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To check the quality of oxytocin and tranexamic acid-two recommended products for prevention and treatment of postpartum hemorrhage (PPH)-used in facilities taking part in an implementation research project to improve PPH diagnosis and management.Between September 2020 and August 2021, oxytocin and tranexamic acid products used in the study facilities in Kenya, Nigeria, South Africa, and Tanzania were collected and transported in cold storage for analysis. Samples were analyzed according to the International (oxytocin) and British Pharmacopeia (tranexamic acid) standards.Of the 17 unique oxytocin products, 33 individual measurements were made. Only six unique products had adequate content and no related substances exceeding the recommended limits. Of 14 tranexamic acid samples, 10 showed adequate content. One product in Kenya and two products in Nigeria from different manufacturers had a high content of related substances, which classified them as substandard.While we were unable to investigate the origin regarding poor manufacturing or poor storage or both, the high number of substandard oxytocin samples is of great concern. Most of the tranexamic acid samples had adequate content but the presence of impurities in multiple products is worrying and requires further study.

Background Access to oxytocin for prevention of postpartum haemorrhage (PPH) in resource-poor settings is limited by the requirement for a consistent cold chain and for a skilled attendant to administer the injection. To overcome these barriers, heat-stable, non-injectable formulations of oxytocin are under development, including oxytocin for inhalation. This study modelled the cost-effectiveness of an inhaled oxytocin product (IHO) in Bangladesh and Ethiopia. Methods A decision analytic model was developed to assess the cost-effectiveness of IHO for the prevention of PPH compared to the standard of care in Bangladesh and Ethiopia. In Bangladesh, introduction of IHO was modelled in all public facilities and home deliveries with or without a skilled attendant. In Ethiopia, IHO was modelled in all public facilities and home deliveries with health extension workers. Costs (costs of introduction, PPH prevention and PPH treatment) and effects (PPH cases averted, deaths averted) were modelled over a 12-month program. Life years gained were modelled over a lifetime horizon (discounted at 3%). Cost of maintaining the cold chain or effects of compromised oxytocin quality (in the absence of a cold chain) were not modelled. Results In Bangladesh, IHO was estimated to avert 18,644 cases of PPH, 76 maternal deaths and 1954 maternal life years lost. This also yielded a cost-saving, with the majority of gains occurring among home deliveries where IHO would replace misoprostol. In Ethiopia, IHO averted 3111 PPH cases, 30 maternal deaths and 767 maternal life years lost. The full IHO introduction program bears an incremental cost-effectiveness ratio (ICER) of between 2 and 3 times the per-capita Gross Domestic Product (GDP) ($1880 USD per maternal life year lost) and thus is unlikely to be considered cost-effective in Ethiopia. However, the ICER of routine IHO administration considering recurring cost alone falls under 25% of per-capita GDP ($175 USD per maternal life-year saved). Conclusions IHO has the potential to expand access to uterotonics and reduce PPH-associated morbidity and mortality in high burden settings. This can facilitate reduced spending on PPH management, making the product highly cost-effective in settings where coverage of institutional delivery is lagging.

Background The launch of novel pharmaceuticals in the developing world faces significant barriers that can delay or ultimately inhibit uptake. Implementation research can provide an understanding of factors influencing the introduction and scale up of a new product and thus can inform implementation strategy development. Objective This study explored the factors likely to influence introduction of a novel oxytocin formulation for the prevention of postpartum hemorrhage in Ethiopia. Methods Qualitative research methods were used to assess barriers and enablers associated with pre-determined domains: regulatory approval, pricing, supply and demand side advocacy, policy inclusion, end-user training and drug supply. Data were collected through focus group discussions and in-depth interviews with community members, healthcare providers and key informants. Verbatim transcripts were translated to English and analyzed using a thematic content framework. Results Approval from stringent regulatory bodies was an enabler for gaining national regulatory approval. Purchasers (government and patients) expressed price sensitivity but would be willing to pay a price comparable to or higher than current alternatives if improved quality is delivered. Endorsement from the World Health Organization was described as critical for national policy inclusion. Supply side advocacy should be directed towards the Ministry of Health, which is receptive to advice from reputable agencies with whom they have an existing relationship. Demand side advocacy should be delivered through existing health system channels such as Ministry of Health authorities (for healthcare workers) and community health workers (for community members). The requirement to purchase the product directly from a single manufacturer was highlighted as a potential barrier for entry into the local supply chain. Conclusion This study highlighted several barriers and enablers associated with the introduction of a new drug product into the health system of Ethiopia. An advanced understanding of these influences can inform the design of locally-appropriate implementation strategies.

The use of real-world data in drug repurposing has emerged due to well-established advantages of drug repurposing in supplementing de novo drug discovery and incentives in incorporating real-world evidence in regulatory approvals. We conducted a scoping review to characterize repurposing studies using real-world data and discuss their potential challenges and solutions. A total of 250 studies met the inclusion criteria, of which 36 were original studies on hypothesis generation, 101 on hypothesis validation, and seven on safety assessment. Key challenges that should be addressed for future progress in using real-world data for repurposing include isolated data sources with poor clinical granularity, false-positive signals from data mining, the sensitivity of hypothesis validation to bias and confounding, and the lack of clear regulatory guidance.

Background: Intramuscular (IM) oxytocin for postpartum haemorrhage (PPH) prevention in resource-poor settings is limited by the need for cold-chain storage and skilled staff for safe injection. We compared the pharmacokinetics (PK) and safety of heat-stable oxytocin inhaled (IH) versus IM administration in women during third stage of labour (TSL). Methods: The phase 1, randomised, open-label clinical study (NCT02999100) was conducted across three centres in the UK and Australia. Participants (Group 1, women in TSL; Group 2, non-pregnant women of childbearing potential) were randomised 1:1 via validated GSK internal software: Group 1, oxytocin 240 IU (400 μg) IH or oxytocin 10 IU (17 μg) IM immediately after delivery; Group 2, intravenous (IV) oxytocin 5 IU (8·5 μg) and oxytocin 240 IU (400 μg) IH at two separate dosing sessions in a cross-over design. Primary endpoints included characterising oxytocin IH PK. The safety population included patients who received ≥1 dose; any PK sample obtained and analysed was included in the PK population. Additional investigations explored the validity of the PK concentration data. Findings: Participants were recruited between November 2016 and March 2019. In Group 1, 29 participants were randomised; 17 received IH (n=9) or IM (n=8) oxytocin. After IH and IM administration most plasma oxytocin concentrations were below quantification limits (2 pg/ml). In Group 2 (n=14), oxytocin IH concentrations remained quantifiable up to 3 hrs post dose. Adverse events were reported for: Group 1, IH n=3 (33%) and IM n=2 (25%); Group 2, n=14 (100%). No deaths were reported. Interpretation: Safety profiles of oxytocin IH and IM were similar; PK profiles could not be defined for oxytocin IH or IM in women in TSL, despite using a highly sensitive assay. Ex vivo investigations suggested oxytocin metabolism occurred in vivo and not during sample collection and processing. Trial Registration: Trial Registration Number, (ClinicalTrials.gov: NCT02999100). The study protocol can be found online (https://clinicaltrials.gov/ProvidedDocs/00/NCT02999100/Prot_000.pdf). Funding: GlaxoSmithKline (GSK 205920; NCT02999100) Declaration of Interest: KG-K, AS-C, KRP, PL, TN, JM, CG, CK and VLO have no conflicts to declare. SK, AC, RAG, SP, IS, AS, KH, MP, ME and SS are employees of and hold stocks in GSK. MPM is an inventor on the patent method and formulation for oxytocin inhalation (WO2013/016754 A1 [PCT/AU2011001430]). Ethical Approval: The study protocol was reviewed and approved by the Office for Research Ethics Committees of Northern Ireland (UK) and the Monash Health Human Research Ethics Committee (Australia) in accordance with Good Clinical Practice (GCP) guidelines.

Background The high prevalence of poor quality essential medicines in low and middle income countries (LMIC) presents considerable risks in terms of both health outcomes and economic cost. Oxytocin injection, the gold standard therapy for management of postpartum haemorrhage (PPH), presents a particular challenge in this area. Recent studies in India, Nigeria and DRC have identified product failure rates, in terms of low drug content, to be 41%, 74% and 80% respectively. Ethiopia bears a high burden of PPH with over 40% of maternal deaths being directly attributed to haemorrhagic causes. This study assessed the quality of oxytocin injection at points in the public and private supply chains to support national efforts to address PPH in Ethiopia. # Methods This study sampled oxytocin injection ampoules from 45 sites across Oromia, Afar regions and the administrative area of Addis Ababa. This included points along the public supply chain from the national point of entry for supplies through regional hubs to points of use (public and private facilities) in urban and rural areas. Collected samples were stored under refrigerated conditions until analysis for oxytocin content, known degradation products and microbiological quality. # Results Ninety-six percent of ampoules passed all tests, while two samples (4%) contained less than the specified oxytocin content. Both samples were collected from rural facilities in Afar, a remote, poorly resourced region with a very hot climate. All supplies collected were sourced from European stringent regulatory approved (SRA) suppliers and, where storage conditions could be determined, approximately 95% of samples were stored in the refrigerator at the time of collection. # Conclusions The study indicates that oxytocin injection in the selected regions is generally of high quality and being stored appropriately. The failed samples detected in Afar suggest challenges remain around maintenance of refrigerated storage in least resourced settings. These findings contrast with recent results in other African countries and support the joint World Health Organization (WHO)/United Nations Children Fund/United Nations Population Fund statement that the availability of high quality oxytocin injection at the point of use is dependent on procurement of supplies from manufacturers approved by WHO or SRAs and storage at 2-8°C throughout the supply chain.

In this study a carrier-free dry powder inhalation (DPI) containing L-arginine (ARG) was developed. As such, it is proposed that ARG could be used for adjunctive treatment of cystic fibrosis and/or tuberculosis. Various processing methods were used to manufacture high-dose formulation batches consisting various amounts of ARG and excipients. The formulations were evaluated using several analytical methods to assess suitability for further investigation. Several batches had enhanced in vitro aerolization properties. Significant future challenges include the highly hygroscopic nature of unformulated ARG powder and identifying the scale of dose of ARG required to achieve the response in lungs.

ObjectiveThis study assessed the potential operational feasibility and acceptability of a heat-stable, inhaled oxytocin (IOT) product for community-based prevention of postpartum haemorrhage in Myanmar.MethodsA qualitative inquiry was conducted between June 2015 and February 2016 through focus group discussions and in-depth interviews. Research was conducted in South Dagon township (urban setting) and in Ngape and Thanlyin townships (rural settings) in Myanmar. Eleven focus group discussions and 16 in-depth interviews were conducted with mothers, healthcare providers and other key informants. All audio recordings were transcribed verbatim in Myanmar language and were translated into English. Thematic content analysis was done using NVivo software.ResultsFuture introduction of an IOT product for community-based services was found to be acceptable among mothers and healthcare providers and would be feasible for use by lower cadres of healthcare providers, even in remote settings. Responses from healthcare providers and community members highlighted that midwives and volunteer auxiliary midwives would be key advocates for promoting community acceptance of the product. Healthcare providers perceived the ease of use and lack of dependence on cold storage as the main enablers for IOT compared with the current gold standard oxytocin injection. A single-use disposable device with clear pictorial instructions and a price that would be affordable by the poorest communities was suggested. Appropriate training was also said to be essential for the future induction of the product into community settings.ConclusionIn Myanmar, where home births are common, access to cold storage and skilled personnel who are able to deliver injectable oxytocin is limited. Among community members and healthcare providers, IOT was perceived to be an acceptable and feasible intervention for use by lower cadres of healthcare workers, and thus may be an alternative solution for the prevention of postpartum haemorrhage in community-based settings in the future.