Trust and the regulation of pharmaceuticals: South Asia in a globalised world

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BACKGROUND: Building appropriate levels of trust in pharmaceuticals is a painstaking and challenging task, involving participants from different spheres of life, including producers, distributors, retailers, prescribers, patients and the mass media. Increasingly, however, trust is not just a national matter, but involves cross-border flows of knowledge, threats and promises. METHODS: Data for this paper comes from the project 'Tracing Pharmaceuticals in South Asia', which used ethnographic fieldwork and qualitative interviews to compared the trajectories of three pharmaceuticals (Rifampicin, Oxytocin and Fluoxetine) from producer to patient in three sites (north India, West Bengal and Nepal) between 2005-08. RESULTS: We argue that issues of trust are crucial in reducing the likelihood of appropriate use of medicines. Unlike earlier discussions of trust, we suggest that trust contexts beyond the patient-practitioner relationship are important. We illustrate these arguments through three case studies: (i) a conflict over ethics in Nepal, involving a suggested revised ethical code for retailers, medical representatives, producers and prescribers; (ii) disputes over counterfeit, fake, substandard and spurious medicines, and quality standards in Indian generic companies, looking particularly at the role played by the US FDA; and (iii) the implications of lack of trust in the DOTS programmes in India and Nepal for the relationships among patients, government and the private sector. CONCLUSIONS: We conclude that the building of trust is a necessary but always vulnerable and contingent process. While it might be desirable to outline steps that can be taken to build trust, the range of conflicting interests in the pharmaceutical field make feasible solutions hard to implement.This paper emerged from the collaborative research project Tracing Pharmaceuticals in South Asia (2006-2009) that was jointly funded by the Economic and Social Research Council and the Department for International Development (RES-167-25-0110)

Registration and local production of essential medicines in Uganda

Universal access to high quality essential medicines is critical to sustainable development (SDG 3.8). However low- and middle-income countries struggle to ensure access to all medicines on their national essential medicines lists (EML). Market registration is the first step in determining both access and availability yet the extent to which essential medicines are registered for use at country level is not known. Companies apply for a marketing authorisation, however low price or lack of a market is a disincentive. Local production has been promoted to ensure availability of essential medicines but research in this area is also limited.; The study took place between 2011 and 2015. We systematically examined the registration status of medicines and vaccines listed in the Ugandan 2012 EML and conducted 20 interviews with regulators, ministry of health representatives, donors, and pharmaceutical producers and analysed quality assurance issues affecting registration, procurement, and local production of medicines in Uganda. In 2017 we conducted a further three interviews to clarify issues around non-registration of essential medicines highlighted by our analysis.; Of the 566 essential medicines and vaccines nearly half (49%; 275/566) had no registered product in 2012. Of the 3130 registered products, just over a quarter (28%; 880/3130) were listed on the EML. Six local producers had registered 138 products of which 40 corresponded to 32 unique essential medicines. Interviews highlighted alternative routes to availability other than registration. Local producers faced considerable barriers to achieving international quality standards required for international procurement of medicines for the domestic market.; Monitoring and audit of the registration of essential and non-essential medicines should be a priority nationally and, regionally through harmonisation of registration requirements in the East African Community. National and regional manufacturing plans should consider local production of unregistered essential medicines

Regulatory enforcement of the marketing of fixed-dose combinations in India: a case study of systemic antibiotics

\ua9 2023, The Author(s).Background: In India, states have licensed the manufacture of large numbers of fixed-dose combination (FDC) drugs without the required prior approval of the central regulator. This paper describes two major regulatory initiatives to address the problem, which began in 2007 and 2013, and examines whether they have been sufficient to remove centrally unapproved systemic antibiotic FDCs from the market. Methods: Information was extracted from documents published by the central regulator and the ministry of health, including the National List of Essential Medicines (NLEM), and court judgments, and analysed alongside sales volume data for 2008–2020 using PharmaTrac market dataset. Results: The regulatory initiatives permitted 68 formulations to be given de facto approvals (‘No Objection Certificates’) outside the statutory regime, banned 46 FDCs and restricted one FDC. Market data show that FDCs as a proportion of total antibiotic sales increased from 32.9 in 2008 to 37.3% in 2020. The total number of antibiotic FDC formulations on the market fell from 574 (2008) to 395 (2020). Formulations with a record of prior central approval increased from 86 (2008) to 94 (2020) and their share of the antibiotic FDC sales increased from 32.0 to 55.3%. In 2020, an additional 23 formulations had been permitted de facto approval, accounting for 10.6% of the antibiotic FDC sales. Even in 2020, most marketed formulations (70.4%, 278/395) were unapproved or banned, and comprised a 15.9% share of the antibiotic FDC sales. The share of NLEM-listed antibiotic FDC sales increased from 21.2 (2008) to 26.7% (2020). Conclusion: The initiatives had limited impact. Regulatory enforcement has been slow and weak, with many unapproved, and even banned, FDCs remaining on the market

Aid conditionalities, international Good Manufacturing Practice standards and local production rights: a case study of local production in Nepal

© 2015 Brhlikova et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This work was supported by the Economic and Social Research Council and the Department for International Development [RES-167-25-0110] through the collaborative research project Tracing Pharmaceuticals in South Asia (2006 – 2009). In addition to the authors of this paper, the project team included: Soumita Basu, Gitanjali Priti Bhatia, Erin Court, Abhijit Das, Stefan Ecks, Patricia Jeffery, Roger Jeffery, Rachel Manners, and Liz Richardson. Martin Chautari (Kathmandu) and the Centre for Health and Social Justice (New Delhi) provided resources drawn upon in writing this paper but are not responsible for the views expressed, nor are ESRC or DFID. Ethical review was provided by the School of Social and Political Science at the University of Edinburgh, and ethical approval in Nepal for the study granted by the Nepal Health Research Council (NHRC)

Standardization as situation-specific achievement: regulatory diversity and the production of value in intercontinental collaborations in stem cell medicine

The article examines the role and challenges of scientific self-governance and standardization in inter-continental clinical research partnerships in stem cell medicine. The paper shows that – due to a high level of regulatory diversity – the enactment of internationally recognized standards in multi-country stem cell trials is a complex and highly situation-specific achievement. Standardization is imposed on a background of regulatory, institutional and epistemic-cultural heterogeneity, and implemented exclusively in the context of select clinical projects. Based on ethnographic data from the first trans-continental clinical trial infrastructure in stem cell medicine between China and the USA, the article demonstrates that locally evolved and international forms of experimental clinical research practices often co-exist in the same medical institutions. Researchers switch back and forth between these schemas, depending on the purposes of their research, the partners they work with, the geographic scale of research projects, and the contrasting demands for regulatory review, that result from these differences. Drawing on Birch’s analysis of the role of standardization in international forms of capital production in the biosciences, the article argues that the integration of local knowledge institutions into the global bioeconomy does not necessarily result in the shutting down of localized forms of value production. In emerging fields of medical research, that are regulated in highly divergent ways across geographical regions, the coexistence of distinct modes of clinical translation allows also for the production of multiple forms of economic value, at varying spatial scales. This is especially so in countries with lenient regulations. As this paper shows, the long-standing absence of a regulatory framework for clinical stem cell applications in China, permits the situation-specific adoption of internationally recognized standards in some contexts, while enabling the continuation of localized forms of value production in others

Systemic antibiotic sales and WHO recommendations, India.

To analyse sales of fixed-dose combination and single antibiotics in India in relation to World Health Organization (WHO) recommendations and national regulatory efforts to control antibiotic sales. We extracted data on sales volumes of systemic antibiotics in India from a market research company sales database. We compared the market share of antibiotic sales in 2020 by WHO AWaRe (Access, Watch and Reserve) category and for those under additional national regulatory controls. We also analysed sales of fixed-dose combinations that were: formally approved for marketing or had a no-objection certificate; on the national essential medicines list; and on the WHO list of not-recommended antibiotics. There were 78 single and 112 fixed-dose combination antibiotics marketed in India, accounting for 7.6 and 4.5 billion standard units of total sales, respectively. Access, Watch and Reserve antibiotics comprised 5.8, 5.6 and 0.1 billion standard units of total market sales, respectively. All additionally controlled antibiotics were Watch and Reserve antibiotics (23.6%; 2.9 billion standard units of total sales). Fixed-dose combinations on the WHO not-recommended list were marketed in 229 formulations, with 114 formulations (49.8%) having no record of formal approval or no-objection certificate. While there were no not-recommended fixed-dose combinations on the national list of essential medicines, 13 of the top-20 selling antibiotic fixed-dose combinations were WHO not-recommended. The sale of Watch group drugs, and antibiotics banned or not approved, needs active investigation and enforcement in India. The evidence base underpinning formal approvals and no-objection certificates for not-recommended fixed-dose combinations should be audited. Analyser les ventes d'antibiotiques en association fixe et à dose unique en Inde, à la lumière des recommandations de l'Organisation mondiale de la Santé (OMS) et des efforts de réglementation à l'échelle nationale visant à contrôler la vente d'antibiotiques. Nous avons prélevé des données relatives aux volumes de vente d'antibiotiques systémiques en Inde dans la base de données commerciales d'une société d'études de marché. Nous avons ensuite comparé la part de marché qu'occupe, en 2020, la vente d'antibiotiques appartenant à chaque catégorie AWaRe (Access, Watch and Reserve) établie par l'OMS, mais aussi de ceux ciblés par des mesures nationales de contrôle supplémentaires. Enfin, nous avons examiné les ventes d'associations fixes: dont la commercialisation a été officiellement approuvée ou qui ont fait l'objet d'un certificat de non-objection; figurant sur la liste nationale de médicaments essentiels; et reprises dans la liste des antibiotiques non recommandés par l'OMS. Nous avons comptabilisé 78 antibiotiques à dose unique et 112 antibiotiques en association fixe sur le marché indien, représentant respectivement 7,6 et 4,5 milliards d'unités standard sur l'ensemble des ventes. Les antibiotiques des catégories Access (dont l'accessibilité est essentielle), Watch (à utiliser sélectivement) et Reserve (de réserve, non recommandés) équivalaient à 5,8 milliards, 5,6 milliards et 0,1 milliard d'unités standard sur le total des transactions. Tous les antibiotiques soumis à des contrôles supplémentaires faisaient partie des catégories Watch et Reserve (23,6%; 2,9 milliards d'unités standard sur l'ensemble des ventes). Des associations fixes déconseillées par l'OMS étaient commercialisées dans 229 formulations, dont 114 (49,8%) ne possédaient ni attestation d'approbation officielle, ni certificat de non-objection. Bien qu'aucune association fixe déconseillée ne soit mentionnée sur la liste nationale de médicaments essentiels, 13 des 20 antibiotiques en association fixe les plus vendus n'étaient pas recommandés par l'OMS. Il est nécessaire de mener une enquête approfondie en Inde sur la vente de médicaments appartenant à la catégorie Watch et d'antibiotiques interdits ou non approuvés, et de prendre des mesures concrètes. Les preuves sur lesquelles reposent les autorisations officielles et les certificats de non-objection pour les associations fixes non recommandées doivent être vérifiées. Analizar las ventas de los antibióticos combinados en dosis fijas y en dosis únicas en la India en relación con las recomendaciones de la Organización Mundial de la Salud (OMS) y los esfuerzos nacionales de regulación para controlar las ventas de los antibióticos. Se extrajeron datos sobre los volúmenes de ventas de antibióticos sistémicos en la India de una base de datos de ventas de empresas de investigación de mercado. Se comparó la cuota de mercado de las ventas de antibióticos en 2020 por categoría AWaRe (Access, Watch and Reserve) de la OMS y para los que estaban sometidos a controles regulatorios nacionales adicionales. También se analizaron las ventas de combinaciones en dosis fijas que estaban: formalmente aprobadas para su comercialización o tenían un certificado de no objeción; en la lista nacional de medicamentos esenciales; y en la lista de antibióticos no recomendados de la OMS. En la India se comercializaron 78 antibióticos en dosis única y 112 antibióticos combinados en dosis fijas, que representaron 7,6 y 4,5 mil millones de unidades estándar de ventas totales, respectivamente. Los antibióticos de acceso, vigilancia y reserva supusieron 5,8, 5,6 y 0,1 mil millones de unidades estándar de las ventas totales del mercado, respectivamente. Todos los antibióticos controlados adicionalmente fueron antibióticos de vigilancia y reserva (23,6 %; 2,9 mil millones de unidades estándar de las ventas totales). Las combinaciones en dosis fijas incluidas en la lista no recomendada de la OMS se comercializaron en 229 formulaciones, de las que 114 (49,8 %) no tenían registro de aprobación formal ni certificado de no objeción. Mientras que no había combinaciones en dosis fijas no recomendadas en la lista nacional de medicamentos esenciales, 13 de las 20 combinaciones en dosis fijas de antibióticos más vendidas no estaban recomendadas por la OMS. Se debe investigar y controlar activamente la venta de medicamentos del grupo Watch y de antibióticos prohibidos o no aprobados en la India. Asimismo, se debe auditar la base de pruebas que sustenta las aprobaciones formales y los certificados de no objeción para las combinaciones en dosis fijas no recomendadas.الغرض تحليل مبيعات تركيبة الجرعة الثابتة، والمضادات الحيوية المفردة في الهند فيما يتعلق بتوصيات منظمة الصحة العالمية (WHO)، والجهود التنظيمية الوطنية للتحكم في مبيعات المضادات الحيوية. الطريقة قمنا باستخراج بيانات عن أحجام مبيعات المضادات الحيوية الجهازية في الهند من قاعدة بيانات مبيعات شركة أبحاث السوق. قمنا بمقارنة الحصة السوقية لمبيعات المضادات الحيوية في عام 2020 حسب فئة AWaRe (الوصول والمراقبة والاحتياطي) التابعة لمنظمة الصحة العالمية (WHO)، وتلك التي تخضع للضوابط التنظيمية الوطنية الإضافية. كما قمنا أيضًا بتحليل مبيعات تركيبات الجرعة الثابتة التي تم: الموافقة عليها رسميًا للتسويق، أو لديها شهادة عدم ممانعة؛ على قائمة الأدوية الأساسية الوطنية؛ وعلى قائمة منظمة الصحة العالمية (WHO) للمضادات الحيوية غير الموصى بها. النتائج تم تسويق مضادات حيوية منها 112 تركيبة ذات جرعة ثابتة، و78 مضادًا حيويًا ذات تركيبة منفردة في الهند، وهو ما يمثل 7.6 و4.5 مليار وحدة قياسية من إجمالي المبيعات على الترتيب. تضم المضادات الحيوية Access وWatch وReserve 5.8 و5.6 و0.1 مليار وحدة قياسية من إجمالي مبيعات السوق على الترتيب. جميع المضادات الحيوية الإضافية الخاضعة للرقابة كانت Watch وReserve (%23.6؛ 2.9 مليار وحدة قياسية من إجمالي المبيعات). تركيبات الجرعة الثابتة الواردة في القائمة غير الموصى بها لدى منظمة الصحة العالمية (WHO) تم تسويقها في 229 مستحضرًا، مع 114 مستحضرًا (49.8%) ليس لها سجل بالموافقة الرسمية أو شهادة عدم ممانعة. على الرغم من عدم وجود تركيبات جرعة ثابتة غير موصى بها في القائمة الوطنية للأدوية الأساسية، فإن 13 من الـ 20 تركيبة جرعة ثابتة من المضادات الحيوية الأكثر مبيعًا لم تكن موصى بها من جانب منظمة الصحة العالمية (WHO). الاستنتاج إن بيع أدوية مجموعة Watch، والمضادات الحيوية المحظورة أو التي لم تحصل على الموافقة، يحتاج إلى تحقيق وإنفاذ فعال في الهند. يجب مراجعة قاعدة الأدلة التي تقوم عليها الموافقات الرسمية، وشهادات عدم الممانعة لتركيبات الجرعة الثابتة غير الموصى بها. 根据世卫组织 (WHO) 推荐的药物目录和控制抗生素销售的国家监管措施,分析印度固定剂量组合抗生素和单一抗生素的销量。. 我们从一家市场调研公司的销售数据库中提取了印度全身性抗生素的销量数据。我们比较了 2020 年按 WHO AWaRe 【可广泛使用 (Access)、谨慎使用 (Watch) 和保留使用 (Reserve)】分级目录和其他国家监管规定分类的抗生素的销售量市场份额。我们还分析了固定剂量组合抗生素(正式批准上市或者具有无异议证明;全国基本药物目录;世卫组织不推荐的抗生素目录)的销量。. 印度有 78 种单一抗生素和 112 种固定剂量组合抗生素上市, 总销量分别为 76 和 45 亿标准单位。可广泛使用 (Access)、谨慎使用 (Watch) 和保留使用 (Reserve) 抗生素的市场总销量分别为 58、56 和 1 亿标准单位。所有额外受监管抗生素均为谨慎使用 (Watch) 和保留使用 (Reserve) 抗生素(占 23.6%,总销售额为 29 亿标准单位)。有 229 种非世卫组织推荐药物目录中的固定剂量组合抗生素上市,其中 114 种(49.8%)没有正式批准或无异议证明。虽然没有国家基本药物清单中不推荐的固定剂量组合抗生素,但在 20 种最畅销的固定剂量组合抗生素中,有 13 种是世卫组织不推荐使用的。. 在印度还需对谨慎使用 (Watch) 类别的药物以及禁用或未批准的抗生素的销量进行积极调查并采取措施。应对不推荐使用的固定剂量组合抗生素取得的正式批准和无异议证明进行审查。. Проанализировать продажи комбинированных препаратов с фиксированными дозами и отдельных антибиотиков в Индии в соответствии с рекомендациями Всемирной организации здравоохранения (ВОЗ) и мерами национального регулирования по контролю за продажами антибиотиков. Авторы извлекли данные об объемах продаж системных антибиотиков в Индии из базы данных по продажам исследовательской компании. Они сравнили рыночную долю продаж антибиотиков в 2020 г. по категориям AWaRe (Access (Доступ), Watch (Наблюдение), Reserve (Резерв)) ВОЗ, а также антибиотиков, на которые распространяются дополнительные национальные регулирующие меры контроля. Авторы также проанализировали продажи комбинированных препаратов с фиксированными дозами, которые были официально одобрены для продажи или имели сертификат об отсутствии возражений, находились в национальном перечне основных лекарственных средств и в списке ВОЗ не рекомендованных для использования антибиотиков. В Индии на рынке представлены 78 отдельных и 112 комбинированных препаратов с фиксированными дозами антибиотиков, что составило 7,6 и 4,5 млрд условных единиц от общего объема продаж соответственно. Антибиотики групп Access, Watch и Reserve составили 5,8; 5,6 и 0,1 млрд условных единиц от общего объема продаж на рынке соответственно. Все дополнительно контролируемые антибиотики относились к антибиотикам групп Watch и Reserve (23,6%; 2,9 млрд условных единиц от общего объема продаж). Комбинированные препараты с фиксированными дозами, включенные в список ВОЗ не рекомендованных для использования антибиотиков, продавались в виде 229 лекарственных форм, при этом 114 форм (49,8%) не имели официального одобрения или сертификата об отсутствии возражений. Хотя в национальном перечне основных лекарственных средств не было нерекомендованных комбинированных препаратов с фиксированными дозами, 13 из 20 наиболее продаваемых комбинированных антибиотиков с фиксированными дозами не были рекомендованы ВОЗ. Продажа антибиотиков группы Watch, а также продажа запрещенных или не имеющих одобрения антибиотиков требует активного расследования и правоприменения в Индии. Необходимо проверить доказательную базу, лежащую в основе официальных одобрений и сертификатов об отсутствии возражений для нерекомендованных комбинированных препаратов с фиксированными дозами

Prescribing indicators at primary health care centers within the WHO African region: a systematic analysis (1995-2015)

Abstract Background Rational medicine use is essential to optimize quality of healthcare delivery and resource utilization. We aim to conduct a systematic review of changes in prescribing patterns in the WHO African region and comparison with WHO indicators in two time periods 1995–2005 and 2006–2015. Methods Systematic searches were conducted in PubMed, Scopus, Web of science, Africa-Wide Nipad, Africa Journals Online (AJOL), Google scholar and International Network for Rational Use of Drugs (INRUD) Bibliography databases to identify primary studies reporting prescribing indicators at primary healthcare centres (PHCs) in Africa. This was supplemented by a manual search of retrieved references. We assessed the quality of studies using a 14-point scoring system modified from the Downs and Black checklist with inclusions of recommendations in the WHO guidelines. Results Forty-three studies conducted in 11 African countries were included in the overall analysis. These studies presented prescribing indicators based on a total 141,323 patient encounters across 572 primary care facilities. The results of prescribing indicators were determined as follows; average number of medicines prescribed per patient encounter = 3.1 (IQR 2.3–4.8), percentage of medicines prescribed by generic name =68.0 % (IQR 55.4–80.3), Percentage of encounters with antibiotic prescribed =46.8 % (IQR 33.7–62.8), percentage of encounters with injection prescribed =25.0 % (IQR 18.7–39.5) and the percentage of medicines prescribed from essential medicines list =88.0 % (IQR 76.3–94.1). Prescribing indicators were generally worse in private compared with public facilities. Analysis of prescribing across two time points 1995–2005 and 2006–2015 showed no consistent trends. Conclusions Prescribing indicators for the African region deviate significantly from the WHO reference targets. Increased collaborative efforts are urgently needed to improve medicine prescribing practices in Africa with the aim of enhancing the optimal utilization of scarce resources and averting negative health consequences