[Harmonizing development, approval and access of drugs for rare diseases in Europe.] / Verso un modello integrato di sviluppo, approvazione e accesso dei farmaci per malattie rare in Europa.

In the past few decades, the regulatory system has changed its approach to speed up the assessment and approval of drugs for the treatment of serious and orphan diseases. However, too early assessments may fail to provide solid evidence to define the therapeutic value of drugs and their fair price. As for rare diseases, patients' expectations amplify such criticalities due to the lack of therapeutic alternatives. The revision of the EU regulation on orphan medicinal products represents an opportunity to promote greater integration between the development and approval of drugs with their subsequent access. For this reason, we propose: 1) establishing a process for evaluating the comparative efficacy and quantification of the therapeutic benefit of a drug at a European level, while addressing incentives towards rarer diseases to support their development and marketing; 2) downsizing the impact of orphan drugs on general sustainability, considering that incentives supporting their development and marketing cannot transform them into new 'blockbusters'. In this perspective, a European procurement - initially intended for drugs for ultra-rare diseases - could improve access by all EU countries through simplifying the burdensome procedures for the pharmaceutical industry; 3) enhancing the contribution of post-authorization research from a public-private partnership perspective to steer the development of drugs already approved towards rarer pathologies or mutations of little commercial interest.

Global access to affordable direct oral anticoagulants.

Poor control of cardiovascular disease accounts for a substantial proportion of the disease burden in developing countries, but often essential anticoagulant medicines for preventing strokes and embolisms are not widely available. In 2019, direct oral anticoagulants were added to the World Health Organization's WHO Model list of essential medicines. The aims of this paper are to summarize the benefits of direct oral anticoagulants for patients with cardiovascular disease and to discuss ways of increasing their usage internationally. Although the cost of direct oral anticoagulants has provoked debate, the affordability of introducing these drugs into clinical practice could be increased by: price negotiation; pooled procurement; competitive tendering; the use of patent pools; and expanded use of generics. In 2017, only 14 of 137 countries that had adopted national essential medicines lists included a direct oral anticoagulant on their lists. This number could increase rapidly if problems with availability and affordability can be tackled. Once the types of patient likely to benefit from direct oral anticoagulants have been clearly defined in clinical practice guidelines, coverage can be more accurately determined and associated costs can be better managed. Government action is required to ensure that direct oral anticoagulants are covered by national budgets because the absence of reimbursement remains an impediment to achieving universal coverage. Tackling cardiovascular disease with the aid of direct oral anticoagulants is an essential component of efforts to achieve the World Health Organization's target of reducing premature deaths due to noncommunicable disease by 25% by 2025.

L'absence de lutte efficace contre les maladies cardiovasculaires contribue grandement à la charge de morbidité pesant sur les pays en développement. Pourtant, les anticoagulants essentiels permettant d'éviter les accidents vasculaires cérébraux et les embolies sont souvent difficiles à obtenir. En 2019, les anticoagulants oraux directs ont été ajoutés à la Liste modèle des médicaments essentiels publiée par l'Organisation mondiale de la Santé. Le présent document vise à résumer les avantages des anticoagulants oraux directs pour les patients souffrant d'une maladie cardiovasculaire, et à évoquer les moyens d'encourager leur utilisation au niveau international. Bien que le coût des anticoagulants oraux directs ait fait débat, intégrer ces médicaments dans la pratique clinique les rendrait plus abordables grâce à diverses méthodes: négociation des prix; achats groupés; appels d'offres concurrentiels; communautés de brevets; et recours accru aux alternatives génériques. En 2017, seulement 14 des 137 pays ayant adopté des listes nationales de médicaments essentiels y avaient inclus des anticoagulants oraux directs. Ce chiffre pourrait augmenter rapidement si les problèmes de disponibilité et d'accessibilité peuvent être résolus. Dès que les profils des patients susceptibles d'être traités par des anticoagulants oraux directs sont clairement établis dans les directives de pratique clinique, la couverture peut être définie avec plus de précision et les dépenses correspondantes, mieux gérées. Les gouvernements doivent s'assurer que ces médicaments sont bien pris en compte dans les budgets nationaux, car l'absence de remboursement demeure un obstacle à la couverture maladie universelle. La lutte contre les maladies cardiovasculaires à l'aide des anticoagulants oraux directs est un élément essentiel des efforts destinés à atteindre l'objectif de l'OMS: faire baisser de 25% d'ici 2025 les décès prématurés dus aux maladies non transmissibles de 25% d'ici 2025.

El mal control de las enfermedades cardiovasculares representa una proporción importante de la carga de enfermedades en los países en desarrollo, y a menudo los medicamentos anticoagulantes esenciales para prevenir los accidentes cerebrovasculares y las embolias no son fácilmente accesibles. En 2019, los anticoagulantes orales directos se añadieron a la lista modelo de medicamentos esenciales de la Organización Mundial de la Salud. Los objetivos del presente artículo son resumir los beneficios de los anticoagulantes orales directos para los pacientes con enfermedades cardiovasculares y discutir las formas de aumentar su uso a nivel internacional. Aunque el coste de los anticoagulantes orales directos ha suscitado debate, la asequibilidad de introducir estos medicamentos en la práctica clínica podría aumentarse al: negociar precios; hacer adquisiciones conjuntas; hacer licitaciones competitivas; utilizar consorcios de patentes; y ampliar el uso de genéricos. En 2017, solo 14 de los 137 países que habían adoptado listas nacionales de medicamentos esenciales incluían un anticoagulante oral directo en sus listas. Este número podría aumentar rápidamente si se pueden abordar los problemas de disponibilidad y asequibilidad. Cuando los tipos de pacientes que pueden beneficiarse de los anticoagulantes orales directos se hayan definido claramente en las directrices de la práctica clínica, la cobertura podrá determinarse con mayor precisión y los costes asociados podrán gestionarse mejor. Es necesario que los gobiernos actúen para garantizar que los anticoagulantes orales directos estén cubiertos por los presupuestos nacionales, ya que la ausencia de reembolso sigue siendo un impedimento para lograr la cobertura universal. La lucha contra las enfermedades cardiovasculares con la ayuda de los anticoagulantes orales directos es un componente esencial de los esfuerzos por alcanzar el objetivo de la OMS de reducir las muertes prematuras debidas a enfermedades no transmisibles en un 25 % para 2025.

Comparison of essential medicines lists in 137 countries.

OBJECTIVE: To compare the medicines included in national essential medicines lists with the World Health Organization's (WHO's) Model list of essential medicines, and assess the extent to which countries' characteristics, such as WHO region, size and health care expenditure, account for the differences. METHODS: We searched the WHO's Essential Medicines and Health Products Information Portal for national essential medicines lists. We compared each national list of essential medicines with both the 2017 WHO model list and other national lists. We used linear regression to determine whether differences were dependent on WHO Region, population size, life expectancy, infant mortality, gross domestic product and health-care expenditure. FINDINGS: We identified 137 national lists of essential medicines that collectively included 2068 unique medicines. Each national list contained between 44 and 983 medicines (median 310: interquartile range, IQR: 269 to 422). The number of differences between each country's essential medicines list and WHO's model list ranged from 93 to 815 (median: 296; IQR: 265 to 381). Linear regression showed that only WHO region and health-care expenditure were significantly associated with the number of differences (adjusted R2 : 0.33; P < 0.05). Most medicines (1248; 60%) were listed by no more than 10% (14) of countries. CONCLUSION: The substantial differences between national lists of essential medicines are only partly explained by differences in country characteristics and thus may not be related to different priority needs. This information helps to identify opportunities to improve essential medicines lists.

Consumption of oral antibiotic formulations for young children according to the WHO Access, Watch, Reserve (AWaRe) antibiotic groups: an analysis of sales data from 70 middle-income and high-income countries.

BACKGROUND: The 2017 WHO Model List of Essential Medicines for Children (EMLc) groups antibiotics as Access, Watch, or Reserve, based on recommendations of their use as first-choice and second-choice empirical treatment for the most common infections. This grouping provides an opportunity to review country-level antibiotic consumption and a potential for stewardship. Therefore, we aimed to review 2015 levels of oral antibiotic consumption by young children globally. METHODS: We analysed wholesale antibiotic sales in 70 middle-income and high-income countries in 2015. We identified oral antibiotic formulations appropriate for use in young children (defined as child-appropriate formulations [CAFs]) using wholesale data from the IQVIA-Multinational Integrated Data Analysis System database, and we estimated 2015 antibiotic consumption in reference to the 2017 WHO EMLc Access, Watch, Reserve (AWaRe) antibiotic groups. We used three metrics for assessment of intra-country patterns: access percentage, defined as the number of CAF standard units of Access antibiotics divided by the total number of CAF standard units; amoxicillin index, defined as the number of amoxicillin CAF standard units divided by the total number of CAF standard units; and access-to-watch index, defined as the ratio of Access-to-Watch CAF standard units. FINDINGS: The overall median volume of CAF antibiotic standard units sold in 2015 per country was 74·5 million (IQR 12·4-210·7 million). The median access percentage among the 70 countries was 76·3% (IQR 62·6-84·2). The amoxicillin index was low (median 30·7%, IQR 14·3-47·3). The median access-to-watch index was 6·0 (IQR 3·1-9·8). CAF antibiotic consumption patterns were highly variable between the 70 countries, without a clear difference between high-income and middle-income countries. INTERPRETATION: Antibiotics in the Access group have a key role in treating young children globally. A simple combination of metrics based on the AWaRe groups can be informative on individual countries' patterns of antibiotic consumption and stewardship opportunities. These metrics could support countries in the development of programmes to improve access to core Access antibiotics, particularly amoxicillin. FUNDING: Global Antibiotic R&D Partnership (German Federal Ministry of Health, Médecins Sans Frontières, Netherlands Ministry of Health, Welfare and Sport, and UK Department for International Development).

GRADE equity guidelines 4: considering health equity in GRADE guideline development: evidence to decision process.

OBJECTIVES: The aim of this paper is to provide detailed guidance on how to incorporate health equity within the GRADE (Grading Recommendations Assessment and Development Evidence) evidence to decision process. STUDY DESIGN AND SETTING: We developed this guidance based on the GRADE evidence to decision framework, iteratively reviewing and modifying draft documents, in person discussion of project group members and input from other GRADE members. RESULTS: Considering the impact on health equity may be required, both in general guidelines and guidelines that focus on disadvantaged populations. We suggest two approaches to incorporate equity considerations: (1) assessing the potential impact of interventions on equity and (2) incorporating equity considerations when judging or weighing each of the evidence to decision criteria. We provide guidance and include illustrative examples. CONCLUSION: Guideline panels should consider the impact of recommendations on health equity with attention to remote and underserviced settings and disadvantaged populations. Guideline panels may wish to incorporate equity judgments across the evidence to decision framework. This is the fourth and final paper in a series about considering equity in the GRADE guideline development process. This series is coming from the GRADE equity subgroup.

[Considerations on limits and profits of registries]. / Riflessioni e confronti sui limiti e i vantaggi dei registri.

The article collects the summary of the discussion occurred in the setting of PRIER II, in the session dedicated to the taxonomy of registries. Shown below, some specific contributions by health professionals working at the regional departments, which deal with registries, as well as the contribution on the same subject by specialists working at some pharmaceutical companies. In particular, after the presentation summarized in the article by prof. Giuseppe Costa1, the contributions, respectively by a representative of the Emilia-Romagna Region, of a health and hospital service and by the PRIER II workgroup, are following. Finally, a collective work with all participants to the working group took place to focus on all the issues considered to be crucial in defining clinical registries. At the same discussion table, institutional representatives of the regulatory national and regional branch were also invited to take into consideration the points of view of all public and private registry users, in particular in their benefits, limits and purposes. Going through the discussion on a specific check list and deepening a number of statements identified by the working group, a list of key points, essential to characterize each clinical registry, was produced.

The role of Cochrane reviews in informing international guidelines: a case study of using the Grading of Recommendations, Assessment, Development and Evaluation system to develop World Health Organization guidelines for the psychosocially assisted pharmacological treatment of opioid dependence.

BACKGROUND AND AIMS: The World Health Organization (WHO), and a growing number of other organizations, have adopted the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system in order to both assess the quality of research evidence and develop clinical practice guidelines. In 2009 WHO published a guideline on psychosocially assisted pharmacological treatment of opioid dependence, based on the results of Cochrane Reviews summarized using the GRADE methodology. The main features of this system are an a priori definition of outcomes and their relevance, and distinction between the quality of evidence (also referred to as confidence in the estimate of intervention effect) and the strength of recommendations. We consider how successful this approach has been. ANALYSIS AND EVIDENCE: We discuss the merits and limitations of using Cochrane Reviews and GRADE framework in developing guidelines in the field of drug addiction. In 2009 a panel of multi-disciplinary international experts identified 15 clinical questions and eight relevant outcomes. Cochrane reviews were available for each clinical question and four outcomes. The panel formulated 15 recommendations. Eight recommendations were classified as strong, two of which were based on high-quality evidence and three on very low-quality evidence. For example, the strong recommendation to use methadone in adequate doses in preference to buprenorphine was based on high-quality evidence, while the strong recommendation not to use the combination of opioid antagonists with heavy sedation in the management of opioid withdrawal was based on low-quality evidence. CONCLUSIONS: An explicit stepwise process of moving from evaluation of the quality of evidence to the definition of the strength of recommendations is important in providing practical and clear clinical guidance for practitioners and policy-makers in addiction.

Feasibility and effectiveness of a low cost campaign on antibiotic prescribing in Italy: community level, controlled, non-randomised trial.

OBJECTIVES: To test the hypothesis that a multifaceted, local public campaign could be feasible and influence antibiotic prescribing for outpatients. DESIGN: Community level, controlled, non-randomised trial. SETTING: Provinces of Modena and Parma in Emilia-Romagna, northern Italy, November 2011 to February 2012. POPULATION: 1,150,000 residents of Modena and Parma (intervention group) and 3,250,000 residents in provinces in the same region but where no campaign had been implemented (control group). INTERVENTIONS: Campaign materials (mainly posters, brochures, and advertisements on local media, plus a newsletter on local antibiotic resistance targeted at doctors and pharmacists). General practitioners and paediatricians in the intervention area participated in designing the campaign messages. MAIN OUTCOMES MEASURES: Primary outcome was the average change in prescribing rates of antibiotics for outpatient in five months, measured as defined daily doses per 1000 inhabitants/day, using health districts as the unit of analysis. RESULTS: Antibiotic prescribing was reduced in the intervention area compared with control area (-4.3%, 95% confidence interval -7.1% to -1.5%). This result was robust to "sensitivity analysis" modifying the baseline period from two months (main analysis) to one month. A higher decrease was observed for penicillins resistant to ß lactamase and a lower decrease for penicillins susceptible to ß lactamase, consistent with the content of the newsletter on antibiotic resistance directed at health professionals. The decrease in expenditure on antibiotics was not statistically significant in a district level analysis with a two month baseline period (main analysis), but was statistically significant in sensitivity analyses using either a one month baseline period or a more powered doctor level analysis. Knowledge and attitudes of the target population about the correct use of antibiotics did not differ between the intervention and control areas. CONCLUSIONS: A local low cost information campaign targeted at citizens, combined with a newsletter on local antibiotic resistance targeted at doctors and pharmacists, was associated with significantly decreased total rates of antibiotic prescribing but did not affect the population's knowledge and attitudes about antibiotic resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT01604096.

[The role of drug registries in the post-marketing surveillance]. / I registri nella sorveglianza post-marketing dei farmaci. Un'introduzione.

The aim of this article is to provide an introduction to issue of Recenti Progressi in Medicina, devoted to the role of drug registries in the post-marketing surveillance. We first motivate the need to implement registries as a tool in promoting the appropriateness of drug use and acquiring additional information on the risk-benefit profile of drugs. Then, the different role that can be played by registries in comparison with prescription monitoring systems and observational studies is clarified. The presentation of some of the most relevant registries established in Italy since the end of the '90s, with the analysis of their strengths and weaknesses, helps to understand some of the crucial issues that should be taken into account before a new registry is adopted. Specifically, we deal with the relationship between objectives - of appropriateness, effectiveness and safety - and methods; the overlapping between drug-based registries and disease-based ones; the duration and extension of data collection, which may be either exhaustive or based on a sampling frame; the importance of ensuring the quality of the data and to minimize the number of subjects who are lost to follow-up; the importance of infrastructures, and of ad hoc funding, for the functioning of a registry; the independence in data analysis and publication of findings.

[A perspective for the role of drug registries in the post-marketing surveillance]. / Una prospettiva per i registri nella sorveglianza post-marketing dei farmaci.

Drug registries are implemented after the authorization of new products and represent a tool for systematic collection of data aimed at obtaining additional knowledge on appropriateness, effectiveness and safety. The design of registries needs to be coherent with the main objective and a study protocol is required before the implementation. A registry aimed at the appropriateness of drug use should be primarily considered for high cost drugs when there is a risk, either for the patients' safety or for public expenditure, in using the drug outside the approved indications. Since the registry is a condition for the access to drugs, and all users are included, an extremely simplified data collection is required. However, the data should be available at regional level to allow record linkage procedures with other databases for conducting outcome studies. When registries are aimed at acquiring new information on the risk profile, the duration and the regional extension of data collection should be coherent with the expected incidence of events of interest. A great attention should be devoted in preventing that patients are lost to follow-up, since the reasons for being lost are frequently associated with harmful outcomes, such as adverse drug reactions. In a registry focused on effectiveness, the main aim consists in ascertaining the reasons (the prognostic factors), for possible discrepancies between premarketing studies and clinical practice. Taking into account the greater incidence of the expected events, there are fewer reasons for extending data collection to all users, whereas the main attention should focus on quality controls and the ascertainment of confounding factors. Given the relevance of the validity issues, in the set out of a registry it is important to think about ad hoc resources and the adequacy of infrastructures. As for any epidemiological study, an adequate qualification of the researcher/clinician in charge of conducting a registry should be guaranteed, together with independence in data analysis and freedom to publish all findings.

Grading quality of evidence and strength of recommendations.

Users of clinical practice guidelines and other recommendations need to know how much confidence they can place in the recommendations. Systematic and explicit methods of making judgments can reduce errors and improve communication. We have developed a system for grading the quality of evidence and the strength of recommendations that can be applied across a wide range of interventions and contexts. In this article we present a summary of our approach from the perspective of a guideline user. Judgments about the strength of a recommendation require consideration of the balance between benefits and harms, the quality of the evidence, translation of the evidence into specific circumstances, and the certainty of the baseline risk. It is also important to consider costs (resource utilisation) before making a recommendation. Inconsistencies among systems for grading the quality of evidence and the strength of recommendations reduce their potential to facilitate critical appraisal and improve communication of these judgments. Our system for guiding these complex judgments balances the need for simplicity with the need for full and transparent consideration of all important issues.

[Relationship between the assessment of coronary risk using the Italian chart and the assessment with the New Zealand chart]. / Relazione tra la valutazione del rischio coronarico calcolato con la carta italiana e quella neozelandese.

OBJECTIVE: To describe the distribution of coronary risk in primary prevention using both the New Zealand and Italian charts, and to assess whether there is a relationship between the two scales built on data from populations at different natural coronary risk. DESIGN: Descriptive study. SETTING: Carpi's district, Territorial Health Authority in Modena province. PARTICIPANTS: Population between 40 and 69 years old without any background of cardiovascular disease. MAIN MEASURES: The variables studied corresponded to the Jackson's New Zealand table and the Italian Progetto Cuore's one. Concordance was assessed with the kappa coefficient. RESULTS: We studied 1850 men and 2235 women with an average age of 56 years. The percentage of 'high' coronary risk men and women at the New Zealand's chart was 27% and 8% respectively. Ten percent of 'high' risk men and no woman were found at the Italian chart. The kappa coefficient to evaluate the agreement on high risk men between the two charts was 'moderate' (kappa = 0.403). No estimation was allowed for women. CONCLUSION: There was moderate agreement between the New Zealand and the Progetto Cuore charts.