Availability of essential, generic medicines before and during COVID-19 at selected public pharmaceutical supply agencies in Ethiopia: a comparative cross-sectional study.

OBJECTIVES: Lockdowns and border closures impacted medicine availability during the COVID-19 pandemic. This study aimed to assess the availability of essential, generic medicines for chronic diseases at public pharmaceutical supply agencies in Ethiopia. DESIGN: Comparative cross-sectional study. SETTING: The availability of essential, generic medicines for chronic diseases was assessed at two public pharmaceutical supply agency hubs. PARTICIPANTS: The current study included public supply agency hub managers, warehouse managers and forecasting officers at the study setting. OUTCOMES: The assessment encompassed the availability of chronic medicines on the day of data collection, as well as records spanning 8 months before the outbreak and 1 year during the pandemic. A total of 22 medicines were selected based on their inclusion in the national essential drug list for public health facilities, including 17 medicines for cardiovascular disease and 5 for diabetes mellitus. RESULTS: The results of the study indicate that the mean availability of the selected basket medicines was 43.3% (95% CI: 37.1 to 49.5) during COVID-19, which was significantly lower than the availability of 67.4% (95% CI: 62.2 to 72.6) before the outbreak (p<0.001). Prior to COVID-19, the overall average line-item fill rate for the selected products was 78%, but it dropped to 49% during the pandemic. Furthermore, the mean number of days out of stock per month was 11.7 (95% CI: 9.9 to 13.5) before the outbreak of COVID-19, which significantly increased to 15.7 (95% CI: 13.2 to 18.2) during the pandemic, indicating a statistically significant difference (p<0.001). Although the prices for some drugs remained relatively stable, there were significant price hikes for some products. For example, the unit price of insulin increased by more than 130%. CONCLUSION: The COVID-19 pandemic worsened the availability of essential chronic medicines, including higher rates of stockouts and unit price hikes for some products in the study setting. The study's findings imply that the COVID-19 pandemic has aggravated already-existing medicine availability issues. Efforts should be made to develop contingency plans and establish mechanisms to monitor medicine availability and pricing during such crises.

The knock-on effects of COVID-19 pandemic on the supply and availability of generic medicines in Ethiopia: mixed methods study.

BACKGROUND: COVID-19 pandemic posed a major impact on the availability and affordability of essential medicines. This study aimed to assess the knock-on effects of the COVID-19 pandemic on the supply availability of non-communicable chronic disease (NCD) medicines and paracetamol products in Ethiopia. METHODS: A mixed methods study was conducted to assess the supply and availability of twenty-four NCD drugs and four paracetamol products listed on the national essential medicines list for hospitals. Data were collected from twenty-six hospitals located in seven zones of Oromia region in the southwestern part of Ethiopia. We extracted data on drug availability, cost and stock out for these drugs between May 2019 and December 2020. The quantitative data were entered into Microsoft Excel and exported to statistical package software for social science (SPSS) version 22 (IBM Corporation, Armonk, NY, USA) software for analysis. RESULTS: The overall mean availability of selected basket medicines was 63.4% (range 16.7% to 80.3%) during the pre-COVID-19 time. It was 46.3% (range 2.8% to 88.7) during the pandemic. There was a relative increase in the availability of two paracetamol products [paracetamol 500 mg tablet (67.5% versus 88.7%) and suppository (74.5% versus 88%)] during the pandemic. The average monthly orders fill rates for the selected products range from 43 to 85%. Pre-COVID-19, the average order fill rate was greater or equal to 70%. However, immediately after the COVID-19 case notification, the percentage of order(s) filled correctly in items and quantities began decreasing. Political instability, shortage of trained human resources, currency inflation, and limited drug financing were considered as the major challenges to medicine supply. CONCLUSION: The overall stock out situation in the study area has worsened during COVID-19 compared to pre-COVID-19 time. None of the surveyed chronic disease basket medicines met the ideal availability benchmark of 80% in health facilities. However, availability of paracetamol 500 mg tablet surprisingly improved during the pandemic. A range of policy frameworks and options targeting inevitable outbreaks should exist to enable governments to ensure that medicines for chronic diseases are consistently available and affordable.

Patient Access in 14 High-Income Countries to New Antibacterials Approved by the US Food and Drug Administration, European Medicines Agency, Japanese Pharmaceuticals and Medical Devices Agency, or Health Canada, 2010-2020.

BACKGROUND: Inaccessibility of medicines in low- and middle-income countries is a frequent challenge. Yet it is typically assumed that high-income countries have complete access to the full arsenal of medicines. This study tests this assumption for new antibacterials, which are saved as a last resort in order to prevent the development of resistance, resulting in insufficient revenues to offset costs. Prior studies report only regulatory approval, missing the important lag that occurs between approval and commercial launch, although some antibiotics never launch in some countries. METHODS: We identified all antibacterials approved and launched in the G7 and 7 other high-income countries in Europe for the decade beginning 1 January 2010, using quantitative methods to explore associations. RESULTS: Eighteen new antibacterials were identified. The majority were accessible in only 3 countries (United States, United Kingdom, and Sweden), with the remaining 11 high-income countries having access to less than half of them. European marketing authorization did not lead to automatic European access, as 14 of the antibacterials were approved by the European Medicines Agency but many fewer were commercially launched. There was no significant difference in access between "innovative" and "noninnovative" antibacterials. Median annual sales in the first launched market (generally the United States) for these 18 antibiotics were low, $16.2M. CONCLUSIONS: Patient access to new antibacterials is limited in some high-income countries including Canada, Japan, France, Germany, Italy, and Spain. With low expected sales, companies may have decided to delay or forego commercialization due to expectations of insufficient profitability.

Overview of the market for novel medicines in the WHO European Region

The Oslo Medicines Initiative (OMI) is a platform through which stakeholders can collaborate to develop ways of achieving better, more affordable access to novel, high-priced medicines. To provide a foundation for this, a series of technical reports was commissioned to explore the issues, canvass ideas and present potential policy approaches for achieving better access and improved affordability. This introductory paper presents an overview of the issues and the complex dynamics involved. At their core is the concern that while the pharmaceutical industry continues to deliver important new therapies, launch prices are rising rapidly and this increasingly limits access for patients. Overall costs of these products are becoming unsustainable for both health-care systems and the patients they serve. Individual governments have limited bargaining power when procuring medicines, and competing policy goals may run counter to efforts to moderate costs. The OMI technical reports offer a broad landscape of ideas for building a forward-looking agenda to address the long-term interests of patients, payers, providers and the pharmaceutical industry.

Antimicrobial Resistance: Is Health Technology Assessment Part of the Solution or Part of the Problem?

Antimicrobial resistance is a serious challenge to the success and sustainability of our healthcare systems. There has been increasing policy attention given to antimicrobial resistance in the last few years, and increased amounts of funding have been channeled into funding for research and development of antimicrobial agents. Nevertheless, manufacturers doubt whether there will be a market for new antimicrobial technologies sufficient to enable them to recoup their investment. Health technology assessment (HTA) has a critical role in creating confidence that if valuable technologies can be developed they will be reimbursed at a level that captures their true value. We identify 3 deficiencies of current HTA processes for appraising antimicrobial agents: a methods-centric approach rather than problem-centric approach for dealing with new challenges, a lack of tools for thinking about changing patterns of infection, and the absence of an approach to epidemiological risks. We argue that, to play their role more effectively, HTA agencies need to broaden their methodological tool kit, design and communicate their analysis to a wider set of users, and incorporate long-term policy goals, such as containing resistance, as part of their evaluation criteria alongside immediate health gains.

National Facilitators and Barriers to the Implementation of Incentives for Antibiotic Access and Innovation.

Prominent reports have assessed the challenges to antibiotic innovation and recommended implementing "pull" incentives, i.e., mechanisms that give increased and predictable revenues for important, marketed antibiotics. We set out to understand countries' perceptions of these recommendations, through frank and anonymous dialogue. In 2019 and 2020, we performed in-depth interviews with national policymakers and antibiotic resistance experts in 13 countries (ten European countries and three non-European) for a total of 73 individuals in 27 separate interviews. Interviewees expressed high-level support for antibiotic incentives in 11 of 13 countries. There is recognition that new economic incentives are needed to maintain a reliable supply to essential antibiotics. However, most countries are uncertain which incentives may be appropriate for their country, which antibiotics should be included, how to implement incentives, and how much it will cost. There is a preference for a multinational incentive, so long as it is independent of national pricing, procurement, and reimbursement processes. Nine countries indicated a preference for a model that ensures access to both existing and new antibiotics, with the highest priority for existing antibiotics. Twelve of thirteen countries indicated that shortages of existing antibiotics is a serious problem. Since countries are skeptical about the public health value of many recently approved antibiotics, there is a mismatch regarding revenue expectations between policymakers and antibiotic innovators. This paper presents important considerations for the design and implementation of antibiotic pull mechanisms. We also propose a multinational model that appears to match the needs of both countries and innovators.

The effect of generic market entry on antibiotic prescriptions in the United States.

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)-aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin-and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.

A one health framework to estimate the cost of antimicrobial resistance.

OBJECTIVES/PURPOSE: The costs attributable to antimicrobial resistance (AMR) remain theoretical and largely unspecified. Current figures fail to capture the full health and economic burden caused by AMR across human, animal, and environmental health; historically many studies have considered only direct costs associated with human infection from a hospital perspective, primarily from high-income countries. The Global Antimicrobial Resistance Platform for ONE-Burden Estimates (GAP-ON€) network has developed a framework to help guide AMR costing exercises in any part of the world as a first step towards more comprehensive analyses for comparing AMR interventions at the local level as well as more harmonized analyses for quantifying the full economic burden attributable to AMR at the global level. METHODS: GAP-ON€ (funded under the JPIAMR 8th call (Virtual Research Institute) is composed of 19 international networks and institutions active in the field of AMR. For this project, the Network operated by means of Delphi rounds, teleconferences and face-to-face meetings. The resulting costing framework takes a bottom-up approach to incorporate all relevant costs imposed by an AMR bacterial microbe in a patient, in an animal, or in the environment up through to the societal level. RESULTS: The framework itemizes the epidemiological data as well as the direct and indirect cost components needed to build a realistic cost picture for AMR. While the framework lists a large number of relevant pathogens for which this framework could be used to explore the costs, the framework is sufficiently generic to facilitate the costing of other resistant pathogens, including those of other aetiologies. CONCLUSION: In order to conduct cost-effectiveness analyses to choose amongst different AMR-related interventions at local level, the costing of AMR should be done according to local epidemiological priorities and local health service norms. Yet the use of a common framework across settings allows for the results of such studies to contribute to cumulative estimates that can serve as the basis of broader policy decisions at the international level such as how to steer R&D funding and how to prioritize AMR amongst other issues. Indeed, it is only by building a realistic cost picture that we can make informed decisions on how best to tackle major health threats.

Infection prevention and control research priorities: what do we need to combat healthcare-associated infections and antimicrobial resistance? Results of a narrative literature review and survey analysis.

BACKGROUND: Infection prevention and control (IPC) is one of the most cost-effective interventions against antimicrobial resistance (AMR). Yet, IPC knowledge gaps often receive little prominence in AMR research agendas. In this article, we construct IPC research priorities, in order to draw attention to these critical research needs. METHODS: We developed a 4-step framework to identify IPC knowledge gaps from literature (narrative review). These gaps were then translated into research priorities and sent to two groups of European IPC experts for validation and critique through an online survey. RESULTS: Seventy-nine publications were retrieved from the literature review, identifying fifteen IPC research gaps. Forty-four IPC experts, clustered in two groups, vetted them. The experts classified all research gaps as medium or high priority. Overall agreement between both groups was average (Kendall's τ = 0.43), with strong alignment on the highest priorities: (i) the assessment of organizational, socio-economic, and behavioural barriers/facilitators for the implementation of IPC programmes, (ii) the impact of overcrowding on the spread of infections and (iii) the impact of infrastructural changes, at facility level, on the reduction of infections. Feedback from experts also identified an additional research gap on the interaction between the human and hospital microbiomes. CONCLUSIONS: We formulated a list of sixteen research priorities and identified three urgent needs. Now, we encourage researchers, funding agencies, policymakers and relevant stakeholders to start addressing the identified gaps.

Financing Pull Mechanisms for Antibiotic-Related Innovation: Opportunities for Europe.

Antibiotic innovation is in serious jeopardy as companies continue to abandon the market due to a lack of profitability. Novel antibiotics must be used sparingly to hinder the spread of resistance, but small companies cannot survive on revenues that do not cover operational costs. When these companies either go bankrupt or move onto other therapeutic areas, these antibiotics may be no longer accessible to patients. Although significant research efforts have detailed incentives to stimulate antibiotic innovation, little attention has been paid to the financing of these incentives. In this article, we take a closer look at 4 potential financing models (diagnosis-related group carve-out, stewardship taxes, transferable exclusivity voucher, and a European-based "pay or play" model) and evaluate them from a European perspective. The attractiveness of these models and the willingness for countries to test them are currently being vetted through the European Joint Action on AMR and Healthcare-Associated Infections (EU-JAMRAI).

A case study on Staphylococcus aureus bacteraemia: available treatment options, antibiotic R&D and responsible antibiotic-use strategies.

OBJECTIVES: This case study addresses: (i) antibiotic treatment options for Staphylococcus aureus bacteraemia (SAB), for both empirical and targeted therapy; (ii) the current status of and priorities for the antibiotic pipeline to ensure access of effective antibiotics for SAB; and (iii) strategies for responsible antibiotic use relevant to the clinical management of SAB. METHODS: Evidence to address the aims was extracted from the following information sources: (i) EUCAST and CLSI recommendations, summaries of product characteristics (SPCs), antibiotic treatment guidelines and the textbook Kucers' The Use of Antibiotics; (ii) the www.clinicaltrial.gov database; and (iii) quality indicators for responsible antibiotic use. RESULTS: Current monotherapy treatment options for SAB include only three drug classes (ß-lactams, glycopeptides and lipopeptides), of which two also cover MRSA bacteraemia (glycopeptides and lipopeptides). The analysis of the antibiotic pipeline and ongoing clinical trials revealed that several new antibiotics with S. aureus (including MRSA) coverage were developed in the past decade (2009-19). However, none belonged to a new antibiotic class or had superior effectiveness and their added clinical value for SAB remains to be proven. Responsible antibiotic use for the treatment of SAB was illustrated using 11 quality indicators. CONCLUSIONS: Awareness of the problem of a limited antibiotic arsenal, together with incentives (e.g. push incentives), is needed to steer the R&D landscape towards the development of novel and effective antibiotics for treating SAB. In the meantime, responsible antibiotic use guided by quality indicators should preserve the effectiveness of currently available antibiotics for treating SAB.

Industrial perceptions of medicines regulatory harmonization in the East African Community.

BACKGROUND: Medicines regulatory harmonization has been recommended as one way to improve access to quality-assured medicines in low- and middle-income countries. The rationale is that by lowering barriers to entry more manufacturers will be enticed to enter the market, while the capacity at the national medicines regulatory authorities is strengthened. The African Medicines Regulatory Harmonization Initiative, agreed in 2009, is developing regional platforms with harmonized regulatory procedures for the registration of medicines. The first region to implement medicines regulatory harmonization was the East African Community (EAC). The harmonization was based on the existing EAC Free Trade Agreement, which officially launched the free movement of goods and services in 2010. METHODS AND FINDINGS: In this study we conducted semi-structured interviews and performed document reviews. The main target group for our interviews was pharmaceutical companies. We interviewed 18 companies, including 64% of the total companies who had experienced the EAC joint product assessment procedure, and two EAC-based national medicines regulatory authorities. We found that generally pharmaceutical companies are supportive of the African-based MRH efforts and appreciative of the progress being achieved. However, many companies are now hesitant to use the joint product assessment procedure until efficiency improvements are made. Common frustrations were the length of time to receive the actual marketing authorization; unexpectedly higher quality standards than national procedures; and challenges in getting all EAC countries to recognize EAC approvals. Smaller, less attractive markets have not yet become more attractive from a corporate perspective, and there is no free trade of pharmaceuticals in the EAC region. CONCLUSIONS: Pharmaceutical companies agree that medicines regulatory harmonization is the way forward. However, regulatory medicines harmonization must actually result in quicker access to the harmonized markets for quality-assured medicines. At this time, improvements are required to the current EAC processes to meet the vision of harmonization.

Ensuring Antibiotic Development, Equitable Availability, and Responsible Use of Effective Antibiotics: Recommendations for Multisectoral Action.

Antibiotic resistance is a growing threat to global public health. The World Health Organization's Global Action Plan on Antimicrobial Resistance recommends engaging multisectoral stakeholders to tackle the issue. However, so far, few studies have addressed barriers to antibiotic development, equitable availability, and responsible antibiotic use from the perspective of stakeholders outside healthcare facilities or patient communities: the so-called third-party stakeholders. Third-party stakeholders include, inter alia, governments, regulatory agencies, and professionals working in antibiotic research and development and medical ethics. This viewpoint provides an overview of barriers to antibiotic development, equitable availability of effective antibiotics, and the responsible use of antibiotics. The barriers were identified in an exploratory, qualitative interview study with an illustrative sample of 12 third-party stakeholders. Recommendations to lift these barriers are presented, together with examples of recently-made progress. The recommendations should guide future antibiotic policies and multisectoral policy action.

Introduction and geographic availability of new antibiotics approved between 1999 and 2014.

BACKGROUND: Despite the urgent need for new, effective antibiotics, few antibiotics of value have entered the market during the past decades. Therefore, incentives have been developed to stimulate antibiotic R&D. For these incentives to be effective, geographic availability for recently approved antibiotics needs to be better understood. In this study, we analyze geographic availability and market introduction of antibiotics approved between 1999 and 2014. MATERIAL AND METHOD: We identified antibiotics, considered new chemical entities (NCEs) for systemic use approved globally between 1999 and 2014, from national medicine agencies' lists of approved drugs, and data from the WHO Collaborating Center for Drug Statistics. Geographic availability was mapped using sales data from IQVIA, and analyzed with regards to class, indication, safety, and origin. RESULTS: Of the 25 identified NCEs, only 12 had registered sales in more than 10 countries. NCEs with the widest geographic availability had registered sales in more than 70 countries within a ten-year timeframe and 30 countries within a three-year timeframe, spreading across five different geographic regions and three country income classes. Half (52%) of the NCEs had an indication for infections caused by antibiotic- resistant bacteria, little diversity was seen regarding target pathogen and indication. Antibiotics originated from and/or marketed by companies from the US or Europe had greater geographic availability compared to Japanese antibiotics, which seldom reached outside of Asia. For 20 NCEs developers chose to fully or partially sublicense marketing rights to a number of companies of different sizes. CONCLUSION: Our findings show great variation in geographic availability of antibiotics, indicating that availability in multiple regions and country income classes is possible, but rarely seen within a few years of market authorization. Sublicensing agreements between multiple companies was common practice. Moreover, differences were seen between countries regarding benefit/risk evaluations and company behavior. These findings could be a potential source of uncertainties, and create barriers to assure that working antibiotics are developed and made available according to public health needs.