Application of exposure bracketing to streamline the development of contraceptive products.

Developing new long-acting products of well-characterized contraceptive drugs is one way to address some of the reasons for unmet need for modern methods of family planning among women in low- and middle-income countries. Development and approval of such products traditionally follow a conventional paradigm that includes large Phase 3 clinical trials to evaluate efficacy (pregnancy prevention) and safety of the investigational product. Exposure-bracketing is a concept that applies known pharmacokinetics and pharmacodynamics of a drug substance to inform its safe and efficacious use in humans. Several therapeutic areas have applied this concept by leveraging established drug concentration-response relationships for approved products to expedite development and shorten the timeline for the approval of an investigational product containing the same drug substance. Based on discussions at a workshop hosted by the Bill & Melinda Gates Foundation in December 2020, it appears feasible to apply exposure-bracketing to develop novel contraceptive products using well-characterized drugs.

Regulation of genetically engineered (GE) mosquitoes as a public health tool: a public health ethics analysis.

BACKGROUND: In recent years, genetically engineered (GE) mosquitoes have been proposed as a public health measure against the high incidence of mosquito-borne diseases among the poor in regions of the global South. While uncertainties as well as risks for humans and ecosystems are entailed by the open-release of GE mosquitoes, a powerful global health governance non-state organization is funding the development of and advocating the use of those bio-technologies as public health tools. In August 2016, the US Food and Drug Agency (FDA) approved the uncaged field trial of a GE Aedes aegypti mosquito in Key Haven, Florida. The FDA's decision was based on its assessment of the risks of the proposed experimental public health research project. The FDA is considered a global regulatory standard setter. So, its approval of the uncaged field trial could be used by proponents of GE mosquitoes to urge countries in the global South to permit the use of those bio-technologies. METHOD: From a public health ethics perspective, this paper evaluates the FDA's 2016 risk assessment of the proposed uncaged field trial of the GE mosquito to determine whether it qualified as a realistic risk evaluation. RESULTS: The FDA's risk assessment of the proposed uncaged field trial did not proximate the conditions under which the GE mosquitoes would be used in regions of the global South where there is a high prevalence of mosquito-borne diseases. CONCLUSION: Given that health and disease have political-economic determinants, whether a risk assessment of a product is realistic or not particularly matters with respect to interventions meant for public health problems that disproportionately impact socio-economically marginalized populations. If ineffective public health interventions are adopted based on risk evaluations that do not closely mirror the conditions under which those products would actually be used, there could be public health and ethical costs for those populations.

The one health landscape in Sub-Saharan African countries.

OBJECTIVES: One Health is transiting from multidisciplinary to transdisciplinary concepts and its viewpoints should move from 'proxy for zoonoses', to include other topics (climate change, nutrition and food safety, policy and planning, welfare and well-being, antimicrobial resistance (AMR), vector-borne diseases, toxicosis and pesticides issues) and thematic fields (social sciences, geography and economics). This work was conducted to map the One Health landscape in Africa. METHODS: An assessment of existing One Health initiatives in Sub-Saharan African (SSA) countries was conducted among selected stakeholders using a multi-method approach. Strengths, weaknesses, opportunities and threats to One Health initiatives were identified, and their influence, interest and impacts were semi-quantitatively evaluated using literature reviews, questionnaire survey and statistical analysis. RESULTS: One Health Networks and identified initiatives were spatiotemporally spread across SSA and identified stakeholders were classified into four quadrants. It was observed that imbalance in stakeholders' representations led to hesitation in buying-in into One Health approach by stakeholders who are outside the main networks like stakeholders from the policy, budgeting, geography and sometimes, the environment sectors. CONCLUSION: Inclusion of theory of change, monitoring and evaluation frameworks, and tools for standardized evaluation of One Health policies are needed for a sustained future of One Health and future engagements should be outputs- and outcomes-driven and not activity-driven. National roadmaps for One Health implementation and institutionalization are necessary, and proofs of concepts in One Health should be validated and scaled-up. Dependence on external funding is unsustainable and must be addressed in the medium to long-term. Necessary policy and legal instruments to support One Health nationally and sub-nationally should be implemented taking cognizance of contemporary issues like urbanization, endemic poverty and other emerging issues. The utilization of current technologies and One Health approach in addressing the ongoing pandemic of COVID-19 and other emerging diseases are desirable. Finally, One Health implementation should be anticipatory and preemptive, and not reactive in containing disease outbreaks, especially those from the animal sources or the environment before the risk of spillover to human.

Public-private partnering as a modus operandi: Explaining the Gates Foundation's approach to global health governance.

In its first decade, The Bill and Melinda Gates Foundation (BMGF) focused much of its efforts on enabling the establishment of transnational public-private partnerships (PPPs) oriented towards increasing low-income country (LIC) access to essential health technologies. Critics have argued these efforts further enriched already profitable firms which long ignored the needs of populations with limited purchasing power, while lessening political will to invest in urgently needed public sector capacity to produce essential health technologies independently of market pressures. Missing from these critical analyses were the perspectives of those shaping BMGF's global health programming. Drawing on interviews with senior BMGF staff and external affiliates undertaken between 2010 and 2012, this article seeks to address this gap. We argue that BMGF's embrace of PPPs was adopted out of the belief that neither public agencies nor industry were capable of providing LICs with essential health technologies autonomously, and that their conflicting mandates required an honest broker to initiate and sustain collaboration between the two sectors. The Foundation's comparative advantage in global health governance was thus seen by those informing its work, as its capacity to negotiate such partnerships, which we argue has also been the basis of its agenda-setting influence in this domain.

The Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials in Mozambique, Pakistan, and India: an individual participant-level meta-analysis

To overcome the three delays in triage, transport and treatment that underlie adverse pregnancy outcomes, we aimed to reduce all-cause adverse outcomes with community-level interventions targeting women with pregnancy hypertension in three low-income countries. Methods: In this individual participant-level meta-analysis, we de-identified and pooled data from the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised controlled trials in Mozambique, Pakistan, and India, which were run in 2014-17. Consenting pregnant women, aged 12-49 years, were recruited in their homes. Clusters, defined by local administrative units, were randomly assigned (1:1) to intervention or control groups. The control groups continued local standard of care. The intervention comprised community engagement and existing community health worker-led mobile health-supported early detection, initial treatment, and hospital referral of women with hypertension. For this meta-analysis, as for the original studies, the primary outcome was a composite of maternal or perinatal outcome (either maternal, fetal, or neonatal death, or severe morbidity for the mother or baby), assessed by unmasked trial surveillance personnel. For this analysis, we included all consenting participants who were followed up with completed pregnancies at trial end. We analysed the outcome data with multilevel modelling and present data with the summary statistic of adjusted odds ratios (ORs) with 95% CIs (fixed effects for maternal age, parity, maternal education, and random effects for country and cluster). This meta-analysis is registered with PROSPERO, CRD42018102564. Findings: Overall, 44 clusters (69 330 pregnant women) were randomly assigned to intervention (22 clusters [36 008 pregnancies]) or control (22 clusters [33 322 pregnancies]) groups. 32 290 (89·7%) pregnancies in the intervention group and 29 698 (89·1%) in the control group were followed up successfully. Median maternal age of included women was 26 years (IQR 22-30). In the intervention clusters, 6990 group and 16 691 home-based community engagement sessions and 138 347 community health worker-led visits to 20 819 (57·8%) of 36 008 women (of whom 11 095 [53·3%] had a visit every 4 weeks) occurred. Blood pressure and dipstick proteinuria were assessed per protocol. Few women were eligible for methyldopa for severe hypertension (181 [1%] of 20 819) or intramuscular magnesium sulfate for pre-eclampsia (198 [1%]), of whom most accepted treatment (162 [89·5%] of 181 for severe hypertension and 133 [67·2%] of 198 for pre-eclampsia). 1255 (6%) were referred to a comprehensive emergency obstetric care facility, of whom 864 (82%) accepted the referral. The primary outcome was similar in the intervention (7871 [24%] of 32 290 pregnancies) and control clusters (6516 [22%] of 29 698; adjusted OR 1·17, 95% CI 0·90-1·51; p=0·24). No intervention-related serious adverse events occurred, and few adverse effects occurred after in-community...

Shaping markets to benefit global health - A 15-year history and lessons learned from the pentavalent vaccine market.

Market shaping for health products used in lower-income countries strives to benefit public health. As a funder of vaccines, Gavi, The Vaccine Alliance (Gavi) has goals for its market shaping efforts, achieved through a strategy developed and implemented by the Gavi Secretariat, UNICEF, the World Health Organization (WHO) and the Bill & Melinda Gates Foundation (BMGF). A case-study of Gavi's fifteen-year engagement with a vaccine against diphtheria, tetanus, pertussis, hepatitis B and haemophilus influenzae type b (pentavalent) provides evidence of the benefits and potential risks of trying to influence markets. During 2001-18, Gavi disbursed US$3.5 billion to support use of 50 million pentavalent doses annually before 2005, increasing to ∼300 million doses annually by 2016. During this time, eight manufacturers invested in vaccine development and manufacturing and the first two manufacturers have subsequently ceased production. Following its strategy, Gavi implemented coordinated market interventions including technical assistance to manufacturers, improving market information transparency, risk-sharing agreements and innovative procurement aiming to stimulate and capitalize on a competitive market. In 2018 supply allows ∼80 million children per year to be immunised, a sixteen-fold increase from 2005, with vaccine-related costs per child for donors and countries of one-quarter the 2005 level. Lessons learned include the importance of frameworks and strategies; the need to adjust interventions with changing conditions; the important role of manufacturers; and the potentially powerful effects of interconnected markets. This case study is limited by its focus on a single health product in a specific market, however the lessons can inform other market shaping efforts when taken in context. While countries and children have improved vaccine access, risks of financial sustainability and continued manufacturer investment in Gavi vaccine markets are being monitored. Gavi should continue implementing a market shaping strategy, adjust with market conditions and expect and measure unintended consequences.

Balancing science and political economy: Tobacco control and global health.

Background: Global tobacco control is a major public health issue, as smoking-related disease burden remains high worldwide. The World Bank and the World Health Organization (WHO) are the driving forces in global tobacco control. However, little research has focused on their development, financing, decision-making, and accountability structures. Methods: We used two strategies to identify the development and structure of global tobacco control initiatives. First, we reviewed the published literature through electronic databases. Second, we conducted grey literature searching. Results: We identified four periods in the Bank's involvement in global tobacco control, from creation of the evidence base in the 1990s to the implementation of tax reforms. We identified three phases in the WHO's efforts, from its early recognition of the link between tobacco and health risks in the 1970s to its implementation of the Framework Convention on Tobacco Control. Both organisations are financed by a handful of private philanthropies, and face similar risks for effective tobacco control: reduced accountability and resource mobilisation, poor decision-making authority due to specific donor influence, and difficulty in monitoring and evaluation. Conclusions: Continued attention should be paid not only to the primary health-related outcomes of tobacco use, but also to the decision-making and financing structures to promote tobacco control activities.

Geneva-Seattle collaboration in support of developing country vaccine manufacturing.

Vaccines were once produced almost exclusively by state-supported entities. While they remain essential tools for public health protection, the majority of the world's governments have allowed industry to assume responsibility for this function. This is significant because while the international harmonisation of quality assurance standards have effectively increased vaccine safety, they have also reduced the number of developing country vaccine producers, and Northern multinational pharmaceutical companies have shown little interest in offering the range of low-priced products needed in low and middle-income-country contexts. This article examines how public-private collaboration is relevant to contemporary efforts aimed at strengthening developing country manufacturers' capacity to produce high-quality, low-priced vaccines. Specifically, it casts light on the important and largely complimentary roles of the World Health Organization, The Bill and Melinda Gates Foundation, and the Seattle-based non-profit PATH, in this process. The take away message is that external support remains critical to ensuring that developing country vaccine manufacturers have the tools needed to produce for both domestic and global markets, and the United Nations supply chain, and collaboration at the public-private interface is driving organisational innovation focused on meeting these goals.

Private actors, global health and learning the lessons of history.

Private business and philanthropic organizations have played a prominent role in the response to the Ebola outbreak in West Africa and the support of global health governance more broadly. While this involvement may appear to be novel or unprecedented, this article argues that this active role for private actors and philanthropies actually mirrors the historical experience of cross-border health governance in the first half of the twentieth century. By examining the experiences, roles and criticisms of the Rockefeller Foundation's International Health Division and the Bill and Melinda Gates Foundation, it is possible to identify potential opportunities for better cooperation between public and private actors in global health governance.

Power in global health agenda-setting: the role of private funding Comment on "Knowledge, moral claims and the exercise of power in global health".

The editorial by Jeremy Shiffman, "Knowledge, moral claims and the exercise of power in global health", highlights the influence on global health priority-setting of individuals and organizations that do not have a formal political mandate. This sheds light on the way key functions in global health depend on private funding, particularly from the Bill & Melinda Gates Foundation.

Reassembling epidemiology: mapping, monitoring and making-up people in the context of HIV prevention in India.

This paper explores how the Gates-funded HIV Initiative in India, known as Avahan, produces sociality. Drawing upon ethnographic research conducted between 2006 and 2012, we illustrate how epidemiological surveillance procedures, undergirded by contemporary managerial and entrepreneurial logics, entwine with and become transformed by the everyday practices of men who have sex with men (many of whom sell sex). The coevolution of epidemiology and sociality, with respect to these communities, is explored in relation to: 1) how individual identities are reproduced in association with standardized units of space and time; 2) how knowledge of mapping and enumeration data is employed in the making up of group membership boundaries, revealing how collective interests come to cohere around the project of epidemic prevention; and 3) how knowledge of epidemiological surveillance and procedures provides a basis on which groups collectively realize and execute local security strategies. While monitoring and evaluation (M&E) specialists continually track and standardize the identities, behaviours and social spaces of local populations (through various mapping, typologization and random sampling procedures, which treat space and time as predictable variables), community members simultaneously retranslate and reroute these standardizing processes into "the local" through everyday spatial management practices for health protection. These grounded epidemiologies, we argue, point to vital sites in the co-creation of scientific knowledge-where the quotidian practices of sex workers reassemble epidemiology, continually altering the very objects that surveillance experts are tracking. We further argue that attention to these re-workings can help us unravel the tremendous successes that have been claimed under Avahan in terms of HIV infections averted.