Leveraging COVID-19 Vaccine Safety Monitoring in Ethiopia and Pakistan to Enhance System-Wide Safety Surveillance.

The rapid development, introduction, and global uptake of COVID-19 vaccines required countries to have strong pharmacovigilance systems in place to monitor and address adverse events following immunization (AEFIs). These systems provide timely data on vaccine safety that support decisions about the potential risks of vaccine adverse events relative to the benefit of disease prevention. In Ethiopia, the monitoring system was limited by the lack of data being submitted through its passive surveillance system, delays in investigating serious adverse events and conducting causality assessments, and the lack of reporting to the World Health Organization (WHO) global database, VigiBase. In Pakistan, the pharmacovigilance system lacked reporting requirements and guidance documentation, regulatory policies were insufficient, and staff lacked the capacity to evaluate AEFI reports. Several interventions were implemented in both countries to improve pharmacovigilance systems and processes necessary to collect, analyze, and report AEFIs from health care facilities to the national level and facilitate the use of global and national electronic reporting tools. In addition, Pakistan improved the regulatory policy environment and engaged vaccine manufacturers and private sector health facilities in AEFI reporting for the first time in the country. Outcomes include an increased number of COVID-19 vaccine-related AEFIs reported and causality assessments completed, which means that potential safety issues were being analyzed more quickly, comprehensively, and accurately. The number of AEFI reports submitted to VigiBase by Pakistan's regulatory authority more than quintupled from approximately 5,000/quarter in 2021 to 28,555/quarter in 2022. In Ethiopia, by October 2022, 44,000 AEFI reports had been received, and 40 causality assessments completed. In both countries, timely AEFI data review and analysis led to prompt recommendations and regulatory actions, highlighting the far-reaching implications of strengthening the country-level pharmacovigilance systems. These strengthened systems are now in place for use with all vaccines.

Modeling the Health and Economic Impact of Substandard and Falsified Medicines: A Review of Existing Models and Approaches.

Substandard and falsified medicines are harmful to patients, causing prolonged illness, side effects, and preventable deaths. Moreover, they have an impact on the health system and society more broadly by leading to additional care, higher disease burden, productivity losses and loss of trust in health care. Models that estimate the health and economic impacts of substandard and falsified medicines can be useful for regulators to contextualize the problem and to make an economic case for solutions. Yet these models have not been systematically catalogued to date. We reviewed existing models that estimate the health and economic impact of substandard and falsified medicines to describe the varying modeling approaches and gaps in knowledge. We compared model characteristics, data sources, assumptions, and limitations. Seven models were identified. The models assessed the impact of antimalarial (n = 5) or antibiotic (n = 2) quality at a national (n = 4), regional (n = 2), or global (n = 1) level. Most models conducted uncertainty analysis and provided ranges around potential outcomes. We found that models are lacking for other medicines, few countries' data have been analyzed, and capturing population heterogeneity remains a challenge. Providing the best estimates of the impact of substandard and falsified medicines on a level that is actionable for decision-makers is important. To enable this, research on the impact of substandard and falsified medicines should be expanded to more medicine types and classes and tailored to more countries that are affected, with greater specificity.

Ethical challenges in designing and conducting medicine quality surveys.

OBJECTIVES: In this paper we discuss the main ethical challenges related to the conduct of medicine quality surveys and make suggestions on how to address them. METHOD: Most evidence-based information regarding medicine quality derives from surveys. However, existing research ethical guidelines do not provide specific guidance for medicine quality surveys. Hence, those conducting surveys are often left wondering how to judge what counts as best practice. A list of the main ethical challenges in the design and conduct of surveys is presented. RESULTS AND CONCLUSIONS: It is vital that the design and conduct of medicine quality surveys uphold moral and ethical obligations and analyse the ethical implications and consequences of such work. These aspects include the impact on the local availability of and access to medicines; the confidentiality and privacy of the surveyors and the surveyed; questions as to whether outlet staff personnel should be told they are part of a survey; the need of ethical and regulatory approvals; and how the findings should be disseminated. Medicine quality surveys should ideally be conducted in partnership with the relevant national Medicine Regulatory Authorities. An international, but contextually sensitive, model of good ethical practice for such surveys is needed.

Fake anti-malarials: start with the facts.

This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (<8 %) were found in just two of the countries, whilst substandard artemisinin-based combinations were present in all six countries and, artemisinin-based monotherapy tablets are still available in some places despite the fact that the WHO has urged regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies since 2007. This report summarizes the presentations that reviewed the public health impact of falsified and substandard drugs, sampling strategies, techniques for drug quality analysis, approaches to strengthen health systems capacity for the surveillance of drug quality, and the ensuing discussion points from the dissemination meeting.

Monitoring the quality of medicines: results from Africa, Asia, and South America.

Monitoring the quality of medicines plays a crucial role in an integrated medicines quality assurance system. In a publicly available medicines quality database (MQDB), the U.S. Pharmacopeial Convention (USP) reports results of data collected from medicines quality monitoring (MQM) activities spanning the period of 2003-2013 in 17 countries of Africa, Asia, and South America. The MQDB contains information on 15,063 samples collected and tested using Minilab® screening methods and/or pharmacopeial methods. Approximately 71% of the samples reported came from Asia, 23% from Africa, and 6% from South America. The samples collected and tested include mainly antibiotic, antimalarial, and antituberculosis medicines. A total of 848 samples, representing 5.6% of total samples, failed the quality test. The failure proportion per region was 11.5%, 10.4%, and 2.9% for South America, Africa, and Asia, respectively. Eighty-one counterfeit medicines were reported, 86.4% of which were found in Asia and 13.6% in Africa. Additional analysis of the data shows the distribution of poor-quality medicines per region and by therapeutic indication as well as possible trends of counterfeit medicines.

The quality of antimalarial medicines in western Cambodia: a case study along the Thai-Cambodian border.

The prevalence, availability, and use of antimalarial medicines (AMLs) were studied in six Cambodian provinces along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in Pursat, Pailin, Battambang, Bantey Meanchey, Oddar Meanchey, and Preah Vihear and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for confirmatory testing. For the second part of the study, face-to-face interviews were conducted using standardized surveys with members of randomly selected households and staff of health facilities in the villages with highest malaria incidence to find out where they acquired their AMLs and which were most frequently used. The results showed an overall failure rate of 12.3% (n = 46 of 374 total AML samples). The causes of medication sample failure were low active pharmaceutical ingredient (API) content, failed dissolution properties, and unacceptably high levels of impurities. A total of 86.2% of survey respondents (n = 1,648 of 1,912) reported a member of their household having malaria in the previous year. The most commonly used medicines were paracetamol (67.1% of respondents), Malarine (A+M co-blistered, 28.6%), artesunate + mefloquine co-blistered (public sector product, 17.3%), quinine (16.7%), and artesunate monotherapy (11.9%). Health staff typically prescribed co-blistered artesunate plus mefloquine in the public sector (67.8%), the artesunate plus mefloquine "social marketing" product from Population Services International (PSI), Malarine (50.3%) in the private sector, artemether (49.7%), chloroquine (39%) and paracetamol (72.9%) to reduce fever.

The quality of antimalarial medicines in eastern Thailand: a case study along the Thai-Cambodian border.

This study examined the prevalence, availability, and use of antimalarial medicines (AMLs) along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in six Thai provinces and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for verification testing. For the second part of the study, face-to-face interviews were conducted with members of randomly selected households and the staff of health facilities in villages with the highest malaria incidence to find out where they acquired their AMLs and which were used most frequently. The results of quality testing showed an overall failure rate of 1% (7 of 709 samples) for active pharmaceutical ingredients (API); however, the API failure rate varied from 0.0% to 2.2% by location and the overall failure rates of samples by province varied from 0.0% to 3.4%. A total of 97.9% (n = 272) of respondents had taken AMLS. The most commonly used medicines were primaquine (30% of respondents), chloroquine (15.8%), artesunate+mefloquine (12%), and quinine (10%). Most respondents (97.9%) had received medications from public hospitals or malaria clinics.

A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia.

BACKGROUND: Since 1998 the serious public health problem in South East Asia of counterfeit artesunate, containing no or subtherapeutic amounts of the active antimalarial ingredient, has led to deaths from untreated malaria, reduced confidence in this vital drug, large economic losses for the legitimate manufacturers, and concerns that artemisinin resistance might be engendered. METHODS AND FINDINGS: With evidence of a deteriorating situation, a group of police, criminal analysts, chemists, palynologists, and health workers collaborated to determine the source of these counterfeits under the auspices of the International Criminal Police Organization (INTERPOL) and the Western Pacific World Health Organization Regional Office. A total of 391 samples of genuine and counterfeit artesunate collected in Vietnam (75), Cambodia (48), Lao PDR (115), Myanmar (Burma) (137) and the Thai/Myanmar border (16), were available for analysis. Sixteen different fake hologram types were identified. High-performance liquid chromatography and/or mass spectrometry confirmed that all specimens thought to be counterfeit (195/391, 49.9%) on the basis of packaging contained no or small quantities of artesunate (up to 12 mg per tablet as opposed to approximately 50 mg per genuine tablet). Chemical analysis demonstrated a wide diversity of wrong active ingredients, including banned pharmaceuticals, such as metamizole, and safrole, a carcinogen, and raw material for manufacture of methylenedioxymethamphetamine ('ecstasy'). Evidence from chemical, mineralogical, biological, and packaging analysis suggested that at least some of the counterfeits were manufactured in southeast People's Republic of China. This evidence prompted the Chinese Government to act quickly against the criminal traders with arrests and seizures. CONCLUSIONS: An international multi-disciplinary group obtained evidence that some of the counterfeit artesunate was manufactured in China, and this prompted a criminal investigation. International cross-disciplinary collaborations may be appropriate in the investigation of other serious counterfeit medicine public health problems elsewhere, but strengthening of international collaborations and forensic and drug regulatory authority capacity will be required.