Context

Despite a significant reduction in maternal mortality over the last 30 years, global progress has stalled. Almost 300,000 women died as a result of pregnancy or childbirth in 2017.[1] Most of these deaths were preventable, and the vast majority occurred in low-and middle-income countries (LMICs). Given the current burden and slowing progress, maternal mortality targets set for the Sustainable Development Goals will not be reached on the current trajectory. A coordinated, integrated effort, with emphasis on expanded access to innovative health interventions, including new, lifesaving commodities, is needed to reach the 2030 targets and address the unacceptably high number of global maternal deaths.

The most common direct cause of maternal morbidity and death is PPH (excessive bleeding after birth), which is responsible for 20% of all maternal mortality.[2] Accelerated adoption and scale-up of tools to reduce maternal morbidity and mortality from PPH represents a near-term opportunity that would support efforts to progress toward targets in high burden countries.

Most cases of PPH are avoidable with appropriate tools. For prevention, WHO recommends the use of an effective uterotonic during the third stage of labor.[3] Studies suggest that for every 12 women who receive active management of third stage of labor, one case of PPH is averted.[4] Use of prophylactic uterotonics is critical to reducing the PPH burden; however, access barriers prevent uptake in many LMICs.

A key barrier lies in the quality of available uterotonics. Oxytocin, the recommended first-line drug for PPH prevention and treatment, requires cold-chain storage to remain effective. Given the challenges in ensuring cold-chain storage in many LMICs, it is often of poor quality. Oxytocin quality also suffers from manufacturing deficiencies, and poor regulatory oversight and procurement practices. In a WHO field test of essential medicines for women and children, 64% of oxytocin samples were non-compliant.[5] When cold-chain cannot be assured, misoprostol, a heat stable alternative is often used. However, like oxytocin, quality issues with misoprostol have also been documented.[6] Compromised product quality can occur at multiple stages along the complex drug supply chain, but monitoring is difficult given limited rapid screening tools that can analyze quality prior to administration.[7]

An additional challenge with oxytocin is that it is recommended for use only in the presence of a skilled birth attendant, as the drug needs to be administered through intravenous or intramuscular injection. Childbirth with a skilled birth attendant remains low in sub-Saharan Africa, restricting access for many women in the region.[8] Misoprostol is available in tablet form, and is recommended by the WHO when delivering outside of a health facility and without a skilled birth attendant, and most recently for distribution during antenatal care contacts for self-administration (with targeted monitoring and evaluation).[9] This recommendation is yet to be scaled.

When prevention is not effective, tranexamic acid is recommended by the WHO for management of all PPH cases as part of the standard PPH treatment package. Tranexamic acid is an old drug, but its recommendation for PPH is recent.[10] As a result, awareness and knowledge for this indication is limited, and uptake remains low. Furthermore, tranexamic acid requires an intravenous injection for administration, limiting its potential for use in many LMICs.

New drugs that respond to the access barriers to the current PPH standards-of-care are becoming available. For example, heat-stable carbetocin – a PPH preventive that does not require cold chain storage – is in early registration stage, and introduction efforts are underway in a few early adopter countries. In addition, new non-injectable, heat-stable formulations of oxytocin are in development. Efforts are also underway to evaluate non-injectable forms of tranexamic acid (e.g. oral, inhalable). These new drug formulations and delivery methods have the potential to overcome delivery barriers and expand access to the community level.

[1] WHO (2019) Trends in maternal mortality 2000 to 2017: estimates by WHO, UNICEF, UNFPA, World Bank Group, and the United Nations Population Division. Geneva: WHO.

[2] Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels JD, et al. Global Causes of Maternal Death: A WHO Systematic Analysis. Lancet Global Health. 2014;2(6): e323-e333.

[3] WHO (2018) WHO recommendations: uterotonics for the prevention of postpartum haemorrhage. Geneva: World Health Organization.

[4] USAID (2007). Prevention of Postpartum Hemorrhage: Implementing Active Management of the Third Stage of Labor (AMTSL) (Report – online). Available at: https://path.azureedge.net/media/documents/MCHN_popphi_amtsl_ref_man_1of3.pdf.

[5] WHO (2016). Survey of the Quality of Medicines Identified by the Commission on Life Saving Commodities for Women and Children (Online) Available at: https://apps.who.int/iris/bitstream/handle/10665/255550/9789241511117-eng.pdf.

[6] Torloni MR, Bonet M, Betrán AP, Ribeiro-do-Valle CC, Widmer M (2020) Quality of medicines for life-threatening pregnancy complications in low- and middle-income countries: A systematic review. PLoS ONE 15(7): e0236060.

[7] Lambert, P., McIntosh, M.P., Widmer, M., Evans, L., Rauscher, M., et al. (2020). Oxytocin quality: evidence to support updated global recommendations on oxytocin for postpartum hemorrhage. J of Pharm Policy and Pract 13, 14

[8] WHO (2020). Sexual and Reproductive Health – Skilled Birth Attendants. Online. Available at: https://www.who.int/reproductivehealth/topics/mdgs/skilled_birth_attendant/en/.

[9] WHO (2020) WHO recommendation on advance misoprostol distribution to pregnant women for prevention of postpartum haemorrhage. Geneva: World Health Organization

[10] WHO (2017). WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage. Geneva: World Health Organization.

Call scope

Under this Call, Unitaid is soliciting proposals for the following interventions aimed at accelerating the adoption and scale-up of innovations to reduce maternal mortality from PPH:

Catalyze early adoption of new and recently recommended drugs for PPH in high-burden countries

Unitaid is soliciting proposals to accelerate the introduction of drugs for PPH that have recently become available (e.g. heat-stable carbetocin) and/or have recently been recommended for PPH (e.g. tranexamic acid, community delivery of misoprostol). Projects should address key barriers that span across policy adoption and dissemination, procurement and supply, and service delivery. In particular, proposals should include a strong focus on demand generation for policy-makers, providers and patients, and should demonstrate close engagement with community and civil society organizations. These projects should also include implementation pilots that demonstrate the impact, cost-effectiveness and operational feasibility of delivery at scale as a means of supporting onwards scale-up.  Activities could also include support for new drugs through early adoption stage-gates, such as country registration, or through studies to validate appropriate packaging, delivery, and training strategies. To maximize impact, implementation models should include delivery at the lowest-level health facilities where use is recommended, and should be transferrable to other high-burden PPH settings to enable scale-up potential in non-project countries.

New and newly recommended PPH drugs will need to be adopted as part of an integrated package of PPH care. Proposals should therefore clearly indicate how the proposed activities will integrate with existing programmes and planned efforts to support a holistic approach to PPH care. While the core focus of proposals should be on positioning new and recently recommended drugs for scale-up, Unitaid will also consider limited ancillary efforts that support increased access to other PPH tools provided there is a clear pathway to scale and commitment from local stakeholders. For example, this could include innovative approaches that address quality issues in currently available drugs (e.g. affordable, low-tech tools to identify low-quality PPH drugs, such as paper-based tests and integrated time temperature indicators).

Proposals should demonstrate how proposed projects will leverage and synergize with other initiatives that are implementing new PPH prevention and treatment approaches. Pilot activities should also demonstrate close engagement with national programmes and other national and regional partners to ensure an enabling environment for sustainability and ownership beyond the life of the project. Emphasis should be placed on translating the outputs of the pilots into activities that will support transition and broader scale-up in project countries and beyond. This should not be limited to the final stages of the project but should aim to ensure strong national commitment to product adoption and meaningful community engagement from the onset. As part of the broader sustainability objective, opportunities for co-funding of pilot implementation activities should be actively explored.

Late-stage development of new drug formulations and/or drug delivery methods

This Call is also soliciting proposals to accelerate the development of new drug formulations and/or drug delivery methods for the prevention and treatment of PPH. Proposed products should aim to address the key limitations of currently available PPH drugs, such as injectable administration. New products should be suited to delivery at low levels of the health system, ideally at community level.

Support for late-stage development can include larger clinical efficacy studies, safety and cost effectiveness studies, and/or comparative studies with clinical standards-of-care. It can also include the development of a commercialization plan considering market size, market sustainability, product prices, and potential use cases; as well as an analysis of demand- and supply-side barriers to introduction (e.g. health worker acceptability assessments), and regulatory and distribution pathways.

Proponents should clearly describe the advantages of the proposed product and its current stage of development; study results to date; future development plans; regulatory pathway; commercialization and manufacturing strategies; and plans to ensure broad access in LMICs.

Applicants are encouraged to consider products that can be introduced in the market within three to five years (i.e. products that could be eligible for purchase by major funders and countries, and supply capacity created to address demand sufficiently within this timeframe), and Unitaid expects that new products should have the potential to be scalable for broad accessibility in LMICs.

Applicants can submit proposals for one or both of the intervention areas outlined above.

Topics which are out of scope for this Call include: basic and early-stage research, development of new chemical entities, single-country interventions and small-scale research studies.

Process for proposal submission

When developing a proposal, please note the following resources:

• Answers to frequently asked questions relevant to proposal development (this document is regularly updated) click here [PDF: 560 KB];

Proposals should clearly demonstrate the use of innovative and sustainable approaches to accelerating uptake of drugs for PPH. Applicants should be clear about the underlying assumptions made in their proposed approach and should highlight any major risks or other factors that may affect the delivery of results. Finally, proposals are expected to outline a lean, concrete and clear pathway to results and impact.

After assessment of the proposals and endorsement by the Unitaid Board all applicants will be officially notified as to whether they will be invited to develop a full grant agreement for Unitaid funding.

Successful applicants should plan to be available for a kick-off meeting with Unitaid (in Geneva, if possible) in early Q3 2021 (exact date TBC). In addition, successful applicants should plan to have sufficient human resources available to advance a first draft of the project plan by Q3 2021.

Important dates

Submission and format of proposals

Proposals, including all annexes, should be submitted electronically to proposalsUnitaid@who.int. A full proposal consists of the following documents:

• Proposal form with scanned version of signed Front page template, [DOC: 170 KB]
• Annex 1: Log frame and GANTT chart template, [XLS: 278 KB]
• Annex 2: Budget details template, [XLS: 24 KB]
• Annex 3: Organizational details and CVs of key team members [no template]
• Annex 4: Country engagement support Letters [no template]
• Annex 5: Declaration of relevant interest template, [DOC: 21 KB]
• Annex 6: Applicable ethics, anti-discrimination and environmental policies template, [DOC: 21 KB]
• Annex 7: Declaration regarding tobacco entities template, [DOC: 24 KB]
• Annex 8: Anti-Terrorism Declaration template, [DOC: 30 KB]
• Annex 9: Audited financial statements for the past 3 years [no template]
• Guidance on Impact Assessment [PDF: 160 KB]
• Financial Guidelines for Unitaid Grantees [PDF: 1,2 MB]
• Unitaid Results Framework [PDF: 2 MB]
• Unitaid Scalability Framework [PDF: 232 KB]

If you have any questions about the application processes throughout any stage of the application review process, please send your queries to the Grant Application Manager:  proposalsUnitaid@who.int

You will find further guidance in the Unitaid proposal process document [PDF: 530 KB].

Webinar on this Call for Proposals: