Gender Aspects in Drug Gender Aspects in Drug Development and Approval Development and Approval The American Experience The American Experience Ameeta Parekh, Ph. D. Ameeta Parekh, Ph. D. Research And Development Director Research And Development Director Office of Women’s Health, FDA National and International Symposium on Gender National and International Symposium on Gender Medicine Medicine Stockholm, Sweden Stockholm, Sweden October 20, 2010 October 20, 2010
Transcript
Gender Aspects in Drug Gender Aspects in Drug Development and ApprovalDevelopment and Approval
The American ExperienceThe American Experience
Ameeta Parekh, Ph. D.Ameeta Parekh, Ph. D.
Research And Development DirectorResearch And Development Director
Office of Women’s Health, FDA
National and International Symposium on Gender MedicineNational and International Symposium on Gender Medicine
Stockholm, SwedenStockholm, Sweden
October 20, 2010October 20, 2010
OUTLINEOUTLINE
US FDA’s Role as a Regulatory AgencyUS FDA’s Role as a Regulatory Agency
Historical Perspective: Women in Clinical TrialsHistorical Perspective: Women in Clinical Trials
Drug Development Paradigm : Gender AspectsDrug Development Paradigm : Gender Aspects
ExamplesExamples
Relevant InitiativesRelevant Initiatives
Is it SEX? OR Is it GENDER?Is it SEX? OR Is it GENDER? IOM definitions – 2001IOM definitions – 2001
SEX – Used as a classification, generally as male or female,
according to the reproductive organs and functions that derive from chromosomal complement
– XY vs. XX
GENDER – Used to refer to a person’s self-representation as
male or female, or how that person is responded to by social institutions on the basis of the individual’s gender presentation
– Masculine vs. feminine
ROLE OF US FDAROLE OF US FDA
Regulatory oversight of many Regulatory oversight of many products:products:
– Focus on DrugsFocus on Drugs
The FACTSThe FACTS
2009 US census population estimates:2009 US census population estimates:– 50.7% women50.7% women
Women outlive men (80.7 years vs 74.8 years)Women outlive men (80.7 years vs 74.8 years) Many diseases place heavy burden on women compared Many diseases place heavy burden on women compared
Women rely more on medical system than menWomen rely more on medical system than men Yet women underrepresented in many clinical trials ANDYet women underrepresented in many clinical trials AND For many diseases treatment guidelines are largely For many diseases treatment guidelines are largely
based on data in menbased on data in men
Drug Development and Approval:Drug Development and Approval:Assessing Women’s HealthAssessing Women’s Health
A walk through FDA historyA walk through FDA history
1906: President Theodore Roosevelt 1906: President Theodore Roosevelt signs the Food and Drug Actsigns the Food and Drug Act
Created USDACreated USDA Prohibited Prohibited interstate interstate
commercecommerce of of adulterated or adulterated or misbranded food and misbranded food and drugsdrugs
Drugs must meet Drugs must meet standards of strengthstrength and and puritypurity
1930-19401930-1940
1937 Elixir 1937 Elixir Sulfanilimide Sulfanilimide marketedmarketed– Solvent: diethylene glycolSolvent: diethylene glycol– 107 deaths107 deaths– Drug seizure by FDA Drug seizure by FDA
(misbranding)(misbranding)
1930-19401930-1940“Chamber of Horrors” Exhibit“Chamber of Horrors” Exhibit
1938: Franklin Delano Roosevelt signs 1938: Franklin Delano Roosevelt signs The Food, Drug, and Cosmetic ActThe Food, Drug, and Cosmetic Act
Manufacturers must Manufacturers must demonstrate drugs are demonstrate drugs are SAFESAFE prior to marketing prior to marketing– Extended coverage to Extended coverage to
cosmetics and medical devicescosmetics and medical devices
Prescription-only drugs Prescription-only drugs must be administered must be administered under the direction of a under the direction of a qualified expertqualified expert
THALIDOMIDETHALIDOMIDE
1957-1962 in UK, Canada, 1957-1962 in UK, Canada, Germany, Japan Germany, Japan
Used for morning sickness Used for morning sickness
12,000 babies with 12,000 babies with phocomeliaphocomelia
Other birth defects:Other birth defects:– Ears, deafness, cardiac, ocular,
facial, renal, GI, poor growth and mental retardation
October 1962: Kennedy Signs October 1962: Kennedy Signs Kefauver-Harris Drug AmendmentsKefauver-Harris Drug Amendments
Manufacturers must Manufacturers must demonstrate drug demonstrate drug EFFICACYEFFICACY
Required drug to be tested Required drug to be tested in in animalsanimals before humans before humans
Subjects must give Subjects must give informed consentinformed consent for use of for use of investigational drugsinvestigational drugs
Manufacturers must Manufacturers must report report adverse eventsadverse events related to related to their drugstheir drugs
ROLE OF FDAROLE OF FDA
Regulatory oversight of many Regulatory oversight of many products:products:
The FDA's mission is to The FDA's mission is to promote and promote and protectprotect the public health by helping the public health by helping safe and effectivesafe and effective products reach the products reach the market in a timely way, and monitoring market in a timely way, and monitoring products for products for continued safetycontinued safety after after they are in use. they are in use.
Regulatory HistoryRegulatory History
1977 Guidelines: General Considerations for the Clinical Evaluation of Drugs
‘…women of childbearing potential should be excluded from the earliest dose-ranging studies.’
…..ALL trials?
…..under representation or exclusion
SEX DISPARITIES IN KNOWLEDGESEX DISPARITIES IN KNOWLEDGE
Sex was NOT recognized as:– A variable in health research– A factor that could affect health and illness
Adapted from Moncher & Douglas, Importance of and Barriers to Including Women in Clinical Trials. In: Principles of Gender-specific Medicine
CHALLENGES: INCLUDING WOMEN CHALLENGES: INCLUDING WOMEN IN CLINICAL STUDIESIN CLINICAL STUDIES
Women are “harder” to study
Less homogeneous
Confounding effects of hormonal & reproductive factors
More difficult to analyze
More expensive (would need more subjects)
Studies would take longer to complete
Fear of liability
Adapted from Moncher & Douglas, Importance of and Barriers to Including Women in Clinical Trials. In: Principles of Gender-specific Medicine
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
EVOLVINGSOCIETAL NEEDS
Death rate (women)
HeadlinesHeadlines
Too Few Women in Clinical Trials?
Study reveals under representation of women in cardiovascular clinical trials
A LOOK BACK IN TIMEA LOOK BACK IN TIME
1985 – US Public Health Task Force: Reported that historical lack of focus on women’s health issues deprived women of proper health care and health information
1986 – NIH established voluntary policy: include women in clinical research
1990 – GAO report: criticizing implementation of 1986 policy
1990 – NIH Office of Research on Women’s Health established
1993 - NIH revitalization Act requires women in studies or no $$$$
FDA HistoryFDA HistoryImportance of subgroup populations….Importance of subgroup populations….
1988 Guideline: Format and Content of the 1988 Guideline: Format and Content of the Clinical and Statistical Section of an Clinical and Statistical Section of an Application Application Recommended data analysis by sex, race and ageRecommended data analysis by sex, race and age
1989 Guideline: Study of Drugs Likely to be 1989 Guideline: Study of Drugs Likely to be Used in the Elderly Used in the Elderly Recommended data analysis by factors such as age and Recommended data analysis by factors such as age and sexsex
1992 GAO Report !
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
How do subgroups get studied?How do subgroups get studied?
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 Policy:Reversed the 1977 Policy:
‘…women of childbearing potential should be excluded from the earliest dose-ranging studies.’
Collection and analysis of data on sex differencesCollection and analysis of data on sex differences
Can reduce risk of fetal exposure through protocol designCan reduce risk of fetal exposure through protocol design
•Requires: NDA submission of information on:
•Trial participation•Safety•Effectiveness
•By gender, age, and race
1998 REGULATION: Investigational New Drug Applications (INDs)
and New Drug Applications (NDAs)( “Demographic Rule”)
21 CFR 314.50 and 21 CFR 312.33
•Requires: INDs to tabulate 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
Where is the evidence?Where is the evidence?
All noise ? No signal?All noise ? No signal?
Cart before the horse?Cart before the horse?
Examples……
CVD MORTALITY
DRUG INDUCED ECG CHANGESDRUG INDUCED ECG CHANGES
QT prolongation QT prolongation
Torsades de pointesTorsades de pointes
Women are: 2-3 times more likely to develop TDP than menmore likely to have LQT/TDP secondary to drug therapy
Prescription Drugs Prescription Drugs WITHDRAWNWITHDRAWN from from the US Market 1997-2000the US Market 1997-2000
Drug Type of Drug Patient Population
Primary Health Risk
Prescription Drugs with Evidence of Greater Health Risks In Women Pondimin Appetite
suppressant Women Valvular heart
disease Redux Appetite
suppressant Women Valvular heart
disease Rezulin Diabetic Women Liver failure
Lotronex Gastrointestinal Women Ischemic colitis Seldanea Antihistamine Women and Men Torsades de Pointes Posicor Cardiovascular Women and Men Lowered heart rate in
elderly women and adverse interactions with
26 other drugs Hismanal Antihistamine Women and Men Torsades de Pointes Propulsidb Gastrointestinal Women and Men Torsades de Pointes
aSeldane-D was also withdrawn from the market. Terfenadine was the active ingredient in both Seldane and Seldane-D;Seldane-D also contained the decongestant pseudoephedrine.bPropulsid remains minimally available on a patient-by-patient basis for those with severely debilitating conditions.Source: GAO analysis in GAO-01-286R Drugs Withdrawn From Market
DEATHSDEATHS Cardiovascular and Renal Drugs Advisory Committee Meeting, 12/12/2007 Cardiovascular and Renal Drugs Advisory Committee Meeting, 12/12/2007
IndicationIndication: rapid conversion of new onset atrial fibrilation/flutter: rapid conversion of new onset atrial fibrilation/flutter
Kaplan-Meier estimates of the cumulative incidence of fractures at 5 years in all patients (A), men (B), and women (C). Fractures were as reported by the clinical site and the HRs (95% CI) for these events are listed for comparisons by treatment group. Bars represent 95% CIs.
Kahn SE, et. al. Diabetes Care. 2008; 31(5): 845-851
FRACTURE RISK FRACTURE RISK ADOPT studyADOPT study
Avandia (rosiglitazone)Avandia (rosiglitazone)
Kahn, et al NEJM. 2006;355 (23):2427-43GSK Dear HealthCare Professional Letter, February 2007
*Majority of fractures in upper arm (humerus), hand or foot. Number with hip or spine fractures was similar among the 3 treatment groups.
LABELING
CHANGE
DIFFERENT RESPONSE TO ASPIRINDIFFERENT RESPONSE TO ASPIRINEfficacyEfficacy
JS Berger et al JAMA. 2006;295:306-313 MENMEN WOMENWOMEN
Ischemic Ischemic StrokeStroke
↓↓
MIMI ↓↓
BleedingBleeding ↑↑ ↑↑
SEX DISPARITIES IN KNOWLEDGESEX DISPARITIES IN KNOWLEDGE
Sex is:– A variable in health research– A factor that could affect health and illness
Adapted from Moncher & Douglas, Importance of and Barriers to Including Women in Clinical Trials. In: Principles of Gender-specific Medicine
SCIENCE
POLITICSPOLICY
So now that we know it IS importantSo now that we know it IS important
How are we doing ?How are we doing ?
How many ?How many ?
What do the analyses show ?What do the analyses show ?
HEALTH I.T. & DATA STANDARDSHEALTH I.T. & DATA STANDARDS
Need for Data StandardizationNeed for Data Standardization
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
Participation in Clinical TrialsParticipation in Clinical Trials
Result:Result:analyzinganalyzing clinical trial data is clinical trial data is difficult and difficult and time consumingtime consuming, especially across many , especially across many trialstrials
Male FemaleMale Female
M FM F
Man WomanMan Woman
M WM W
0 10 1
1 01 0
1 21 2
OtherOther
Most clinical trialsMost clinical trials : :don’t employ adon’t employ a standard for data standard for data exchangeexchangedon’t use standardized analytic tools or don’t use standardized analytic tools or techniquestechniques
Women's Participation in Late Phase Clinical Trials for Drugs
GAO1992
GAO2001 Yang2009
0
20
40
60
80
100
Jan88-Jun91 Aug98-Dec00 2000-2002
Per
cen
tag
es
Jan88-Jun91 Aug98-Dec00 2000-2002
US GAO Report, 1992, 1-39, http://archive.gao.gov/d35t11/147861.pdfUS GAO Report, 2001, 1-36, www.gao.gov/new.items/d01754.pdfYang, et.al.,Journal of Women’s Health, Vol 18, No.3, 2009Pinnow et.al, Women’s Health Issues, 29, 2009
Women's Participation in Early Phase Clinical Trials for Drugs
Pinnow 2009*Yang2009GAO2001
0
20
40
60
80
100
Aug98-Dec00 2000-2002 2006-2007
Per
cen
tag
es
Aug98-Dec00 2000-2002 2006-2007
*trials enrolling both sexes have 38.8%w omen
Data Analysis by Sex in Clinical Trials for Drugs
Yang2009GAO2001
GAO1992
0
20
40
60
80
100
Jan88-Jun91 Aug98-Dec00 2000-2002
Per
cen
tag
es
Jan88-Jun91 Aug98-Dec00 2000-2002
How are we doing?
Ongoing InitiativesOngoing Initiatives
Data Standardization InitiativeData Standardization Initiative
REMS: A Risk Evaluation and Mitigation Strategy (REMS) is a REMS: A Risk Evaluation and Mitigation Strategy (REMS) is a required risk management plan that utilizes tools beyond routine required risk management plan that utilizes tools beyond routine labeling to ensure that the benefits of a drug outweigh its risks.labeling to ensure that the benefits of a drug outweigh its risks.
Sentinel : An active surveillance system for monitoring drugs, Sentinel : An active surveillance system for monitoring drugs, using electronic data from healthcare information holdersusing electronic data from healthcare information holders
MedWatch: MedWatch: Facilitate adverse event reporting; to disseminate Facilitate adverse event reporting; to disseminate safety information out to healthcare providers and their patients at safety information out to healthcare providers and their patients at the point of carethe point of care
NIH-FDA collaboration : Joint Leadership Council to enable the NIH-FDA collaboration : Joint Leadership Council to enable the Agencies to work together to advance and improve Regulatory Agencies to work together to advance and improve Regulatory ScienceScience
Remarks at Personalized Medicine Coalition’s 6Remarks at Personalized Medicine Coalition’s 6 thth Annual Keynote Luncheon:Annual Keynote Luncheon:Margaret Hamburg, M.D., FDA CommissionerMargaret Hamburg, M.D., FDA Commissioner
National Press Club, February 25, 2010National Press Club, February 25, 2010
‘…‘…. we can have much better outcomes . we can have much better outcomes for patients if we can discern what for patients if we can discern what distinguishes one group from another, in distinguishes one group from another, in terms of both positive and negative terms of both positive and negative responses, and design a clinical trial responses, and design a clinical trial based on that knowledge.’based on that knowledge.’
…..but it provides opportunities for personalized therapy
FDA Mission:FDA Mission:Protecting and Promoting Protecting and Promoting
Public HealthPublic Health
OWH Mission:OWH Mission:Protecting and Advancing Protecting and Advancing
