Research Study:

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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

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Problem

Millenium Development Goal #5:Reduce Maternal Mortality

1.7 Million Pregnant Women

600,000 have complications

> 1 million are prescribed drugs

2 die every day

See References slide

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Problem

80%

See References slide

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Policy Window Opens

FDA Draft Guidance:

Pregnant Women in Clinical Trials: Scientific and Ethical

Considerations

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Policy Window Theory of Change

Kingdon: Agendas, Alternatives, and Public Policies

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Kingdon recommends:

Indicators of the existence and magnitude of issue

Promotion of constituent feedback

Kingdon: Agendas, Alternatives, and Public Policies

Quantitative methodology

Qualitative methodology

Special studies of the issue

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Quantitative Study

ClinicalTrials.govU.S. industry-sponsored Phase IV studiesExclusion criteria

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Quantitative Study Results555

Studies

Potentially include

Appropriately excluded*

84 No Response

65Responded

46Excluded

301 Excluded

19Not

Excluded

452 98

2Not

Excluded 149

UnknownConfirmed criteria = 368 studies

Total excluding = 347 (94%)

Total not excluding = 21 (6%)

* Pregnant women were excluded because the drug was in FDA Category D or X, or the age or topic (menopause, contraception, lactation) prohibited pregnancy.

Enrollment limited to pregnant women

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Qualitative Study

Key Informant interviews: Pharma companies

Big Pharma……………5Biotech…………….......3

Industry attorneys………..3 IRBs……………………….3 PhRMA association……...1 FDA………………………..1

(N = 16)

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Qualitative Study Results

Key Concerns Key Potential SolutionsCausing harm to the fetus;

scientific concernsStudy design; scientific advances in modeling and

animal testing; Phase III & post-marketing studies

LitigationGuidance/regulation; informed consent; indemnifica-

tion; improved awareness of issue in public domain

Enrollment concernsPk testing on small numbers; partnerships with

OPRU /obstetrical community, data from multiple sources

Impact on initial approval Post-approval studies

Lack of regulatory agency support, regulations

FDA guidance document, international harmonization

Business concernsDefine market; conduct post-approval studies; devise

incentives and protections

Lack of experience Collaboration, best practices, innovation, science

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Plan for Change: Problem

Problem

Awareness of the issue as a

problem

Politics

Influence within

company, within

industry, within country

Policies

Propose potential

solutions for consideration and debate

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Plan for Change in Problem Stream

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

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Plan for Change: Policies

Problem

Awareness of the issue as a

problem

Politics

Influence within

company, within

industry, within country

Policies

Propose potential

solutions for consideration and debate

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Plan for Change in Policy Stream

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

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Plan for Change: Politics

Problem

Awareness of the issue as a

problem

Politics

Influence within

company, within

industry, within country

Policies

Propose potential

solutions for consideration and debate

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Plan for Change in Political Stream

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

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Impact of Deliverables

Problem Stream

Policy Stream

Political Stream

Publica-tion(s)

√ √

White Paper

√ √ √

Presenta-tions

√ √

Involve-ment

√ √ √

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The purpose of this study was to:

1. Quantify the problem and

2. Isolate and barriers to and opportunities for change

3. In order to influence policy

4. That will improve maternal health

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Questions?

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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.

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Back-up Slides

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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.

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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

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Ethics

Arguments for and against inclusionBeneficence/Non-maleficenceJusticeAutonomy/RespectEthic of CareStakeholder theory

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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

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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.

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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.