gender aspects in drug development and approval the american experience n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Gender Aspects in Drug Development and Approval The American Experience PowerPoint Presentation
Download Presentation
Gender Aspects in Drug Development and Approval The American Experience

Loading in 2 Seconds...

play fullscreen
1 / 46

Gender Aspects in Drug Development and Approval The American Experience - PowerPoint PPT Presentation


  • 165 Views
  • Uploaded on

Gender Aspects in Drug Development and Approval The American Experience. Ameeta Parekh, Ph. D. Research And Development Director Office of Women’s Health, FDA National and International Symposium on Gender Medicine Stockholm, Sweden October 20, 2010. OUTLINE.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Gender Aspects in Drug Development and Approval The American Experience' - danelle


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
gender aspects in drug development and approval the american experience

Gender Aspects in Drug Development and ApprovalThe American Experience

Ameeta Parekh, Ph. D.

Research And Development Director

Office of Women’s Health, FDA

National and International Symposium on Gender Medicine

Stockholm, Sweden

October 20, 2010

outline
OUTLINE
  • US FDA’s Role as a Regulatory Agency
  • Historical Perspective: Women in Clinical Trials
  • Drug Development Paradigm : Gender Aspects
  • Examples
  • Relevant Initiatives
is it sex or is it gender iom definitions 2001
Is it SEX? OR Is it GENDER?IOM 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 fda
ROLE OF US FDA
  • Regulatory oversight of many products:
    • Focus on Drugs
the facts
The FACTS
  • 2009 US census population estimates:
    • 50.7% women
  • Women outlive men (80.7 years vs 74.8 years)
  • Many diseases place heavy burden on women compared to men
    • Heart disease
    • Cancer
    • Rheumatoid arthritis
    • Lupus
    • Osteoporosis
  • Women rely more on medical system than men
  • Yet women underrepresented in many clinical trials AND
  • For many diseases treatment guidelines are largely based on data in men
1906 president theodore roosevelt signs the food and drug act
1906: President Theodore Roosevelt signs the Food and Drug Act
  • Created USDA
  • Prohibited interstate commerce of adulterated or misbranded food and drugs
  • Drugs must meet standards ofstrength and purity
1930 1940
1930-1940
  • 1937 Elixir Sulfanilimide marketed
    • Solvent: diethylene glycol
    • 107 deaths
    • Drug seizure by FDA (misbranding)
1930 1940 chamber of horrors exhibit
1930-1940“Chamber of Horrors” Exhibit
  • Lash-Lure (aniline eyelash dye)
    • Blindness
  • Other products:
    • Womb supporter→punctured the uterus
    • Hair dyes→ lead poisoning
    • Lotions/creams→ mercury poisoning
1938 franklin delano roosevelt signs the food drug and cosmetic act
Manufacturers must demonstrate drugs are SAFE prior to marketing

Extended coverage to cosmetics and medical devices

Authorized factory inspections

Prescription-only drugs must be administered under the direction of a qualified expert

1938: Franklin Delano Roosevelt signs The Food, Drug, and Cosmetic Act
thalidomide
THALIDOMIDE
  • 1957-1962 in UK, Canada, Germany, Japan
  • Used for morning sickness
  • 12,000 babies with phocomelia
  • Other birth defects:
    • Ears, deafness, cardiac, ocular, facial, renal, GI, poor growth and mental retardation
october 1962 kennedy signs kefauver harris drug amendments
Manufacturers must demonstrate drug EFFICACY

Required drug to be tested in animals before humans

Subjects must give informed consent for use of investigational drugs

Manufacturers must report adverse events related to their drugs

October 1962: Kennedy Signs Kefauver-Harris Drug Amendments
role of fda
ROLE OF FDA
  • Regulatory oversight of many products:

The FDA's mission is to promote and protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use.

regulatory history
Regulatory 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 knowledge
SEX 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 in clinical studies
CHALLENGES: INCLUDING WOMEN IN 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 responds
SOCIETY RESPONDS
  • Critics of 1977 guideline
    • Precludes a female’s ability to make a decision
    • Violates principle of autonomy (informed consent)
  • Advocacy Groups
    • Females denied access to important and innovative therapies
headlines
Headlines

Too Few Women in Clinical Trials?

HIV Clinical Trials Need Women, Minority Participants

Women lag behind men in cancer trial representation

Study reveals under representation of women in cardiovascular clinical trials

a look back in time
A 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 history importance of subgroup populations
FDA HistoryImportance of subgroup populations….
  • 1988 Guideline: Format and Content of the Clinical and Statistical Section of an Application Recommended data analysis by sex, race and age
  • 1989 Guideline: Study of Drugs Likely to be Used in the Elderly Recommended data analysis by factors such as age and sex

1992 GAO Report !

slide22
Women were NOT ADEQUATELY INCLUDED in clinical studies

60% of drugs – representation of women less thanprevalence with disease

Data NOT analyzed for SEX differences

Lack of understanding of sex/gender differencesFDA OWH: 1994

REPORT ON FDA

1992 GAO Report

1993 guideline study and evaluation of gender differences in the clinical evaluation of drugs
1993 GUIDELINE:Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs
  • Reversed the 1977 Policy:‘…women of childbearing potential should be excluded from the earliest dose-ranging studies.’
  • Collection and analysis of data on sex differences
    • Effectiveness
    • Adverse effects
    • PK
  • Can reduce risk of fetal exposure through protocol design
slide25

1998 REGULATION:

Investigational New Drug Applications (INDs)

and New Drug Applications (NDAs)

( “Demographic Rule”)

21 CFR 314.50 and 21 CFR 312.33

  • Requires:
  • NDA submission of information on:
    • Trial participation
    • Safety
    • Effectiveness
  • By gender, age, and race
  • Requires:INDs to tabulate the number of participants according to:
    • Gender (sex)
    • Age
    • Race
slide26

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?
  • Cart before the horse?

Examples……

drug induced ecg changes
DRUG INDUCED ECG CHANGES
  • QT prolongation
  • Torsades 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 withdrawn from the us market 1997 2000
Prescription Drugs WITHDRAWN from the US Market 1997-2000

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

slide31

DEATHSCardiovascular and Renal Drugs Advisory Committee Meeting, 12/12/2007 Indication: rapid conversion of new onset atrial fibrilation/flutter

NOT APPROVED

http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4327s-02-index.htm

slide32

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 adopt study avandia rosiglitazone
FRACTURE RISK ADOPT studyAvandia (rosiglitazone)

LABELING

CHANGE

*Majority of fractures in upper arm (humerus), hand or foot. Number with hip or spine fractures was similar among the 3 treatment groups.

Kahn, et al NEJM. 2006;355 (23):2427-43

GSK Dear HealthCare Professional Letter, February 2007

slide34

DIFFERENT RESPONSE TO ASPIRIN

Efficacy

JS Berger et al JAMA.

2006;295:306-313

sex disparities in knowledge1
SEX 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

slide36

SCIENCE

POLITICS

POLICY

so now that we know it is important
So now that we know it IS important
  • How are we doing ?
  • How many ?
  • What do the analyses show ?
need for data standardization
Need for Data Standardization

Study #1

Study #2

Study #4

Study #3

participation in clinical trials
Participation in Clinical Trials

Result:analyzing clinical trial data is difficult and time consuming, especially across many trials

  • Male Female
  • M F
  • Man Woman
  • M W
  • 0 1
  • 1 0
  • 1 2
  • Other

Most clinical trials :

don’t employ astandard for data exchange

don’t use standardized analytic tools or techniques

slide42

How are we doing?

US GAO Report, 1992, 1-39, http://archive.gao.gov/d35t11/147861.pdf

US GAO Report, 2001, 1-36, www.gao.gov/new.items/d01754.pdf

Yang, et.al.,Journal of Women’s Health, Vol 18, No.3, 2009

Pinnow et.al, Women’s Health Issues, 29, 2009

ongoing initiatives
Ongoing Initiatives
  • Data Standardization Initiative
  • REMS: A Risk Evaluation and Mitigation Strategy (REMS) is a required risk management plan that utilizes tools beyond routine labeling to ensure that the benefits of a drug outweigh its risks.
  • Sentinel : An active surveillance system for monitoring drugs, using electronic data from healthcare information holders
  • MedWatch: Facilitate adverse event reporting; to disseminate safety information out to healthcare providers and their patients at the point of care
  • NIH-FDA collaboration : Joint Leadership Council to enable the Agencies to work together to advance and improve Regulatory Science
slide44

Remarks at Personalized Medicine Coalition’s 6th Annual Keynote Luncheon:Margaret Hamburg, M.D., FDA CommissionerNational Press Club, February 25, 2010

  • ‘…. we can have much better outcomes for patients if we can discern what distinguishes one group from another, in terms of both positive and negative responses, and design a clinical trial based on that knowledge.’
slide46

FDA Mission:Protecting and Promoting Public HealthOWH Mission:Protecting and Advancing the Health of Women