Availability and stock-outs of paediatric antiretroviral treatment formulations at health facilities in Kenya and Uganda.

INTRODUCTION: The large number of deaths among children with HIV is driven by poor antiretroviral treatment (ART) coverage among this cohort. The aim of the study was to assess the availability and stock-outs of paediatric and adult ART formulations in Kenya and Uganda across various regions and types of health facilities. METHODS: A survey on availability and stock-outs of paediatric ART at health facilities was adapted from the standardized Health Action International-WHO Medicine Availability Monitoring Tool. All preferred and limited-use formulations, and three phased-out formulations according to the 2021 WHO optimal formulary list were included in the survey, as well as a selection of adult ART formulations suitable for older children, adolescents, and adults. Availability data were collected in June-July 2022 and stock-out data were obtained over the previous year from randomly selected public and private-not-for-profit (PNFP) facilities registered to dispense paediatric ART across six districts per country. All data were analysed descriptively. RESULTS: In total, 144 health facilities were included (72 per country); 110 were public and 34 PNFP facilities. Overall availabilities of preferred paediatric ART formulations were 52.2% and 63.5% in Kenya and Uganda, respectively, with dolutegravir (DTG) 10 mg dispersible tablets being available in 70.2% and 77.4% of facilities, respectively, and abacavir/lamivudine dispersible tablets in 89.8% and 98.2% of facilities. Of note, availability of both formulations was low (37.5% and 62.5%, respectively) in Kenyan PNFP facilities. Overall availabilities of paediatric limited-use products were 1.1% in Kenya and 1.9% in Uganda. At least one stock-out of a preferred paediatric ART formulation was reported in 40.0% of Kenyan and 74.7% of Ugandan facilities. Nevirapine solution stock-outs were reported in 43.1% of Ugandan facilities, while alternative formulations for postnatal HIV prophylaxis were not available. CONCLUSIONS: Recommended DTG-based first-line ART for children across all ages was reasonably available at health facilities in Kenya and Uganda, with the exception of Kenyan PNFP facilities. Availability of paediatric ART formulations on the limited-use list was extremely low across both countries. Stock-outs were reported regularly, with the high number of reported stock-outs of neonatal ART formulations in Uganda being most concerning.

Adoption of new medicines in primary care: A comparison between the uptake of new oral anticoagulants and diabetes medicines.

AIMS: To gain insight in the uptake and practice variation in the prescription of 2 new medicine groups for common conditions in primary care (direct-acting oral anticoagulants [DOACs] and incretin-based therapies) from introduction, around 2007, to 2019 and the correlation between the adoption of those medicines in primary care. METHODS: Prescription data from general practices in the Dutch Nivel Primary Care Database from 2007 to 2019 were used. The percentage of patients with prescriptions for DOACs of all patients with prescriptions for DOACs and vitamin K antagonists was calculated per practice per year, as was the percentage of patients prescribed incretin-based therapies as a proportion of all patients with diabetes medication. Multilevel models were used to estimate practice variation for DOACs and incretin-based therapies, expressed as intraclass correlation coefficients. Linear regression analysis was used to study the association between the prescription of DOACs and incretin-based therapies. RESULTS: Per year, 46-424 general practices and 179 933-1 654 376 patients were included. In 2019, the mean percentage of patients per practice using DOACs or incretin-based therapies was 54.9 and 9.7%, respectively. The intraclass correlation coefficient decreased from 0.75 to 0.024 for DOACs and from 0.33 to 0.074 for incretin-based medicines during the study period. No clear correlation was found between the prescription of DOACs and incretin-based therapies. CONCLUSION: DOACs and incretin-based therapies have different adoption profiles and practice variation is large, especially in the years before these medicines were introduced in guidelines. Early adopters of both medicine classes differ.

Illustrating the Financial Consequences of Outcome-Based Payment Models From a Payers Perspective: The Case of Autologous Gene Therapy Atidarsagene Autotemcel (Libmeldy®).

OBJECTIVES: To illustrate the financial consequences of implementing different managed entry agreements (managed entry agreements for the Dutch healthcare system for autologous gene therapy atidarsagene autotemcel [Libmeldy]), while also providing a first systematic guidance on how to construct managed entry agreements to aid future reimbursement decision making and create patient access to high-cost, one-off potentially curative therapies. METHODS: Three payment models were compared: (1) an arbitrary 60% price discount, (2) an outcome-based spread payment with discounts, and (3) an outcome-based spread payment linked to a willingness to pay model with discounts. Financial consequences were estimated for full responders (A), patients responding according to the predicted clinical pathway presented in health technology assessment reports (B), and unstable responders (C). The associated costs for an average patient during the time frame of the payment agreement, the total budget impact, and associated benefits expressed in quality-adjusted life-years of the patient population were calculated. RESULTS: When patients responded according to the predicted clinical pathway presented in health technology assessment reports (scenario B), implementing outcome-based reimbursement models (models 2 and 3) had lower associated budget impacts while gaining similar benefits compared with the discount (scenario 1, €8.9 million to €6.6 million vs €9.2 million). In the case of unstable responders (scenario C), costs for payers are lower in the outcome-based scenarios (€4.1 million and €3.0 million, scenario 2C and 3C, respectively) compared with implementing the discount (€9.2 million, scenario 1C). CONCLUSIONS: Outcome-based models can mitigate the financial risk of reimbursing atidarsagene autotemcel. This can be considerably beneficial over simple discounts when clinical performance was similar to or worse than predicted.

The impact of scheduling ketamine as an internationally controlled substance on anaesthesia care in Sub-Saharan Africa: a case study and key informant interviews.

BACKGROUND: Access to anaesthesia and surgical care is a major problem for people living in Sub-Saharan Africa. In this region, ketamine is critical for the provision of anaesthesia care. However, efforts to control ketamine internationally as a controlled substance may significantly impact its accessibility. This research therefore aims to estimate the importance of ketamine for anaesthesia and surgical care in Sub-Saharan Africa and assess the potential impact on access to ketamine if it were to be scheduled. METHODS: This research is a mixed-methods study, comprising of a cross-sectional survey at the hospital level in Rwanda, and key informant interviews with experts on anaesthesia care in Sub-Saharan Africa. Data on availability of four anaesthetic agents were collected from hospitals (n = 54) in Rwanda. Semi-structured interviews with 10 key informants were conducted, collecting information on the importance of ketamine, the potential impact of scheduling ketamine internationally, and opinions on misuse of ketamine. Interviews were transcribed verbatim and analysed using a thematic analysis approach. RESULTS: The survey conducted in Rwanda found that availability of ketamine and propofol was comparable at around 80%, while thiopental and inhalational agents were available at only about half of the hospitals. Significant barriers impeding access to anaesthesia care were identified, including a general lack of attention given to the specialty by governments, a shortage of anaesthesiologists and migration of trained anaesthesiologists, and a scarcity of medicines and equipment. Ketamine was described as critical for the provision of anaesthesia care as a consequence of these barriers. Misuse of ketamine was not believed to be an issue by the informants. CONCLUSION: Ketamine is critical for the provision of anaesthesia care in Sub-Saharan Africa, and its scheduling would have a significantly negative impact on its availability for anaesthesia care.

Suspected adverse reactions reported for blood, blood components, and blood products in VigiBase.

INTRODUCTION: Since being designated as medicines by World Health Organization (WHO), blood components are subject to pharmacovigilance reporting. Using VigiBase, the WHO global database of individual case safety reports (ICSRs), we characterized reports of adverse reactions for all blood products. STUDY DESIGN AND METHODS: ICSRs involving blood products as the suspected medicine in VigiBase between 1968 and 2021 were extracted. MedDRA preferred terms and the International Society of Blood Transfusion haemovigilance definitions were used to stratify adverse reactions. Descriptive statistics were used to characterize ICSR demographics. RESULTS: A total of 111,033 ICSRs containing 577,577 suspected adverse reactions with 6152 MedDRA preferred terms were reported for 34 blood products. There were 12,153 (10.9%) reports for blood components, 98,135 (88.4%) reports for plasma-derived medicines, and 745 (0.7%) reports for recombinant products. The majority of reports (21.0% and 19.7%, respectively) were from patients aged 45-64 and over 65 years. The Americas contributed the most ICSRs (49.7%). Top reported suspected adverse reactions were for the following MedDRA preferred terms: headache (3.5%), pyrexia (2.8%), chills (2.8%), dyspnoea (1.8%), and nausea (1.8%). CONCLUSION: VigiBase already has a large number of reports on blood products. When compared to other existing haemovigilance databases, our study found reports from a broader range of countries and reporters. This may provide us with new perspectives, but for VigiBase to reach its full potential in haemovigilance some alterations in what is captured in reports are required.

Oral anticoagulants in patients with atrial fibrillation at low stroke risk: a multicentre observational study.

AIMS: There is currently no consensus on whether atrial fibrillation (AF) patients at low risk for stroke (one non-sex-related CHA2DS2-VASc point) should be treated with an oral anticoagulant. METHODS AND RESULTS: We conducted a multi-country cohort study in Sweden, Denmark, Norway, and Scotland. In total, 59 076 patients diagnosed with AF at low stroke risk were included. We assessed the rates of stroke or major bleeding during treatment with a non-vitamin K antagonist oral anticoagulant (NOAC), a vitamin K antagonist (VKA), or no treatment, using inverse probability of treatment weighted (IPTW) Cox regression. In untreated patients, the rate for ischaemic stroke was 0.70 per 100 person-years and the rate for a bleed was also 0.70 per 100 person-years. Comparing NOAC with no treatment, the stroke rate was lower [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.56-0.94], and the rate for intracranial haemorrhage (ICH) was not increased (HR 0.84; 95% CI 0.54-1.30). Comparing VKA with no treatment, the rate for stroke tended to be lower (HR 0.81; 95% CI 0.59-1.09), and the rate for ICH tended to be higher during VKA treatment (HR 1.37; 95% CI 0.88-2.14). Comparing NOAC with VKA treatment, the rate for stroke was similar (HR 0.92; 95% CI 0.70-1.22), but the rate for ICH was lower during NOAC treatment (HR 0.63; 95% CI 0.42-0.94). CONCLUSION: These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a question that can be tested through a randomized controlled trial.

Missing data on accessibility of children's medicines.

Child-appropriate medicines are essential for the safe and effective treatment of children, yet we have observed a large gap in the data required to adequately monitor access to these medicines. We have examined data on the availability and pricing of child-appropriate medicines across 50 surveys. Child-appropriate medicines for nine out of 12 priority diseases in children were infrequently surveyed or not at all. A similar data deficit on age-appropriate medicines is detectable in the broader scientific literature. We also note that existing instruments for collecting data on the availability or prices of medicines are limited in their ability to generate the required data for children. We have identified four priorities as key for improved monitoring of access to medicines for children: (i) dedicated child medicine surveys are needed on availability and prices of child-appropriate medicines; (ii) standardized survey instruments should include age-appropriate medicines and dosages; (iii) health facility service readiness survey tools should include the collection of data on the price of child-appropriate medicines in addition to the availability of medicines; and (iv) sustainable development goal indicator 3.b.3 should be modified to enable the monitoring of access to medicines for children. These deficiencies need to be addressed to ensure the monitoring of access to child medicines as part of the sustainable development goal agenda for 2030 and to implement appropriate interventions for improving access for this vulnerable population.

Disposer de médicaments adaptés aux enfants est essentiel à l'administration d'un traitement sûr et efficace. Pourtant, nous avons observé de vastes lacunes dans les données requises pour évaluer l'accès à ces médicaments. Nous avons passé 50 enquêtes au crible, à la recherche d'informations sur la disponibilité et le prix des médicaments pédiatriques. Dans le cas de neuf maladies infantiles prioritaires sur douze, les médicaments adaptés aux enfants n'étaient pas ou peu étudiés. Même constat dans le contexte plus large de la littérature scientifique. Nous avons également remarqué que les instruments servant à récolter des données sur la disponibilité ou le prix des médicaments avaient leurs limites et ne permettaient pas d'obtenir les informations requises concernant les enfants. Nous avons identifié quatre priorités majeures en vue d'améliorer la surveillance de l'accès aux médicaments pédiatriques: (i) la réalisation d'enquêtes sur les médicaments pédiatriques afin d'en connaître la disponibilité et le prix; (ii) l'intégration des médicaments et dosages adéquats dans les instruments d'enquête standard; (iii) outre la disponibilité, la prise en compte du prix des médicaments à usage pédiatrique dans les outils d'évaluation de l'état de préparation des services au sein des établissements de santé; et enfin, (iv) la modification de l'indicateur 3.b.3 des objectifs de développement durable, qui prévoirait dès lors un contrôle de l'accès aux médicaments adaptés aux enfants. Ces lacunes doivent être comblées pour assurer un suivi en matière d'accès aux médicaments pédiatriques dans le cadre du Programme de développement durable à l'horizon 2030, mais aussi pour adopter les mesures correspondantes afin d'améliorer la prise en charge de cette population vulnérable.

Los medicamentos indicados para los niños son esenciales para su tratamiento seguro y eficaz, pero se ha observado un gran vacío en los datos necesarios para supervisar de manera adecuada el acceso a estos medicamentos. Se han analizado los datos sobre la disponibilidad y el precio de los medicamentos indicados para los niños en 50 encuestas. Estos medicamentos para nueve de las 12 enfermedades prioritarias infantiles se encuestaron con poca frecuencia o no se encuestaron en absoluto. En la literatura científica más general, se detecta un déficit de datos similar sobre los medicamentos adecuados para la edad. También se observa que los instrumentos existentes para recopilar los datos sobre la disponibilidad o los precios de los medicamentos son limitados en su capacidad para generar los datos necesarios en el caso de los niños. Se han identificado cuatro prioridades para mejorar el seguimiento del acceso a los medicamentos pediátricos: (i) se necesitan encuestas específicas sobre la disponibilidad y los precios de los medicamentos indicados para los niños; (ii) los instrumentos de encuesta estandarizados deben incluir medicamentos y dosis adecuados para la edad; (iii) las herramientas de encuesta sobre la disponibilidad de los servicios sanitarios deben incluir la recopilación de los datos sobre el precio de los medicamentos indicados para los niños, además de la disponibilidad de los medicamentos; y (iv) el indicador 3.b.3 del Objetivo de Desarrollo Sostenible se debe modificar para permitir el seguimiento del acceso a los medicamentos pediátricos. Es preciso solucionar estas deficiencias para garantizar el seguimiento del acceso a los medicamentos pediátricos como parte de la agenda de los objetivos de desarrollo sostenible para 2030 y aplicar las intervenciones adecuadas para mejorar el acceso de esta población vulnerable.

Pre-approval and post-approval availability of evidence and clinical benefit of conditionally approved cancer drugs in Europe: A comparison with standard approved cancer drugs.

AIMS: Cancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post-approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown. METHODS: We identified all CMA cancer indications converted to SMA in 2006-2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post-approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses. RESULTS: We included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post-approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P = .31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57-3.4). CONCLUSION: While CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA.

Reported Challenges in Health Technology Assessment of Complex Health Technologies.

OBJECTIVES: With complex health technologies entering the market, methods for health technology assessment (HTA) may require changes. This study aimed to identify challenges in HTA of complex health technologies. METHODS: A survey was sent to European HTA organizations participating in European Network for HTA (EUnetHTA). The survey contained open questions and used predefined potentially complex health technologies and 7 case studies to identify types of complex health technologies and challenges faced during HTA. The survey was validated, tested for reliability by an expert panel, and pilot tested before dissemination. RESULTS: A total of 22 HTA organizations completed the survey (67%). Advanced therapeutic medicinal products (ATMPs) and histology-independent therapies were considered most challenging based on the predefined complex health technologies and case studies. For the case studies, more than half of the reported challenges were "methodological," equal in relative effectiveness assessments as in cost-effectiveness assessments. Through the open questions, we found that most of these challenges actually rooted in data unavailability. Data were reported as "absent," "insufficient," "immature," or "low quality" by 18 of 20 organizations (90%), in particular data on quality of life. Policy and organizational challenges and challenges because of societal or political pressure were reported by 8 (40%) and 4 organizations (20%), respectively. Modeling issues were reported least often (n = 2, 4%). CONCLUSIONS: Most challenges in HTA of complex health technologies root in data insufficiencies rather than in the complexity of health technologies itself. As the number of complex technologies grows, the urgency for new methods and policies to guide HTA decision making increases.

Healthcare workers' perspectives on access to sexual and reproductive health services in the public, private and private not-for-profit sectors: insights from Kenya, Tanzania, Uganda and Zambia.

BACKGROUND: Access to sexual and reproductive health services remains a challenge for many in Kenya, Tanzania, Uganda and Zambia. Health service delivery in the four countries is decentralised and provided by the public, private and private not-for-profit sectors. When accessing sexual and reproductive health services, clients encounter numerous challenges, which might differ per sector. Healthcare workers have first-hand insight into what impediments to access exist at their health facility. The aim of this study was to identify differences and commonalities in barriers to access to sexual and reproductive health services across the public, private and private not-for-profit sectors. METHODS: A cross-sectional survey was conducted among healthcare workers working in health facilities offering sexual and reproductive health services in Kenya (n = 212), Tanzania (n = 371), Uganda (n = 145) and Zambia (n = 243). Data were collected in July 2019. Descriptive statistics were used to describe the data, while binary logistic regression analyses were used to test for significant differences in access barriers and recommendations between sectors. RESULTS: According to healthcare workers, the most common barrier to accessing sexual and reproductive health services was poor patient knowledge (37.1%). Following, issues with supply of commodities (42.5%) and frequent stockouts (36.0%) were most often raised in the public sector; in the other sectors these were also raised as an issue. Patient costs were a more significant barrier in the private (33.3%) and private not-for-profit sectors (21.1%) compared to the public sector (4.6%), and religious beliefs were a significant barrier in the private not-for-profit sector compared to the public sector (odds ratio = 2.46, 95% confidence interval = 1.69-3.56). In all sectors delays in the delivery of supplies (37.4-63.9%) was given as main stockout cause. Healthcare workers further believed that it was common that clients were reluctant to access sexual and reproductive health services, due to fear of stigmatisation, their lack of knowledge, myths/superstitions, religious beliefs, and fear of side effects. Healthcare workers recommended client education to tackle this. CONCLUSIONS: Demand and supply side barriers were manifold across the public, private and private not-for-profit sectors, with some sector-specific, but mostly cross-cutting barriers. To improve access to sexual and reproductive health services, a multi-pronged approach is needed, targeting client knowledge, the weak supply chain system, high costs in the private and private not-for-profit sectors, and religious beliefs.

Impact of medicine shortages on patients - a framework and application in the Netherlands.

BACKGROUND: Medicine shortages are often described in plain numbers, suggesting all shortages have a uniform impact. However, some shortages have a direct and serious effect on patients and need a prompt reaction from stakeholders. This study aims to create a broad framework to assess the impact of a shortage. METHOD: We identified high impact shortages and selected exemplary shortages which we considered our learning cases. From five learning cases, we identified elements that had a potentially profound impact on one or more of these cases. We tested data saturation on the elements with another five test cases. Based on these elements, we created a framework to assess impact of shortages on patients and presented practical examples how to rate these different elements. Subsequently, we visualised the impact of these five learning cases on patients in radar charts. RESULTS: The five elements which we identified as potentially having a large impact were 1) alternative product, 2) disease, 3) susceptibility, 4) costs and 5) number of patients affected. The five learning cases rated high on different elements, leading to diverse and sometimes even opposite patterns of impact. CONCLUSION: We created a framework for assessing the impact of a medicine shortage on patients by means of five key elements. By rating these elements, an indication of the impact can be obtained.

Understanding innovation of health technology assessment methods: the IHTAM framework.

Adequate methods are urgently needed to guarantee the good practice of health technology assessment (HTA) for technologies with novel properties. The aim of the study was to construct a conceptual framework to help understand the innovation of HTA methods (IHTAM). The construction of the IHTAM framework was based on two scoping reviews, one on the current practice of innovating methods, that is existing HTA frameworks, and one on theoretical foundations for innovating methods outside the HTA discipline. Both aimed to identify and synthesize concepts of innovation (i.e., innovation processes and roles of stakeholders in innovation). Using these concepts, the framework was developed in iterative brainstorming sessions and subsequent discussions with representatives from various stakeholder groups. The framework was constructed based on twenty documents on innovating HTA frameworks and fourteen guidelines from three scientific disciplines. It includes a generic innovation process consisting of three phases ("Identification," "Development," and "Implementation") and nine subphases. In the framework, three roles that HTA stakeholders can play in innovation ("Developers," "Practitioners," and "Beneficiaries") are defined, and a process on how the stakeholders innovate HTA methods is included. The IHTAM framework visualizes systematically which elements and stakeholders are important to the development and implementation of novel HTA methods. The framework could be used by all stakeholders involved in HTA innovation to learn how to engage dynamically and collaborate effectively throughout the innovation process. HTA stakeholders in practice have welcomed the framework, though additional testing of its applicability and acceptance is essential.

Addressing uncertainty in relative effectiveness assessments by HTA organizations.

This study outlines the ways in which different health technology assessment (HTA) organizations deal with uncertainty in relative effectiveness assessments (REAs), using the GRADE framework as a common reference. Guidelines regarding REA and uncertainty assessment methods and three most recent HTA reports (as of April 2020) of seven HTA organizations in Germany, England and Wales, France, the Netherlands, Europe (EUnetHTA), the USA, and Canada were included. First, it was analyzed how each organization addressed uncertainty on the following levels of evidence: (i) individual studies, (ii) body of evidence for one outcome, (iii) body of evidence across all outcomes, and (iv) added net benefit. Second, the extent to which HTA organizations considered the eight domains of certainty of evidence defined by GRADE was assessed. For individual studies, checklists were the most common approach to express uncertainty (4/7 organizations). Uncertainty in the body of evidence for all outcomes and in added benefit was combined in a single conclusion by five organizations. All organizations reported on at least 4/5 downgrading domains of GRADE, while the three upgrading domains were reported less. The operationalization of the assessment of multiple domains was unclear due to vague or absent guidelines. HTA organizations consider most domains of the GRADE framework, but approaches to assess uncertainty within REAs on different levels of evidence differ substantially between organizations. More alignment and guidance on the best methods to deal with uncertainty within HTA could lead to more clarity for stakeholders and to more aligned reimbursement recommendations.

A comparative human rights analysis of laws and policies for adolescent contraception in Uganda and Kenya.

BACKGROUND: Improving access to adolescent contraception information and services is essential to reduce unplanned adolescent pregnancies and maternal mortality in Uganda and Kenya, and attain the SDGs on health and gender equality. This research studies to what degree national laws and policies for adolescent contraception in Uganda and Kenya are consistent with WHO standards and human rights law. METHODS: This is a comparative content analysis of law and policy documents in force between 2010 and 2018 governing adolescent (age 10-19 years) contraception. Between and within country differences were analysed using WHO's guidelines "Ensuring human rights in the provision of contraceptive information and services". RESULTS: Of the 93 laws and policies screened, 26 documents were included (13 policies in Uganda, 13 policies in Kenya). Ugandan policies include a median of 1 WHO recommendation for adolescent contraception per policy (range 0-4) that most frequently concerns contraception accessibility. Ugandan policies have 6/9 WHO recommendations (14/24 sub-recommendations) and miss entirely WHO's recommendations for adolescent contraception availability, quality, and accountability. On the other hand, most Kenyan policies consistently address multiple WHO recommendations (median 2 recommendations/policy, range 0-6), most frequently for contraception availability and accessibility for adolescents. Kenyan policies cover 8/9 WHO recommendations (16/24 sub-recommendations) except for accountability. CONCLUSIONS: The current policy landscapes for adolescent contraception in Uganda and Kenya include important references to human rights and evidence-based practice (in WHO's recommendations); however, there is still room for improvement. Aligning national laws and policies with WHO's recommendations on contraceptive information and services for adolescents may support interventions to improve health outcomes, provided these frameworks are effectively implemented.

The unmet need for contraception among adolescents is high in Uganda and Kenya, and has many negative consequences, including unwanted pregnancy, exposure to unsafe abortion, and maternal morbidity and mortality. National laws and policies play an important role in determining adolescents' access to contraception. For example, national laws and policies can shape the government programs that provide (or withhold) contraception, and the social norms influencing adolescents' access to contraception. Therefore, this research compares national laws and policies that determine access to contraception services and information for adolescents in Uganda and Kenya with WHO's recommendations for access to contraception.This is an analysis of the content of Ugandan and Kenyan laws and policies in force between 2010 and 2018. The content of these documents was analyzed using WHO's nine recommendations for how contraception information and services should be provided: non-discrimination, availability, accessibility, acceptability, quality, informed decision-making, confidentiality, participation, accountability.Ninety-three documents were screened and 26 documents were included in the analysis: 13 policies from Uganda and 13 policies from Kenya. On average, Ugandan policies include one WHO recommendation for adolescent contraception per policy and Kenyan policies include two WHO recommendations. This recommendation most frequently mentioned in all policies is the accessibility of contraception (for example, for adolescents living remotely, integrated in adolescent HIV or pre-/post-natal care, etc.). Together, all Ugandan policies mentioned 6/9 WHO recommendations whereas all Kenyan policies cover 8/9 WHO recommendations.In conclusion, Ugandan and Kenyan policies are consistent with many of WHO's recommendations for access to contraception, however, there is still room for improvement.

Trends in access to anti-malarial treatment in the formal private sector in Uganda: an assessment of availability and affordability of first-line anti-malarials and diagnostics between 2007 and 2018.

BACKGROUND: Malaria is the single largest cause of illness in Uganda. Since the year 2008, the Global Fund has rolled out several funding streams for malaria control in Uganda. Among these are mechanisms aimed at increasing the availability and affordability of artemisinin-based combination therapy (ACT). This paper examines the availability and affordability of first-line malaria treatment and diagnostics in the private sector, which is the preferred first point of contact for 61% of households in Uganda between 2007 and 2018. METHODS: Cross-sectional surveys were conducted between 2007 and 2018, based on a standardized World Health Organization/Health Action International (WHO/HAI) methodology adapted to assess availability, patient prices, and affordability of ACT medicines in private retail outlets. A minimum of 30 outlets were surveyed per year as prescribed by the standardized methodology co-developed by the WHO and Health Action International. Availability, patient prices, and affordability of malaria rapid diagnostic tests (RDTs) was also tracked from 2012 following the rollout of the test and treat policy in 2010. The median patient prices for the artemisinin-based combinations and RDTs was calculated in US dollars (USD). Affordability was assessed by computing the number of days' wages the lowest-paid government worker (LPGW) had to pay to purchase a treatment course for acute malaria. RESULTS: Availability of artemether/lumefantrine (A/L), the first-line ACT medicine, increased from 85 to100% in the private sector facilities during the study period. However, there was low availability of diagnostic tests in private sector facilities ranging between 13% (2012) and 37% (2018). There was a large reduction in patient prices for an adult treatment course of A/L from USD 8.8 in 2007 to USD 1.1 in 2018, while the price of diagnostics remained mostly stagnant at USD 0.5. The affordability of ACT medicines and RDTs was below one day's wages for LPGW. CONCLUSIONS: Availability of ACT medicines in the private sector medicines retail outlets increased to 100% while the availability of diagnostics remained low. Although malaria treatment was affordable, the price of diagnostics remained stagnant and increased the cumulative cost of malaria management. Malaria stakeholders should consolidate the gains made and consider the inclusion of diagnostic kits in the subsidy programme.

Early Cost-Effectiveness of Onasemnogene Abeparvovec-xioi (Zolgensma) and Nusinersen (Spinraza) Treatment for Spinal Muscular Atrophy I in The Netherlands With Relapse Scenarios.

OBJECTIVES: Onasemnogene Abeparvovec-xioi (AVXS-101) is a gene therapy intended for curative treatment of spinal muscular atrophy (SMA) with an expected price of around €2 000 000. The goal of this study is to perform a cost-effectiveness analysis of treatment of SMA I patients with AVXS-101 in The Netherlands including relapse scenarios. METHODS: An individual-based state-transition model was used to model treatment effect and survival of SMA I patients treated with AVXS-101, nusinersen and best supportive care (BSC). The model included five health states: three health states according to SMA types, one for permanent ventilation and one for death. Deterministic and probabilistic sensitivity analyses were performed. Effects of relapsing to lower health states in the years following treatment was explored. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) for AVXS-101 versus BSC is €138 875/QALY, and €53 447/QALY for AVXS-101 versus nusinersen. If patients relapse within 10 years after treatment with AVXS-101, the ICER can increase up to 6-fold, with effects diminishing thereafter. Only relapses occurring later than 50 years after treatment have a negligible effect on the ICER. To comply with Dutch willingness-to-pay reference values, the price of AVXS-101 must decrease to €680 000. CONCLUSIONS: Based on this model, treatment with AVXS-101 is unlikely to be cost-effective under Dutch willingness-to-pay reference values. Uncertainty regarding the long-term curative properties of AVXS-101 can result in multiplication of the ICER. Decision-makers are advised to appropriately balance these uncertainties against the price they are willing to pay now.

Persistence and adherence to non-vitamin K antagonist oral anticoagulant treatment in patients with atrial fibrillation across five Western European countries.

AIMS: To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings. METHODS AND RESULTS: We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only. RESULTS: Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up. CONCLUSION: Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban.

Implementation and performance of haemovigilance systems in 10 sub-saharan African countries is sub-optimal.

BACKGROUND: Haemovigilance is an important element of blood regulation. It includes collecting and evaluating the information on adverse events resulting from the use of blood and blood components with the aim to improve donor and patient safety. We describe the results of the pilot of the integrated GBT+ Blood for the haemovigilance function in 10 sub-Saharan African countries. METHODS: We piloted the integrated WHO Global Benchmarking Tool plus Blood (GBT+ Blood) to assess the haemovigilance function of national regulatory authorities (NRAs) in Ethiopia, Kenya, Malawi, Nigeria, Liberia, Rwanda, South Africa, Tanzania, Uganda, and Zimbabwe. Data obtained from documents and face to face interviews were used to determine the status of implementation and performance of the following six indicators; legal provisions regulations and guidelines, organisation and governance, human resources, regulatory processes, transparency and accountability and finally, monitoring progress and assessing impact, by estimating median scores across 20 sub-indicators. In addition, a cluster analysis was performed. RESULTS: The countries showed inter-organisation variability in implementation and performance of the haemovigilance function. The overall median score (all sub-indicators) was 44 % (range: 7.5 % - 70 %). The lowest average performance scores were for the arrangement for effective organisation and coordination (35 %) and human resources (35 %) indicators. The highest average scores were observed for the mechanism to promote transparency and mechanism to monitor regulatory performance indicators (50 % and 60 %, respectively). We identified clusters of best-implemented sub-indicators from the procedures for haemovigilance and poorly implemented sub-indicators from the legal provisions, regulations and guidelines for haemovigilance and human resources. CONCLUSIONS: Implementation of sub-indicators and performance of haemovigilance systems varied greatly for all countries with a few countries performing reasonably well in the implementation of some sub-indicators under procedures for haemovigilance. Most countries were poorly implementing sub-indicators in the legal provisions, arrangement for effective organisation and human resources indicators. The legislative provisions in most countries were at a nascent stage. There is a need to set up targeted and customised technical support coupled with prioritised interventions to strengthen the capacities of NRAs.

Efficacy gap between phase II and subsequent phase III studies in oncology.

AIMS: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. METHODS: All oncology drugs approved by the European Medicines Agency (2007-2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression-free survival (PFS) and median overall survival (OS) were analysed through weighted mixed-effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. RESULTS: A total of 81 phase II-III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was -4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and -0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from -46.6% to 47.3% for ORR, from -5.3 to 35.9 months for PFS and from -13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. CONCLUSIONS: The lack of marked average differences between phases may encourage decision-makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects.

Differences in Health Technology Assessment Recommendations Among European Jurisdictions: The Role of Practice Variations.

BACKGROUND: Health technology assessment (HTA) plays an important role in reimbursement decision-making in many countries, but recommendations vary widely throughout jurisdictions, even for the same drug. This variation may be due to differences in the weighing of evidence or differences in the processes or procedures, which are known as HTA practices. OBJECTIVE: To provide insight into the effects of differences in practices on interpretation of intercountry differences in HTA recommendations for conditionally approved drugs. METHODS: HTA recommendations for conditionally approved drugs (N = 27) up until June 2017 from England/Wales, France, Germany, the Netherlands, and Scotland were included. Recommendations and practice characteristics were extracted from these five jurisdictions and this data was validated. The effect of nonsubmissions, resubmissions, and reassessments; cost-effectiveness assessments; and price negotiations on changes in the percentage of negative recommendations and the interpretation of intercountry differences in HTA outcomes were analyzed using Fisher exact tests. RESULTS: The inclusion of cost-effectiveness assessments led to significant increases in the proportion of negative recommendations in England/Wales (from 4% to 50%, P<.01) and Scotland (from 21% to 71%, P<.01). The subsequent inclusion of price negotiations led to significant reductions in the proportion of negative recommendations in England/Wales (from 50% to 14%, P<.01), France (from 31% to 3%, P=.012), and Germany (from 34% to 0%, P<.01). Results indicated that the inclusion of nonsubmissions and resubmissions might affect Scottish negative HTA recommendations (from 7% to 21%), but this effect was not significant. No significant effects were observed in the Netherlands, possibly owing to sample size. CONCLUSION: Variations in HTA practices between international jurisdictions can have a substantial and significant impact on conclusions about recommendations by HTA bodies, as exemplified in this cohort of conditionally approved products. Studies comparing international HTA recommendations should carefully consider possible practice variations between jurisdictions.