Modeling the economic burden of postpartum hemorrhage due to substandard uterotonics in Ghana.

Uterotonics are essential in preventing postpartum hemorrhage (PPH), the leading direct cause of maternal death worldwide. However, uterotonics are often substandard in low- and middle-income countries, contributing to poor maternal health outcomes. This study examines the health and economic impact of substandard uterotonics in Ghana. A decision-tree model was built to simulate vaginal and cesarean section births across health facilities, uterotonic quality and utilization, PPH risk and diagnosis, and resulting health and economic outcomes. We utilized delivery data from Ghana's maternal health survey, risks of health outcomes from a Cochrane review, and E-MOTIVE trial data for health outcomes related to oxytocin quality. We compared scenarios with and without substandard uterotonics, as well as scenarios altering uterotonic use and care-seeking behaviors. We found that substandard uterotonic use contributes to $18.8 million in economic burden annually, including $6.3 million and $4.8 million in out-of-pocket expenditures in public and private sectors, respectively. Annually, the National Health Insurance Scheme bears $1.6 million in costs due to substandard uterotonic use. Substandard uterotonics contribute to $6 million in long-term productivity losses from maternal mortality annually. Improving the quality of uterotonics could reduce 20,000 (11%) PPH cases, 5,000 (11%) severe PPH cases, and 100 (11%) deaths due to PPH annually in Ghana. Ensuring the quality of uterotonics would result in millions of dollars in cost savings and improve maternal health outcomes for the government and families in Ghana. Cost savings from improving uterotonic quality would provide financial protection and help Ghana advance toward Universal Health Coverage.

The drug drought in maternal health: an ongoing predicament.

We developed a comprehensive database of medicines that are used or are being investigated for pre-eclampsia or eclampsia, preterm birth or labour, postpartum haemorrhage, intrauterine growth restriction, and fetal distress and that were in active development between 2000 and 2021. A total of 444 candidates were identified: approximately half of candidates were in active development, two-thirds had been repurposed after initially being used for another condition, and just under half were in preclinical studies. Only 64 candidates were in active late-stage (phase 3) development as of Oct 25, 2021, and given the slow pace of biomedical development, it could take years before any of these products eventually make it to market. A lack of innovation for maternal health medicines persists, and the market continues to fail pregnant individuals. There is a need for collective action from all relevant stakeholders to accelerate investment in the development of new or improved medicines for pregnancy-related conditions.

Quality testing of mifepristone and misoprostol in 11 countries.

OBJECTIVE: Previous studies have demonstrated quality concerns with misoprostol. Mifepristone, however, has not been extensively assessed for quality. Between 2020 and 2021, Concept Foundation and the International Planned Parenthood Federation conducted a study to determine the quality of these medical abortion drugs in low- and middle-income countries (LMIC). METHODS: The collection of batch samples of misoprostol and mifepristone was carried out by trained sampling agents in selected LMIC. Single drug packs and combipacks were sampled. A World Health Organization prequalified laboratory conducted testing method verifications and subsequent sample analysis. Tests included identification, assay, related substances, and content uniformity for misoprostol, and identification, assay, related substances, and dissolution for mifepristone. RESULTS: Samples were collected from Burkina Faso, Cambodia, Democratic Republic of Congo, India, Kyrgyzstan, Moldova, Nepal, Nigeria, Pakistan, Uganda and Vietnam. Sixty-four pooled batch samples were tested, consisting of 31 combipacks, 26 misoprostol-only and seven mifepristone-only products. Overall, 54.7% of samples were non-compliant with one or more of the specifications, representing 51.6% of combipack products, 57.1% of misoprostol tablets analyzed and 23.7% of mifepristone tablets. One falsified misoprostol-only product was found. CONCLUSION: The present study confirms that a significant problem still exists in relation to the quality of medical abortion drugs in LMIC. For misoprostol, our findings suggest that historical concerns around primary packaging may have been largely resolved but that manufacturing processes for both finished product and active pharmaceutical ingredient need to be improved. The present study also provides evidence of mifepristone quality issues.

The compatibility of oxytocin and tranexamic acid injection products when mixed for co-administration by infusion for the treatment of postpartum haemorrhage: An in vitro investigation.

OBJECTIVE: To investigate the compatibility of oxytocin and tranexamic acid injection products when mixed for the purpose of co-administration by intravenous infusion. DESIGN: Compatibility testing. SETTING: Hospitals taking part in a multicentre postpartum haemorrhage treatment (E-MOTIVE) trial in Kenya, Nigeria, Tanzania and South Africa. SAMPLE: Oxytocin and tranexamic acid products. METHODS: The compatibility of two sentinel products of oxytocin injection and tranexamic acid injection in 200-mL infusion bags of both 0.9% w/v saline and Ringer's lactate solution was assessed. We analysed all tranexamic acid-oxytocin combinations, and each evaluation was conducted for up to 3 h. Subsequently, the compatibility of multiple tranexamic acid products with reference oxytocin products when mixed in 0.9% w/v saline over a period of 1 h was investigated. MAIN OUTCOME MEASURES: Concentration of oxytocin over time after mixing with tranexamic acid products. RESULTS: We found significant interaction between certain oxytocin and tranexamic acid products after mixing them in vitro and observing for 1 h. The interaction substantially impacted oxytocin content leading to reduction in concentration (14.8%-29.0%) immediately on mixing (t = 0 min). In some combinations, the concentration continued to decline throughout the stability assessment period. Oxytocin loss was observed in 7 out of 22 (32%) of combinations tested. CONCLUSIONS: In a clinical setting, mixing certain oxytocin and tranexamic acid products before administration may result in an underdosing of oxytocin, compromising care in an emergency life-threatening situation. The mixing of oxytocin and tranexamic acid injection products for co-administration with intravenous infusion fluids should be avoided until the exact nature of the observed interaction and its implications are understood.

Reclassifying contraceptives as over-the-counter medicines to improve access.

Self-care interventions include over-the-counter contraceptives, which enable individuals to make informed, autonomous decisions about fertility management. As there is a substantial unmet need for contraception in many countries, increasing access by establishing sound, affordable and effective regulation of over-the-counter contraceptives could help reduce unintended pregnancies and improve maternal health. We performed a review of 30 globally diverse countries: (i) to assess national regulatory procedures for changing oral contraceptives, emergency contraceptives and injectable contraceptives from prescription-only to over-the-counter products; and (ii) to determine whether national lists of over-the-counter medicines included contraceptives. Of the 30 countries, 13 (43%) had formal regulatory procedures in place for changing prescription-only medicines to over-the-counter medicines, 11 (36%) had national lists of over-the-counter medicines, and four (13%) included contraceptives on those lists. Changing from prescription-only to over-the-counter medicines presents challenges for national medicines regulatory authorities and manufacturers, involving, for example, reporting side-effects, quality control and the often poorly-defined process of switching to over-the-counter products. To facilitate the over-the-counter availability of contraceptives, countries should consider adopting a formal regulatory procedure for reclassifying prescription-only contraceptives as over-the-counter contraceptives. Although the availability of over-the-counter contraceptives can increase users' independence and anonymity and improve access, there may also be disadvantages, such as higher out-of-pocket costs and the need for accurate self-assessment. Basic remedial actions to improve, harmonize and standardize regulatory procedures for the reclassification of contraceptives are proposed with the aim of enabling national medicines regulatory authorities to manage the switch to over-the-counter contraceptives and to control their quality.

Les soins autoadministrés incluent les contraceptifs en vente libre, qui permettent aux individus de prendre des décisions réfléchies et autonomes concernant le contrôle de la fécondité. Vu le besoin criant de contraception dans de nombreux pays, faciliter l'accès en proposant des méthodes de régulation sûres, efficaces et abordables par le biais de contraceptifs en vente libre pourrait contribuer à diminuer le nombre de grossesses non désirées et à améliorer la santé maternelle. Nous avons passé en revue 30 pays aux profils variés: (i) pour évaluer les procédures réglementaires nationales visant à modifier le statut des contraceptifs oraux, d'urgence et injectables afin qu'ils soient en vente libre au lieu d'être considérés comme des médicaments sur ordonnance; et (ii) pour déterminer si les contraceptifs figuraient sur les listes nationales de médicaments en vente libre. Sur les 30 pays observés, 13 (43%) avaient mis en place des procédures réglementaires officielles en vue de modifier le statut des contraceptifs, 11 (36%) possédaient des listes nationales de médicaments en vente libre et quatre (13%) y avaient inscrit les contraceptifs. Le passage du statut de médicament sur ordonnance à celui de médicament en vente libre représente un défi pour les autorités nationales de réglementation pharmaceutique et les fabricants, notamment en matière de déclaration des effets secondaires, de contrôle de la qualité et en raison d'un processus souvent mal défini. S'ils souhaitent favoriser la disponibilité des contraceptifs en vente libre, les pays devraient envisager l'adoption d'une procédure réglementaire officielle destinée à reclassifier les contraceptifs sur ordonnance en contraceptifs en vente libre. Bien que cette disponibilité puisse accroître l'autonomie et l'anonymat des usagers et améliorer l'accès à la contraception, elle présente également des désavantages car elle entraîne une hausse des frais non remboursés et requiert une autoévaluation correcte. Le présent document formule des mesures correctrices élémentaires servant à améliorer, harmoniser et normaliser les procédures réglementaires de reclassification des contraceptifs. Objectif: permettre aux autorités nationales de réglementation pharmaceutique de superviser le passage au statut de médicament en vente libre et de contrôler la qualité.

Las intervenciones de cuidado personal incluyen los anticonceptivos de venta libre, que permiten a las personas tomar decisiones informadas y autónomas sobre la gestión de la fertilidad. Dado que en muchos países existe una importante necesidad insatisfecha de anticoncepción, aumentar el acceso mediante el establecimiento de una normativa sólida, asequible y eficaz de los anticonceptivos de venta libre podría ayudar a reducir los embarazos no deseados y mejorar la salud materna. Se realizó una revisión de 30 países de todo el mundo: (i) para evaluar los procedimientos normativos nacionales relativos al cambio de los anticonceptivos orales, los anticonceptivos de urgencia y los anticonceptivos inyectables de medicamentos de venta con receta a productos de venta libre; y (ii) para determinar si las listas nacionales de medicamentos de venta libre incluían los anticonceptivos. De los 30 países, 13 (43 %) contaban con procedimientos normativos formales para el cambio de medicamentos de venta con receta a medicamentos de venta libre, 11 (36 %) tenían listas nacionales de medicamentos de venta libre, y cuatro (13 %) incluían los anticonceptivos en esas listas. El cambio de los medicamentos de venta con receta a los de venta libre supone un desafío para las autoridades nacionales de regulación de medicamentos y para los fabricantes, ya que implica, por ejemplo, la notificación de los efectos secundarios, el control de calidad y el proceso, que suele estar mal definido, de pasar a los productos de venta libre. Para facilitar la disponibilidad de los anticonceptivos sin receta, los países deberían considerar la adopción de un procedimiento normativo formal para reclasificar los anticonceptivos de venta con receta como anticonceptivos de venta sin receta. Aunque la disponibilidad de los anticonceptivos de venta libre puede aumentar la independencia y el anonimato de los usuarios y mejorar el acceso, también puede haber desventajas, como los mayores costos de bolsillo y la necesidad de una autoevaluación precisa. Se proponen acciones correctivas básicas para mejorar, armonizar y estandarizar los procedimientos normativos para la reclasificación de los anticonceptivos, con el objetivo de que las autoridades nacionales de regulación de medicamentos puedan gestionar el cambio a los anticonceptivos sin receta y controlar su calidad.

Challenges in updating national guidelines and essential medicines lists in Sub-Saharan African countries to include WHO-recommended postpartum hemorrhage medicines.

Despite the 2017 WHO recommendations on tranexamic acid (TXA) for the treatment of postpartum hemorrhage (PPH), the 2018 uterotonic recommendations (which included heat-stable carbetocin (HSC) for the prevention of PPH) and their inclusion in the WHO Essential Medicines List (EML), both drugs are still underused or not used at all to manage PPH in many countries with a high burden. HSC is currently being registered in low- and middle-income countries and its policy inclusion is limited and slow. TXA (also heat stable) is available in many countries but is not registered for PPH treatment, which may have contributed to the delay in its inclusion in national guidelines and EMLs. For both drugs, national guidelines will need to be revised and updated for their optimal uptake. We implemented an advocacy initiative to accelerate the necessary normative policy change to ensure access to quality-assured and heat-stable medicines for the prevention and treatment of PPH in Sub-Saharan African countries. Our initiative aimed to raise awareness of the importance of recently recommended medicines for the prevention and treatment of PPH and support the process to update PPH guidelines and EMLs to include these drugs. We highlight the lessons learned during the initiative, including the challenges and opportunities identified in updating PPH policies at the national level.

Regulatory standards and processes for over-the-counter availability of hormonal contraception and drugs for medical abortion in five countries in the Eastern Mediterranean Region.

The World Health Organization 2019 WHO consolidated guideline on self-care interventions for health: sexual and reproductive health and rights includes recommendations on self-administration of injectable contraception, over-the-counter (OTC) oral contraception and self-management of medical abortion. A review of the regulatory status of these two self-care interventions can highlight processes required to ensure that the quality of the medicines and safety of individuals are safeguarded in the introduction and scale-up in countries. This review outlines the legal regulatory status of prescription-only medicine (POM) and OTC contraceptives, including emergency contraception, and drugs for medical abortion in Egypt, Jordan, Lebanon, Morocco and Tunisia using information obtained from internet searches, regulatory information databases and personal contacts. In addition, the review examines whether the national medicines regulatory authorities have documented procedures available to allow for a change in status from a POM to OTC to allow for increased accessibility, availability and uptake of self-care interventions recommended by WHO. Egypt, Jordan and Lebanon have a documented national OTC list available. The only contraceptive product mentioned in the OTC lists across all five countries is ellaOne (ulipristal acetate for emergency contraception), which is publicly registered in Lebanon. None of the five countries has an official documented procedure to apply for the change of POM to OTC. Informal procedures exist, such as the ability to apply to the national medicines regulatory authority for OTC status if the product has OTC status in the original country of manufacture. However, many of these procedures are not officially documented, highlighting the need for establishing sound, affordable and effective regulation of medical products as an important part of health system strengthening. From a public health perspective, it would be advantageous for licensed products to be available OTC. This is particularly the case for settings where the health system is under-resourced or over-stretched due to health emergencies. Readiness of national regulatory guidelines and OTC procedures could lead to increased access, availability and usage of essential self-care interventions for sexual and reproductive health and rights.

Cost of goods sold analysis and recommendations to reduce costs of co-packaged mifepristone-misoprostol for medical abortion.

OBJECTIVE: Understanding the price components of the mifepristone/misoprostol (combi-pack) for medical abortion to improve access is critical for identifying strategies to reduce product costs for quality-assured formulations and expanding its availability and use. METHODS: We constructed a cost of goods sold analysis using data collected from manufacturing companies in Bangladesh, China and India supported by publicly available information related to the product formulation, active pharmaceutical ingredients (API), manufacturing location, manufacturer profiles and other individual model components. Key model components were the active pharmaceutical ingredients (quality-assured or not), excipients, labour cost, operating cost and packaging. RESULTS: Combi-pack direct production cost ranges from US$1.08 for finished products which are not quality assured to US$3.05 for products containing quality assured active pharmaceutical ingredients, which means that with a 30% administrative fee applied to those prices, it could be made available between US$1.40 and US$3.97 depending on location, manufacturer's profile, optimal market situation and the quality of the active pharmaceutical ingredients. The main model component impacting on the cost range is the purchase price of mifepristone active pharmaceutical ingredient and the current differential between quality-assured material supported by adequate documentation and API for which quality assurance cannot be demonstrated. Compared to India cost of goods sold is lower in Bangladesh primarily due to lower operating costs, including the cost of labour. CONCLUSIONS: It is feasible to lower the cost of quality-assured combi-packs, through reducing mifepristone API cost and selection of the manufacturing location. However, manufacturers need to be incentivised to achieve WHO pre-qualification with a carefully built business case and require support in identifying and sourcing competitively priced material and manufacturing products to the necessary standard.

Current research on carbetocin and implications for prevention of postpartum haemorrhage.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and is a significant contributor to severe maternal morbidity and long-term disability. Carbetocin may be an underused uterotonic for prevention of PPH. A number of studies are being conducted that may challenge the place of oxytocin as the first choice of uterotonics for prevention of PPH. This paper describes the current research into carbetocin and ranking of effectiveness of uterotonics that may provide important new information to assist healthcare decision makers to ensure that women receive an effective uterotonic for prevention of PPH. METHODS: We searched the WHO International Clinical Trials Registry Platform for current studies on effectiveness of carbetocin for prevention of PPH following vaginal delivery with sample sizes large enough to provide quality evidence to support potential changes to international guidelines. We also searched the Cochrane Library for current systematic reviews including carbetocin used in prevention of PPH. RESULTS: Susceptibility to degradation from exposure to heat is one of the key causes of reduced effectiveness of oxytocin in preventing PPH from uterine atony. Although heat stable and effective in preventing PPH, misoprostol is also subject to degradation due to exposure to moisture and produces some side-effects. Other uterotonics (including ergometrine and combinations of oxytocin, ergometrine and misoprostol) are also available and used with varying safety and effectiveness profiles and quality issues. Efforts to reduce maternal mortality from PPH include research studies seeking to identify safe, stable, effective uterotonics. Heat stable carbetocin is the subject of two major clinical studies into its effectiveness in preventing PPH following vaginal deliveries, information that could expand its application for prevention of PPH. CONCLUSION: Heat stable carbetocin is being investigated as a potential alternative to oxytocin. This paper describes two current clinical trials on carbetocin and a network meta-analysis ranking of all uterotonic agents, including carbetocin, which combined may provide evidence supporting expansion of the use of the heat stable formulation of carbetocin in PPH prevention.

A study of the capability of manufacturers of generic hormonal contraceptives in lower- and middle-income countries.

PURPOSE: Studies were undertaken to assess the capability, competence and capacity of manufacturers of oral and injectable hormonal contraceptives in lower- and middle-income countries. METHODS: A qualitative study on 41 companies, which comprised in-depth interviews and facility observations, was undertaken. Also an in-depth quantitative study of 14 companies was undertaken, of which 3 have not been included in the first study. Following review of a questionnaire and other documentation, a visit was undertaken to each factory to assess staff competence, manufacturing facilities, manufacturing processes, quality management, worker safety and environmental protection. RESULTS: Of the 44 companies from 15 countries, less than 30% would meet the current Good Manufacturing Practice requirements of the World Health Organization (WHO), the Pharmaceutical Inspection Cooperation Scheme or any stringent regulatory authority; a further 20% could comply with investment and improvements in quality management. Few companies are able to develop adequate registration dossiers. CONCLUSION: There is a limited number of companies that are capable of manufacturing high-quality generic products and which can provide a complete registration dossier for use outside their home markets. It is essential that, in the future, procurement agencies only use suppliers that are prequalified by WHO for the procurement of hormonal contraceptives.