PREGNANCY PREVENTION: Advancing New Methods for an Old Friend

1. PREGNANCY PREVENTION: Advancing New Methods foran Old Friend CAPT Jason Woo, MD, MPH, FACOG Contraceptive and Reproductive Health Branch National Institute of Child Health and Human Development

2. Contraceptive Effectiveness

3. Objectives • Identify gaps in the use of existing contraceptive methods to prevent unintended pregnancies. • Describe novel areas for development of alternative forms and types of contraceptive methods. • Describe the leadership role of the National Institute of Child Health and Human Development in developing and collaborating with other stakeholders to advancing new contraceptive methods to address the problem of unplanned pregnancy around the world.

4. Simpler Objectives • Why pregnancy prevention remains a challenge • What is the future for new contraceptive methods • What are we doing now

5. World Population On October 31, 2011, the 7 billionth person, was born in poverty in Africa or Asia

6. Protecting the Environment

9. The Cheapest Way To Curb Carbon Dioxide: Contraception • According to a new report from the prestigious London School of Economics, birth control is a less expensive way to reduce carbon dioxide emissions than most green energy strategies. March 18, 2009 Bloomberg News 2010

10. Protect the Environment

11. Maternal, Infant and Child Mortality

12. Gender Equality

13. Costs of Unintended Pregnancy

14. What is an “Unintended Pregnancy”? A pregnancy that is either…. mistimed (occurs earlier than desired) Or unwanted (is not wanted at all) at the time of conception What is an Unplanned Pregnancy”? A pregnancy that occurred when the woman used a contraceptive method or when she did not desire to become pregnant but did not use a method.

15. Planning status and outcome of all pregnancies in developing countries 2008 Source: S. Singh et al Studies in Family Planning 41, 241-250 (2010).

17. Unintended pregnancies are very common…. • In 2008, 86 million (41%) of 208 million pregnancies globally were unintended • The proportions of live births reported as mistimed or unwanted varies by country, but overall are approximately equal Sources: Singh et al, 2010; Bradley et al, 2011

18. Tremendous variations by region Source: Singh et al, 2010

19. Outcomes of Unplanned births Source: Gipson et al, 2008; Malacher et al, 2010

20. Outcomes of “Unintended” Pregnancies • High rate of abortions • Greater maternal morbidity and mortality in countries where abortion is illegal and unsafe • Physical Abuse and Violence during pregnancy • Greater household dysfunction • History of greater exposure to psychological, physical and sexual abuse during the woman’s childhood

21. Immediate Outcomes of Unintended Pregnancies vary widely by region

22. Why do unintended pregnancies happen? • Unmet need: Non-use of contraception – when sexually active and a pregnancy is not desired • Switching or discontinuing a contraceptive method • Incorrect use or method failure • Unplanned sex • Unwanted sex • Non-consensual and/or violent sex • Early marriage

24. Failure and discontinuation are major determinants of unintended pregnancy and fertility • The total fertility rate would be 4-29% lower without failure • More than half of the total unwanted fertility rate is due to either a contraceptive failure or a contraceptive discontinuation • The total unwanted fertility rate would be between 0.2 and 1.1 births lower without failure and discontinuation Blanc et al, 1999

25. Reasons for non-use Women with unmet need for contraceptives, 2008 Access-related and other concerns Method related concerns 104 million women living in Sub-Saharan Africa, South Central Asia, Southeast Asia with method-related reasons for non-use; Darroch et al 2011

26. But….Evidence about reasons for non-use, use, failure and discontinuation is still limited • Full range and complexity of women’s concerns about individual methods • How specific method characteristics can hamper choice and use • Reasons for choosing traditional methods rather than modern methods • Clarification of meaning of “other reasons” for non-use • Reasons for long-term vs. short-term non-use • Sub-group differences in unmet need and in outcomes of non-use “Acceptability Research” Source: Darroch et al, 2011

27. In the U.S. most unintended pregnancies occur when women fail to use contraceptives or use their method inconsistently

28. Half of women at risk are not fully protected from unintended pregnancy

29. In 2008, more than two-thirds (69%) of all pregnancies among unmarried U.S. women aged 20–29 were unintended, compared with only half of pregnancies among reproductive-age women overall

30. Women with unmet need are diverse in goals but more likely to be young, poor and rural % of women with unmet need for modern methods

31. Unintended Pregnancies • Unintended pregnancies can lead to unwanted births, which may have adverse outcomes for mother and child(ren) • Unintended pregnancies can lead to unsafe abortion, which may have adverse outcomes for the mother • The majority of unintended pregnancies can be prevented through reducing unmet need for effective, appropriate contraceptive methods • Over two-thirds of unmet need is attributed to method-related issues less than one-third to access-related issues • However, a substantial proportion of unintended pregnancies result from failure, discontinuation and switching • The right to choose the number and spacing of births through having only intended pregnancies is most neglected among poor, young, rural women

32. Gap Issues • Acceptability • Better user efficacy • Fewer systemic side effects • Additional beneficial effects to use (Multi-use product) • Avoids cultural-social/religious barriers • Usability • Does not require skilled intermediary • Easier management of side effects • Can be used on-demand • Suited to diverse requirements imposed by the variety of conditions throughout the world • Access

33. Keys for new products • Do not cause systemic side effects • Can be used on demand • Do not require partner participation or knowledge • Benefits of New Technologies • Reduce user’s dependence on trained providers • Suited to diverse requirements imposed by the variety of conditions throughout the world

34. Institute of Medicine Report • New Frontiers in Contraceptive Research: A Blueprint for Action • Released: January 20, 2004 • 13 Primary Recommendations

35. New Frontiers in Contraceptive ResearchTarget Discovery and Validation • Promising New Targets • Key Areas for discovery: • Male spermatogenesis pathway • Sperm maturation (both sperm and epididymal proteins) • Sperm capacitation, motility and chemotaxis in the female reproductive tract • Proteins and molecules in the female reproductive system (vagina, cervix, uterus and oviduct) – focus on epithelium • Sperm-egg interactions (both sperm and egg proteins and molecules) • Maturation and ovulation of the egg

37. Potential Targets

38. Oocyte Spermatogenesis Maturation Trimming Glycoprocessing Environment Function Motility Orientation Binding Sperm-Zona Interaction Acrosomal Reaction Fusion ?? Differentiation Stem cells Meiosis Spermiogenesis Capacitation Intervention Points for Male Contraceptives

39. Genes Involved in the Regulation of Male Reproduction in the Mouse

40. New Non-hormonal Methods for Women Non-hormonal methods that regulate ovulation are in the early stages of exploration. • Ovulatory-selective expression library • 31 ovulation-selective • 13 ovulation-specific • (Hourvitz et al, J Endocrinol 2006) • Phosphodiesterase 3 inhibitors • (Jensen et al, Contraception 2005) • Progesterone receptor modulators

41. Accelerate the Discovery and Development of Compounds that Modulate Existing and Emerging Targets • Validated targets are only useful if compounds can be identified to modulate those targets in humans • Selection of lead molecules for development remains a challenge • Need a high throughput drug discovery approach

42. Acceptability of a Male Contraceptive Method • Heinemann et al 2005 J Androl – Expectations toward a novel male fertility control method and potential user types: results of a multinational survey. • Lye et al 2004 Mol Cell Endocrinol – Male contraception – a topic with many facets. • Anderson & Baird 2000 Endocrine Reviews – Male Contraception • Glasier et al 2000 Human Reproduction – Would women trust their partners to use a male pill?

43. Do Men Want a Male Contraceptive? Heinemann et al 2005 J Androl. Expectations toward a novel male fertility control method…

44. Challenges in Contraception • Inadequate attention and resources • Target Criteria Considerations – which to develop • Shift in focus from discovery to adaptation • Customer Population • Healthy • Product for preventive use (extended exposure) vs disease use • Contracepting for a significant part of their lives (> 30 yrs) • Safety / Side Effect Profile • Product Acceptability • Cultural Issues • Male Role • Side Affects

45. Contraception and Reproductive Health BranchCenter for Population ResearchEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of Health

46. Contraception and Reproductive Health BranchMission • Conduct and support research and training to develop new contraceptive methods for men and women. • Conduct and support research on the safety and efficacy of existing contraceptive methods. • Support research and training in selected areas of Reproductive Health with a special focus on pelvic floor disorders.

47. Contraceptive Research and Development Contraceptive Centers Grants (U54) Male Contraceptive Development Program (U01) Research Contract For New Development Small Business, Academic Researchers Support Contracts Biological Testing Facility Chemical Synthesis Facility Peptide Synthesis Facility Contraceptive Clinical Trials Network Investigator Initiated Grants

48. Compounds in CRHB Pipeline • Progesterone Receptor Modulators • CDB-2914 (licensed to HRA Pharma and marketed in Europe) Approved by FDA, August 13, 2010 • CDB-4124 (licensed to Repros Therapeutics) • Estrogen • Estradiol dinitrate ester (CDB-1357) (Evestra is licensing) • GnRH antagonist • Acyline (CDB-3883) • Progestin • Levonorgestrelbutanoate (CDB-1830) Jointly developed with WHO • Androgenic Steroids • Dimethandroloneundecanoate (CDB-4521) • 11β-methyl-19 nortestosterone 17β-dodecylcarbonate (CDB-4730) • Nonhormonalantispermatogenic agents • Indenopyridine (CDB-4022) • Lonidamine analog (CDB-4776)

49. Investigator-initiated Research Portfolio • Variety of mechanisms; e.g. R01, R03, R21, R43, R44 Example areas of research include: • Effects of hormonal contraceptives on bone density • Male sterilization – intra vas device • Female sterilization – thermal transcervical device • Effect of continuous versus sequential OCs • FSH antisense strategy for contraception • Identification of male contraceptive lead compounds • Selective blockers of oocyte maturation • Progestin effects on uterine hemostasis and angiogenesis

50. Cooperative Research Program on Male Fertility Regulation (U01) • Amory, J; University of Washington, Seattle, WA BDADs as a male contraceptive • Clapham, D; Children's Hospital, Boston, MA Male contraception/CatSper 1-4 sperm-specific ion channels • Herr, J; University of Virginia, Charlottesville, VA Testis-specific serine threonine kinases 1 and 2 • Matzuk, M; Baylor College of Medicine, Houston, TX Inhibition of spermatogenic-specific proteins • O'Brien, D; University of North Carolina, Chapel Hill, NC Inhibition of sperm-specific isoform of GAPDS • O’Rand; University of North Carolina, Chapel Hill, NC Inhibition of eppin-semenogelin binding to inhibit sperm motility • Tereda, N; University of Florida, Gainesville, FL Inhibition of a testis-specific isoform of adenine nucleotide translocase • Wolgemuth, D; Columbia University, New York, NY Rentinoid antagonists for inhibition of spermatogenesis