SUGGESTED CITATION The Ethics Working Group on ZIKV Research & Pregnancy. Pregnant Women & the Zika Virus Vaccine Research Agenda: Ethics Guidance on Priorities, Inclusion, and Evidence Generation. Baltimore, MD: June 2017. *Corresponding Author: Carleigh Krubiner ([email protected]) This work was supported by the Wellcome Trust [203160/Z/16/Z] TABLE OF CONTENTS Acknowledgments i Executive Summary 1 Introduction 9 Background 11 Zika Virus and Congenital Zika Syndrome: The Need for a Vaccine 11 The State of Vaccine Development 12 Pregnant Women, Vaccines, & the Biomedical Research Agenda 14 Maternal Immunizations 14 The Evidence Gap for Pregnant Women 15 Ethical Principles for Pregnant Women and Biomedical Research 17 Recommendations 22 Imperative I: Vaccines Acceptable for Use in Pregnancy 22 Imperative II: Timely Collection of Data 34 Imperative III: Fair Access to Trials 58 Appendix A: Working Group Members 66 Appendix B: Consultation Strategy 68 Appendix C: GFBR Satellite Consultation Meeting 70 Appendix D: Zika Virus State of the Science and Epidemic 72 References 80 ACKNOWLEDGMENTS The development of this guidance was led by Ruth Faden, Carleigh Krubiner, Anne Lyerly, and Margaret Little. We are grateful to all our colleagues on the Ethics Working Group on ZIKV Research & Pregnancy for their significant contributions to the development and drafting of this guidance: Allison August, Richard Beigi, Anna Durbin, Ruth Karron, Nancy Kass, Florencia Luna, Ricardo Palacios, Alexander Precioso, Carla Saenz, Jeanne Sheffield, and Beatriz da Costa Thome. This guidance is truly a product of our Working Group, reflective of its diverse expertise and shared commitments. This guidance benefitted from the comments and input from a wide range of experts who participated in individual or group consultations with members of the Working Group. These discussions provided us with invaluable insights that critically shaped the content the guidance and helped ensure our recommendations accounted for the most-up-date evidence. We are thankful to all of the individuals who shared their time and expertise to advance this guidance, among them: Derrick Aarons, Jon Abramson, Francoise Baylis, Nathalie Broutet, Severine Caluwaerts, Alejandro Cravioto, Sarah Despres, Debora Diniz, Titus Divala, Kimberly B. Fortner, Bruce Gellin, Ilona Telefus Goldfarb, Barney Graham, Akira Homma, Sofia Salas Ibarra, Mary Kasule, Maureen Kelley, Ruth Macklin, Reinaldo de Menezes Martins, María de Jesús Medina- Arellano, Ajoke Sobanjo-ter Meulen, Joseph Millum, Kayvon Modjarrad, Thomas P. Monath, Kaitlyn Morabito, Flor Muñoz, Agueda Muñoz del Carpio Toia, Lisa Noguchi, David O'Connor, Gloria Palma, Ludovic Reveiz, Laura E. Riley, Jeff Roberts, Philip K. Russell, Sithembile Ruzario, Xochitl Sandoval, Sergio Surugi de Siqueira, Elizabeth Stringer, Geeta Swamy, Douglas Wassenaar, and Heather Watts. We would also like to thank Gail Javitt for reviewing sections of the guidance that relate to FDA regulatory issues. We are incredibly appreciative of our project team members and staff, who provided tremendous research and administrative support from the earliest stages of the project to the final draft of the guidance. Special thanks to Elana Jaffe and Marisha Wickremsinhe who dedicated countless hours combing through the literature, organizing consultation calls and meetings, orchestrating Working Group meetings, and working with the team through multiple iterations of the guidance, among many other inputs that are too numerous to name. Additional thanks to Haley Swartz, Sappho Gilbert, Kristen Sullivan, and the communications and administrative teams at Johns Hopkins University, the University of North Carolina, and Georgetown University who supported this work. In particular, we want to acknowledge Kelly Heuer, who designed the beautiful layout of this report, and Nico Staple, who transformed the text into an interactive web interface to engage audiences in new and creative ways. This work would not have been possible without the financial support from the Wellcome Trust. We are grateful to Dan O’Connor, Katherine Littler, and João Rangel de Almeida for their support of our work and to Dan and Katherine for their substantive and technical feedback at various stages of the project. We also want to express our thanks to Jeremy Farrar for his enthusiasm for and interest in our work, and for his counsel. Pregnant Women and the Zika Virus Vaccine Agenda Acknowledgements | p. i EXECUTIVE SUMMARY Introduction The rapid spread of the Zika virus (ZIKV) has galvanized the global public health community toward development of ZIKV vaccines. The most dire consequence of ZIKV infection, congenital Zika syndrome (CZS), is a result of infection during pregnancy. As a consequence, pregnant women figure prominently in global concerns about ZIKV. They should also figure prominently in ZIKV vaccine development, but the way forward is not well established. Historically, the needs of pregnant women have not been adequately represented in the development of biomedical interventions, including vaccines. New products are rarely designed with the specific needs of pregnant women in mind, and for many interventions evidence about safety and efficacy in pregnancy is limited and late in coming. Investigators have also been reticent to conduct interventional biomedical research with pregnant women. There are many causes for this reticence, including misinterpretations or overly cautious interpretations of what is allowed under research regulations and international norms, as well as concerns about legal liability. Moreover, biomedical research with pregnant women is ethically complicated. Assessments of risk and prospect for benefit must take into account the interests of both the pregnant woman and the fetus, which are usually but not always aligned. In the case of ZIKV, the interests of pregnant women and their offspring do align. Pregnant women have the deepest interest in the health of their babies, and will suffer along with their children if CZS is not averted. Nevertheless, significant questions remain about what specifically is required to ensure that these interests are adequately protected and fairly taken into account in ZIKV vaccine research and development (R&D). Guidance is also needed on the conditions under which is it ethically acceptable, if not required, to include pregnant women in ZIKV vaccine trials. These questions are of particular urgency as the pace of vaccine development accelerates and threats to pregnant women and their offspring from new outbreaks continue. The Ethics Working Group on ZIKV Research & Pregnancy To address these questions, we received funding from the Wellcome Trust to form the Ethics Working Group on ZIKV Research & Pregnancy. Our fifteen-member Working Group is comprised of experts in bioethics, public health, philosophy, pediatrics, obstetrics and maternal–fetal medicine, vaccine research, and maternal immunization, including five colleagues from Latin America. Pregnant Women and the Zika Virus Vaccine Agenda Executive Summary | p. 1 To ensure that our recommendations were grounded in the most up-to-date state of the science and public health response to ZIKV, we conducted consultations with over 60 leading experts in vaccine science and immunology, flaviviruses and general virology, clinical trial design, public health and emergency preparedness, obstetrics and maternal– fetal medicine, pediatrics, infectious diseases, research ethics, and legislative and regulatory affairs concerning vaccines and biologics. These consultations were supplemented with extensive reviews of the scientific literature and academic research on international ethics guidance and regulations regarding research with pregnant women, and historical analyses exploring concepts of risk perception. Our guidance applies to the current situation of continuing ZIKV outbreaks with limited effective prevention modalities and no existing vaccine approved for use, as well as to any future scenarios in which critical evidence gaps remain on the safety and efficacy of ZIKV vaccines in pregnancy. We focus on research and development efforts for ZIKV vaccines intended for use in the context of ZIKV outbreaks. This focus coheres with that of the Target Product Profile of the World Health Organization (WHO) to coordinate research efforts and set priorities for ZIKV vaccine development. Furthermore, ZIKV vaccines meant for use in the context of an outbreak are the ones that will be most needed for use in pregnancy to prevent the imminent risks of congenital ZIKV exposure. The guidance outlines three moral imperatives: (1) to develop a ZIKV vaccine that can be responsibly and effectively used during pregnancy, (2) to collect data specific to safety and immunogenicity in pregnancy for all ZIKV vaccine candidates to which pregnant women may be exposed, and (3) to ensure pregnant women have fair access to participate in ZIKV vaccine trials that offer a reasonably favorable ratio of research-related risks to potential benefits. From these imperatives, the guidance specifies concrete recommendations for how a range of relevant actors can ensure ethical inclusion of pregnant women’s interests at various stages in ZIKV vaccine research and development and across the product lifecycle. RECOMMENDATIONS I M P E R AT I V E I The global research and public health community should pursue and prioritize development of ZIKV vaccines that will be acceptable for use by pregnant women in the context of an outbreak. Significant efforts are currently underway to develop ZIKV vaccines with the primary objective of preventing congenital Zika syndrome (CZS). Not every ZIKV vaccine candidate under development needs to be acceptable or suitable for use in pregnancy. Pregnant Women and the Zika Virus Vaccine Agenda Executive Summary | p. 2 However, the strategy of developing a vaccine targeted to women of childbearing potential (WOCBP) before they become pregnant, while critically important, will not be sufficient to effectively and equitably prevent the harms of CZS. Previous experience with immunization programs underscores that not all women will be immunized ahead of pregnancy, leaving them and their offspring unprotected from CZS. Moreover, evidence demonstrating that the risks associated with congenital ZIKV infection persist into the second and third trimesters negates concerns that a ZIKV vaccine would only offer benefit if administered early in or ahead of pregnancy. By acceptable for use in pregnancy we mean that relevant advisory bodies, public health practitioners, and policymakers could support the use of such a vaccine by pregnant women in an outbreak setting based on the expected benefits associated with the vaccine and its safety profile. Recommendation 1. Pregnant women should be affirmed as a priority population for ZIKV vaccines intended for use in areas experiencing ongoing transmission and in future outbreaks. ‣ DIRECTED TO relevant global and national health organizations, policymakers, funders, and other entities who are shaping the ZIKV vaccine research agenda. Recommendation 2. Financial and other in-kind resources should be allocated to fund and facilitate development of ZIKV vaccines that will be acceptable for use in pregnancy. ‣ DIRECTED TO relevant global and national health organizations, policymakers, sponsors, funders, and research institutions in a position to contribute resources, financial or otherwise. Recommendation 3. Available and appropriate incentive mechanisms should be identified and leveraged to support development of ZIKV vaccines that will be acceptable for use pregnancy. Strategies to mitigate disincentives that would impede such development should be pursued. ‣ DIRECTED TO relevant policymakers, regulatory authorities, vaccine advisory committees, sponsors, and funders that oversee and/or administer programs that create incentives or mitigate disincentives that may influence product development decisions and strategies. Pregnant Women and the Zika Virus Vaccine Agenda Executive Summary | p. 3 I M P E R AT I V E I I The development of all ZIKV vaccines targeted to women of childbearing potential, whether expected to be acceptable for use in pregnancy or not, should include timely collection of data to inform judgments about safety and efficacy of administration in pregnancy. Two important sets of considerations stand behind this imperative: [1] Failure to gather appropriate and timely data about vaccine use in pregnancy can significantly delay or deny pregnant women and their offspring the potential benefits of safe and effective vaccines, and [2] Inadequate data on vaccines to which pregnant may be inadvertently exposed can lead to unnecessary harms in the event of unintentional administration. Without appropriate data, public health officials, providers, and pregnant women will be unable to make informed decisions about the responsible use of ZIKV vaccines in pregnancy and the responsible management of unintentional exposures to ZIKV vaccines in pregnancy. For ZIKV vaccine candidates under development that are anticipated to be acceptable for use in pregnancy in public health programs and clinical settings: Recommendation 4. Clinical development plans should include timely collection of data on key indicators and outcomes of safety and efficacy of administration in pregnancy, including data collected from a cohort of pregnant study participants (and their offspring) who are enrolled in clinical trials at the same time as other general population study groups. ‣ DIRECTED TO vaccine developers, sponsors, oversight bodies, and regulatory authorities. For all authorized ZIKV vaccines deemed acceptable for use in pregnancy: Recommendation 5. To further develop the evidence base on the safety and efficacy of administering these vaccines in pregnancy, prospective studies should be conducted with pregnant women who receive the vaccine in public health and clinical settings to systematically collect data from them and their offspring. ‣ DIRECTED TO public health agencies, manufacturers, and researchers. Where applicable, regulatory authorities should utilize available, enforceable mechanisms to require post-authorization research and pharmacovigilance plans for pregnant women and their offspring. Pregnant Women and the Zika Virus Vaccine Agenda Executive Summary | p. 4 For ZIKV vaccine candidates under development that are not anticipated to be acceptable for use in pregnancy but are targeted to women of childbearing potential: Recommendation 6. Clinical development plans should include systematic collection of relevant indicators and outcomes of safety and efficacy of administration in pregnancy from all instances in which women participating in trials are unknowingly pregnant at the time of exposure or become pregnant within a relevant window of vaccine administration. ‣ DIRECTED TO vaccine developers, sponsors, oversight bodies, and regulatory authorities. For ZIKV vaccines authorized for use in public health programs, outbreak responses, or other non-research contexts that are not deemed acceptable for use in pregnancy at the time of authorization: Recommendation 7. Inadvertent administration of vaccines to pregnant women in public health and clinical settings should be anticipated, and mechanisms should be in place for the systematic collection and analysis of data from them and their offspring on relevant indicators and outcomes of safety and efficacy in pregnancy. ‣ DIRECTED TO public health agencies, manufacturers, and researchers. Where applicable, regulatory authorities should utilize available, enforceable mechanisms to require such systems and post-authorization study. FIGURE ES.1 | SUMMARY OF RECOMMENDATIONS 4–7 *WOCBP: Women of childbearing potential . Pregnant Women and the Zika Virus Vaccine Agenda Executive Summary | p. 5