Research Study:

1. Research Study: The Participation of Pregnant Women in Clinical Research: Implications for Practice within the U.S. Pharmaceutical Industry University of North Carolina Gillings School of Global Public Health Kristine Shields MSN, DrPH 2012

2. Millenium Development Goal #5: Reduce Maternal Mortality 1.7 Million Pregnant Women 2 die every day 600,000 have complications > 1 million are prescribed drugs Problem See References slide

3. Problem 80% Bioterrorism Abortion Thalidomide Death See References slide

4. Policy Window Opens FDA Draft Guidance: Pregnant Women in Clinical Trials: Scientific and Ethical Considerations

5. Policy Window Theory of Change Kingdon: Agendas, Alternatives, and Public Policies

6. Indicators of the existence and magnitude of issue Promotion of constituent feedback Kingdon recommends: Special studies of the issue • Quantitative methodology • Qualitative methodology Kingdon: Agendas, Alternatives, and Public Policies

7. Quantitative Study • ClinicalTrials.gov • U.S. industry-sponsored Phase IV studies • Exclusion criteria

8. 555 Studies 5 452 98 Enrollment limited to pregnant women Potentially include Appropriately excluded* 301 Excluded 149 Unknown 2 Not Excluded Confirmed criteria = 368 studies Total excluding = 347 (94%) Total not excluding = 21 (6%) 84 No Response 65 Responded 19 Not Excluded 46 Excluded * Pregnant women were excluded because the drug was in FDA Category D or X, or the age or topic (menopause, contraception, lactation) prohibited pregnancy. Quantitative Study Results

9. Key Informant interviews: Pharma companies Big Pharma……………5 Biotech…………….......3 Industry attorneys………..3 IRBs……………………….3 PhRMA association……...1 FDA………………………..1 (N = 16) Qualitative Study

10. Qualitative Study Results

11. Problem Awareness of the issue as a problem Politics Influence within company, within industry, within country Plan for Change: Problem Policies Propose potential solutions for consideration and debate

12. Solution: Communicate the extent of pregnant women’s exclusion from clinical research and why this is a problem Increase awareness of the 'issue as a problem' among individuals in industry, IRBs, and industry associations Intervention: Publication on quantitative results in peer-reviewed scientific literature White Paper distribution to industry associations (PhRMA and BIO), to key informants, and to colleagues in the industry Plan for Change in Problem Stream

13. Problem Awareness of the issue as a problem Politics Influence within company, within industry, within country Plan for Change: Policies Policies Propose potential solutions for consideration and debate

14. Solution: Provision of potential solutions for industry consideration in guidance responses & internal policies Industry perspective included in discussion of the issue Provision of potential solutions for Merck's draft response Intervention: White Paper to FDA, PhRMA, BIO, and pharmaceutical and biotech companies (via key informants) Present study findings at FDA hearing, if applicable Participate in drafting response to FDA’s call for comment Plan for Change in Policy Stream

15. Problem Awareness of the issue as a problem Politics Influence within company, within industry, within country Plan for Change: Politics Policies Propose potential solutions for consideration and debate

16. Solution: Personal influence on internal deliberations on issue Issue remains in public and professional consciousness; Continued advocacy for increased evidence-based treatment for pregnant women Intervention: Continue involvement in issue Continue involvement in other industry and non-industry organizations Additional publications and presentations provide information for advocates to influence legislators, legislation Plan for Change in Political Stream

17. Impact of Deliverables

18. The purpose of this study was to: • Quantify the problem and • Isolate and barriers to and opportunities for change • In order to influence policy • That will improve maternal health

19. Questions?

20. REFERENCES • [i]Daniel I et al. Magnitude of maternal morbidity during labor and delivery: United States, 1993-1997. American Journal of Public Health 2003; 93(4):631-4. • [ii] Heron M et al. Deaths: Final data for 2006, National Vital Statistics Reports 2009; 57(14):116, available at http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_14.pdf. • [iii] Andrade SE et al. Prescription drug use in pregnancy. American Journal of Obstetrics and Gynecology 2004; 191:398-407. • [iv] Glover DD et al., Prescription, over-the-counter, and herbal medicine use in a rural obstetric population. American Journal of Obstetrics & Gynecology 2003; 188:1039-1041. • [v] Lo WY & Friedman JM. Teratogenicity of recently introduced medication in human pregnancy. Obstetrics & Gynecology 2002; 100:465-473.

21. Back-up Slides

22. Has this been done before? • Precedent: • Pediatric Exclusivity Provision, FDAMA (1997) • Best Pharmaceuticals for Children Act (2002) • Pediatric Research Equity Act (2003) • Results: • increase in pediatric drug testing • changes in labeling regarding dosing and pk, safety, lack of efficacy, etc.

23. How will study results promote a Plan for Change? Leadership is a “process of influencing others to understand and agree about what needs to be done and how to do it, and the process of facilitating individual and collective efforts to accomplish shared objectives.” Gary Yukl, 2006

24. Ethics • Arguments for and against inclusion • Beneficence/Non-maleficence • Justice • Autonomy/Respect • Ethic of Care • Stakeholder theory

25. Public Health Advocacy • Every public health decision is a political decision. • Public health historically fails to close the sale with policy-makers and politicians. • Public health officials tend to be scientists at heart with an innate aversion to politics. • We must leverage status as public health leaders to get the political system working for public health - and not against it. Risa Lavizzo-Mourey, President and CEO, RWJF 2008

26. Limitations: Qualitative • Limited to U.S. Phase IV clinical trials – not generalizable ex-US. • Phase IV is proxy for Phase II and III trials because I cannot evaluate if it would be appropriate for pregnant women to be included in Phase II or III studies from the data source or in the public domain. • Some of the inclusion and exclusion criteria listed may not mention pregnancy or pregnancy potential. Cannot assume that if pregnancy is not mentioned as an exclusion criterion then pregnant women can be included as study subjects. In order to validate the initial findings, any protocols that do not mention pregnancy or pregnancy prevention per se will be contacted. • However, this still may not address de facto exclusion, i.e. the "inadvertent" failure to recruit pregnant women.

27. Limitations: Qualitative • Participants interviewed may or may not represent the perspectives of other companies and organizations or a consensus on the subject. • In telephone interviews physical proximity, visual clues such as body language and facial expressions are lost. • Convenience sample based on my contacts in the industry and related organizations. Most, but not all, participants will be known to have worked on pregnancy-related issues which will improve their ability to discuss the issue in depth but this may introduce bias as they may not represent the thinking of the industry at large. • In the interview data analysis, findings could be subject to other interpretations that may differ from my interpretation. Using evidence from inside and outside industry will add to the validity of the findings by using triangulation –to see if similar themes are identified. • As someone with background in women's health, I bring knowledge but also certain biases to this study. I acknowledge that I agree with proponents who seek a more rational and inclusive policy toward pregnant women in research studies. And I acknowledge that, while I will strive to maintain objectivity in the data collection and analysis, my biases may influence my findings.