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Gender Aspects in Drug Development and Approval The American Experience

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.

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Gender Aspects in Drug Development and Approval The American Experience

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  1. 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

  2. OUTLINE • US FDA’s Role as a Regulatory Agency • Historical Perspective: Women in Clinical Trials • Drug Development Paradigm : Gender Aspects • Examples • Relevant Initiatives

  3. 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

  4. ROLE OF US FDA • Regulatory oversight of many products: • Focus on Drugs

  5. 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

  6. Drug Development and Approval:Assessing Women’s Health • A walk through FDA history

  7. 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

  8. 1930-1940 • 1937 Elixir Sulfanilimide marketed • Solvent: diethylene glycol • 107 deaths • Drug seizure by FDA (misbranding)

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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

  18. Death rate (women) EVOLVINGSOCIETAL NEEDS

  19. 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

  20. 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 $$$$

  21. 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 !

  22. 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

  23. How do subgroups get studied?

  24. 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

  25. 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

  26. 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

  27. Where is the evidence? • All noise ? No signal? • Cart before the horse? Examples……

  28. CVD MORTALITY

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. DIFFERENT RESPONSE TO ASPIRIN Efficacy JS Berger et al JAMA. 2006;295:306-313

  35. 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

  36. SCIENCE POLITICS POLICY

  37. So now that we know it IS important • How are we doing ? • How many ? • What do the analyses show ?

  38. HEALTH I.T. & DATA STANDARDS

  39. Need for Data Standardization Study #1 Study #2 Study #4 Study #3

  40. 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

  41. 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

  42. 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

  43. 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.’

  44. …..but it provides opportunities for personalized therapy

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

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