasesEarliest phases•Some therapeutic areas Some therapeutic areas (e.g., CVD)(e.g., CVD)

REPORT ON FDA

FDA….FDA….Not there yetNot there yet

FY2002 - FY2002 - Congressional MandateCongressional Mandate “…“…create a database focused on women’s health create a database focused on women’s health

activities, to include demographic data in clinical activities, to include demographic data in clinical trials”trials”

Needed:Needed: Ability to tracktrack this in an quick this in an quick AutomatedAutomated process process Data Standards Information/Knowledge Management IT infrastructure & advances

DATA STANDARDSDATA STANDARDS

DATA STANDARDSDATA STANDARDS

Male FemaleMale Female

M FM F

Man WomanMan Woman

M WM W

0 10 1

1 01 0

1 21 2

Any Combination Any Combination or othersor others

SUBJIDSUBJID SEXSEX

00010001 MM

00020002 FF

00030003 FF

00040004 MM

00050005 FF

Study #1

IDID GENDERGENDER

A1A1 MaleMale

A2A2 MaleMale

A3A3 FemaleFemale

A4A4 FemaleFemale

A5A5 MaleMale

USUBIDUSUBID SEXSEX

0001100011 00

0001200012 11

0001300013 11

0001400014 00

0001500015 11

PTIDPTID GENDERGENDER

00010001 11

00020002 11

00030003 22

00040004 22

00050005 11

Study #2

Study #3

Study #4

DATA STANDARD FOR SEXDATA STANDARD FOR SEX

M, F, UM, F, U

Male, female, unknownMale, female, unknown

In Closing……In Closing……

Historical framework Historical framework – Women in clinical studiesWomen in clinical studies

FDA OWH 1994FDA OWH 1994

Regulatory frameworkRegulatory framework– Regulations, guidances, etc.Regulations, guidances, etc.– Bio-informatics, and many other Bio-informatics, and many other

innovations to close the knowledge gapinnovations to close the knowledge gap