Essential medicines for universal health coverage

Importance Substandard and falsified medicines burden health systems by diverting resources to ineffective or harmful therapies, causing medical complications and prolonging illnesses. However, the prevalence and economic impact of poor-quality medicines is unclear. Objective To conduct a systematic review and meta-analysis to assess the prevalence and estimated economic burden of substandard and falsified essential medicines in low- and middle-income countries. Data Sources Five databases (PubMed, EconLit, Global Health, Embase, and Scopus) were searched from inception until November 3, 2017. Study Selection Publications were assessed to determine whether they examined medicine quality and the prevalence and/or economic burden of substandard and falsified medicines in low- and middle-income countries. Studies with a sample size of 50 or more were included in the meta-analysis. Data Extraction and Synthesis The study is registered in PROSPERO and reported via the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Study quality was assessed using an adapted Medicine Quality Assessment Reporting Guidelines scoring metric. Multiple reviewers conducted the data extraction and quality assessment independently. Main Outcomes and Measures Prevalence and/or estimated economic impact of substandard and falsified medicines. Results Two hundred sixty-five studies that estimated the prevalence of poor-quality essential medicines in low- and middle-income countries were identified. Among 96 studies that tested 50 samples or more (67 839 total drug samples), overall prevalence of poor-quality medicines was 13.6% (95% CI, 11.0%-16.3%), with regional prevalence of 18.7% in Africa (95% CI, 12.9%-24.5%) and 13.7% in Asia (95% CI, 8.2%-19.1%). Of studies included in the meta-analysis, 19.1% (95% CI, 15.0%-23.3%) of antimalarials and 12.4% (95% CI, 7.1%-17.7%) of antibiotics were substandard or falsified. Eight approximations of the economic impact, focused primarily on market size, with poor or undisclosed methods in estimation were identified, ranging from $10 billion to $200 billion. Conclusions and Relevance Poor-quality essential medicines are a substantial and understudied problem. Methodological standards for prevalence and rigorous economic studies estimating the burden beyond market size are needed to accurately assess the scope of the issue and inform efforts to address it. Global collaborative efforts are needed to improve supply-chain management, surveillance, and regulatory capacity in low- and middle-income countries to reduce the threat of poor-quality medicines. Trial Registration PROSPERO Identifier:CRD42017080266

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Prevalence and Estimated Economic Burden of Substandard and Falsified Medicines in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

Global antibiotic consumption and usage in humans, 2000-18: a spatial modelling study.

Substandard/counterfeit antimicrobial drugs are a growing global problem The most common substandard/counterfeit antimicrobials include beta-lactams (among antibiotics) and chloroquine and artemisin derivatives (among antimalarials) The most common type of substandard/counterfeit antimicrobial drugs have a reduced amount of the active drug, and the majority of them are manufactured in Southeast Asia and Africa Counterfeit antimicrobial drugs may cause increased mortality and morbidity and pose a danger to patients Here we review the literature with regard to the issue of substandard/counterfeit antimicrobials and describe the prevalence of this problem, the different types of substandard/counterfeit antimicrobial drugs, and the consequences for the individuals and global public health Local, national, and international initiatives are required to combat this very important public health issue

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Substandard/Counterfeit Antimicrobial Drugs

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)31509-X.pdf

The path to longer and healthier lives for all Africans by 2030: the Lancet Commission on the future of health in sub-Saharan Africa.

Objective: To explore the evidence available of poorquality (counterfeit and substandard) medicines in the literature. Design: Systematic review. Data sources: Databases used were EMBASE, MEDLINE, PubMed and the International Pharmaceutical Abstracts, including articles published till January 2013. Eligibility criteria: Prevalence studies containing original data. WHO definitions (1992) used for counterfeit and substandard medicines. Study appraisal and synthesis: Two reviewers independently scored study methodology against recommendations from the MEDQUARG Checklist. Studies were classified according to the World Bank classification of countries by income. Data extraction: Data extracted: place of study; type of drugs sampled; sample size; percentage of substandard/counterfeit medicines; formulations included; origin of the drugs; chemical analysis and stated issues of counterfeit/substandard medicines. Results: 44 prevalence studies were identified, 15 had good methodological quality. They were conducted in 25 different countries; the majority were in low-income countries (11) and/or lower middle-income countries (10). The median prevalence of substandard/counterfeit medicines was 28.5% (range 11–48%). Only two studies differentiated between substandard and counterfeit medicines. Prevalence data were limited to antimicrobial drugs (all 15 studies). 13 studies involved antimalarials, 6 antibiotics and 2 other medications. The majority of studies (93%) contained samples with inadequate amounts of active ingredients. The prevalence of substandard/counterfeit antimicrobials was significantly higher when purchased from unlicensed outlets (p<0.000; 95% CI 0.21 to 0.32). No individual data about the prevalence in upper middle-income countries and high-income countries were available. Limitations: Studies with strong methodology were few. The majority did not differentiate between substandard and counterfeit medicines. Most studies assessed only a single therapeutic class of antimicrobials.

https://bmjopen.bmj.com/content/bmjopen/3/8/e002923.full.pdf

Substandard and counterfeit medicines: a systematic review of the literature

Objective: To determine the extent of substandard and falsified medicines in the UK. Design: A retrospective review of drug alerts and company-led recalls. Setting: The Medicines and Healthcare Products Regulatory Agency (MHRA) website search for drug alerts issued between 2001 and 2011. Eligibility criteria: Drug alerts related to quality defect in medicinal products. Main outcome measure: Relevant data about defective medicines reported in drug alerts and company-led recalls, including description of the defect, type of formulation, year of the alert and category of the alert. Results: There were 280 substandard medicines of which 222 were recalled. The two most frequent problems were contamination (74 incidents) and issues related to packaging (98 incidents). Formulations for parenteral administration (117 incidents) were the formulation most frequently affected. There were 11 falsified medicines, as defined by the MHRA, reported over the 11-year period. The number of defective medicines reported by the MHRA increased 10-fold from 5 in 2001 to 50 in 2011. Conclusions: Substandard medicines are a significant problem in the UK. It is uncertain whether the increasing number of reports relates to improved detection or an increase in the number of substandard medicines.

https://bmjopen.bmj.com/content/bmjopen/3/7/e002924.full.pdf

Substandard and falsified medicines in the UK: a retrospective review of drug alerts (2001-2011)

Objective To determine the extent of substandard and falsified medicines in the UK. Design A retrospective review of drug alerts and company-led recalls. Setting The Medicines and Healthcare Products Regulatory Agency (MHRA) website search for drug alerts issued between 2001 and 2011. Eligibility criteria Drug alerts related to quality defect in medicinal products. Main outcome measure Relevant data about defective medicines reported in drug alerts and company-led recalls, including description of the defect, type of formulation, year of the alert and category of the alert. Results There were 280 substandard medicines of which 222 were recalled. The two most frequent problems were contamination (74 incidents) and issues related to packaging (98 incidents). Formulations for parenteral administration (117 incidents) were the formulation most frequently affected. There were 11 falsified medicines, as defined by the MHRA, reported over the 11-year period. The number of defective medicines reported by the MHRA increased 10-fold from 5 in 2001 to 50 in 2011. Conclusions Substandard medicines are a significant problem in the UK. It is uncertain whether the increasing number of reports relates to improved detection or an increase in the number of substandard medicines.

Counterfeit and substandard medicines in the UK: A retrospective review of drug alerts (2001-2011)

Objective To explore the quality and safety of medicines in Canada. Design A retrospective review of drug recalls and risk communication documents conveying issues relating to defective (ie, substandard and falsified) medicines. Setting The Health Canada website search for drug recalls and risk communication documents issued between 2005 and 2013. Eligibility criteria Drug recalls and risk communication documents related to quality defect in medicinal products. Main outcome measure Relevant data about defective medicines reported in drug recalls and risk communication documents, including description of the defect, type of formulation, year of the recall and category of the recall or the document. Results There were 653 defective medicines of which 649 were substandard. The number of defective medicines reported by Health Canada increased from 42 in 2005 to 143 in 2013. The two most frequently reported types of defects were stability (205 incidents) and contamination issues (139 incidents). Some of these defects were found to be more prominent and repetitive over other types within some manufacturers. Tablet formulation (251 incidents) was the formulation most frequently compromised. No significant differences were observed between the manufacturers and distributors in the number of substandard medicines reported under each defect type. There were only four falsified medicines reported over the 9-year period. Conclusions Substandard medicines are a problem in Canada and have resulted in an increasing number of recalled medicines. Most of the failures were related to stability issues, raising the need to investigate the root causes and for stringent preventative measures to be implemented by manufacturers.

https://bmjopen.bmj.com/content/bmjopen/4/10/e006088.full.pdf

Quality of medicines in Canada: a retrospective review of risk communication documents (2005–2013)

Aim To explore the prevalence and global health implications of counterfeit (fraudulently) and substandard (failed to pass quality measurements) medicines. Methods A systematic review was conducted using Embase, Medline, PubMed and International Pharmaceutical Abstracts, including articles published till May 2011. Only prevalence studies containing original data were included. Data was collected on prevalence of these drugs, year of the study, location, drugs involved, sample size, paediatric formulations and drug concentrations of counterfeit/substandard medicines. Results Forty-two prevalence studies were identified. The overall median prevalence of counterfeit and substandard medicines reported was 36%. These studies were conducted in thirty-eight different countries; the majority (34 studies) were focussed on low-income countries (LIC) and lower-middle-income countries (LMIC), the remainder having mixed groups. The median prevalence in the samples was similar in LIC and LMIC in Africa and Asia (35% to 38%). No individual data about the prevalence in upper-middle-income countries (UMIC) and high-income countries (HIC) was available. Antimicrobial drugs were the most extensively studied group of medicines (34 studies); antimalarials were the focus in two thirds (22 studies). Seven studies compared the failure rate in authorised and unauthorised suppliers, the percentage of failed samples was significantly higher in the unauthorised suppliers (41.2% versus 23.4%; p= 0.0001). Studies showed inadequate amount of active ingredients (83%), absence of active ingredients (15%) and excessive amount of active ingredients (15%). Only eleven studies included paediatric formulations (i.e. syrup and suspension) in their sampling process and one third (113) of the 338 samples tested were substandard. Conclusion There is a widespread use of counterfeit and substandard medicines throughout Africa and Asia in LIC and LMIC. More than a third of medicines available in these countries could be counterfeit or substandard. The extent of the problem in UMIC and HIC is not certain. There is limited evidence on paediatric formulations and children would be at higher risk from dose changes. The use of poor quality medicines can lead to a lack of efficacy, therapeutic failure, toxicity, and the emergence of drug resistance. Public education, legislations and strong law enforcement are needed to curb this trade.

Tariq Almuzaini

Papers

Substandard and counterfeit medicines: a systematic review of the literature

Substandard and falsified medicines in the UK: a retrospective review of drug alerts (2001-2011)

Counterfeit and substandard medicines in the UK: A retrospective review of drug alerts (2001-2011)

Quality of medicines in Canada: a retrospective review of risk communication documents (2005–2013)

A systematic review of counterfeit and substandard medicines