The issue of substandard medicine

Precise, independent estimates are also needed to describe the health and economic effects of poor-quality medicines to build the evidence base for successful policy interventions to curb substandard medicines

Increasing access to essential medicines is integral to the effort to reduce global morbidity and mortality. While access and health outcomes have generally improved in recent decades, these efforts face a serious obstacle from the threat of substandard and falsified (SF) medicines. Poor-quality medicines increase risks of morbidity and mortality by prolonging illnesses and heighten the risk of treatment failure, poisoning, and adverse drug interactions. Circulation of SF medicines with little clinical effectiveness also places entire communities at risk of drug resistance, posing a threat to global treatment effectiveness, as well as undermining people’s overall trust in the health system and its legitimate health care professionals. Over time, diminished trust in licensed health care professionals may further encourage informal care-seeking and self-medication. Poor health outcomes can also erode trust in the manufacturers of genuine pharmaceutical products, which are often challenging to distinguish from SF ones without the use of verification technologies

The risks posed by these medicines extend beyond health outcomes. Poor-quality medicines cause increased costs for patients and the health system. Some of these costs, such as resources wasted on ineffective therapies and treating additional complications, are borne primarily by consumers and health facilities. Others, such as decreased economic productivity resulting from prolonged illness, reduced sales and tax revenue, and costs of anticounterfeiting initiatives, are borne by governments, companies, the pharmaceutical industry, donors, and society as a whole. Furthermore, SF medicines purchased through the use of personal savings, sale of assets, or borrowing can lead people into poverty.

Substandard and falsified medicines are a complex but critical global health issue. The World Health Organization (WHO) estimates that 10.5% of medicines worldwide are substandard or falsified. Furthermore, most of the burden falls on low- and middle-income countries (LMICs) because of poor pharmaceutical governance, weak technical capacity, and poor supply-chain management. Until recently, the efforts to combat SF medicines have been fragmented because of the complexity of the issue and intellectual property rights disputes. In 2017, in an effort to draw the issue away from intellectual property rights and reframe it solely as a public health issue, the World Health Assembly officially adopted the term substandard and falsified to replace the previous term, substandard/spurious/falsely labeled/falsified/counterfeit (SSFFC). Substandard medicines are officially defined as “authorized medical products that fail to meet either their quality standards or specification, or both” and may result through poor manufacturing, shipping or storage conditions, or when the drug is sold beyond the expiration date. Falsified medicines are defined as “medical products that deliberately/fraudulently misrepresent their identity, composition or source.”

This issue not only has significant health and economic consequences, but directly threatens global health security and efforts to meet the United Nations Sustainable Development Goal 3.8, to achieve universal access to safe and effective essential medicines. Despite this, the full extent of the problem is unclear. Furthermore, research efforts to examine the issue have often faced poor methodological quality and exhibited high amounts of variability. To address these issues, we systematically reviewed and analyzed the existing evidence to assess the prevalence and estimated economic burden of SF essential medicines across LMICs.

According to my systematic review and meta-analysis reveal that 13.6% of essential medicines tested in LMICs failed quality analysis. The highest prevalence of poor-quality medicines was observed in Africa, where 18.7% of samples were substandard or falsified. Deficiencies in quality were more prevalent among antimalarials (19.1%) than antibiotics (12.4%), while further studies are needed to understand the quality profile of other essential medicines.

This review identified a significant amount of study heterogeneity and potential issues of quality of the prevalence data reported in publications. This is a significant issue as poor-quality prevalence data affect analyses of the health and economic effects of SF medicines as well as crucial policy and regulatory efforts to address the issue. Unfortunately, controversy over the role of industry in defining the problem of SF medicines has slowed global efforts to address this issue in recent decades. The International Medical Products Anti-counterfeiting Taskforce (IMPACT), established by the WHO in 2006, disbanded over perceived industry connections, and intellectual property concerns waylaid the agreement on the definition of SF medical products. There are concerns that anticounterfeiting efforts could adversely affect the legitimate generic drug industry—essential for access to medicines in LMICs—have been central to the debate. This dispute has distracted from the public health and socioeconomic consequences as well as efforts to accurately assess the scope of the issue. As a result, efforts have been disjointed, and numerous studies with small sample sizes that do not use rigorous randomization, collection, and analysis methods have been conducted.

This review also identifies a significant gap in the literature on the economic burden of SF medicines due to the poor-quality of reported economic estimates and limited focus, primarily on market size. Robust economic analysis capturing the broader economic burden of SF medicines, such as additional costs of treatment and productivity losses, is critical to understanding the extent of the problem, raising awareness, developing intervention strategies, and fostering change. Future economic research is important to inform efforts to combat the falsification of medications and should be conducted following rigorous economic methods.

As demonstrated in the results of our prevalence subgroup analysis, use of less rigorous research, analysis, and reporting methods is detrimental to efforts to assess the scope of the issue because of the number of biases they introduce. Studies aiming to support policy development should therefore follow rigorous standards of sampling, analysis, reporting, and disclosure. While metrics such as MEDQUARG exist to guide in the reporting of studies of the prevalence of SF medicines, greater effort and emphasis need to be placed on researching and standardizing international sampling, collection, and analysis protocols. Improving quality control and laboratory capacity in LMICs is also crucial as the GPHF-Minilab that is used in these settings in lieu of full pharmacopeial analysis has poor sensitivity to detect substandard medicines. Furthermore, to ensure that these efforts bear fruit, greater transparency is needed in the disclosure of industry-related potential conflicts of interest. This heterogeneity in findings serves to caution against extrapolating SF prevalence to other regions and across medicine categories.

Countries with weak pharmaceutical governance and poor pharmacovigilance are at the greatest risk from SF medications. Weak regulatory capacity to license manufacturers, ensure good manufacturing practices, and perform quality control encourages the illicit manufacture and distribution of SF medications. Poor supply chain management and surveillance not only open the door to allow SF medicines to permeate the supply chain, but also cause stock-outs that drive patients to purchase medicines from unregulated markets. Therefore, efforts to improve supply-chain management, surveillance, and regulatory capacity in LMICs are essential to reduce the threat of SF medicines. The successes of the Promoting the Quality of Medicines and the WHO prequalified drug programs demonstrate that these efforts can reduce the prevalence of SF medicines.While the effects of SF medications disproportionately rest on LMICs, SF medicines originate from and are reported in every country worldwide. The global nature of the medicine supply chain implies that weaknesses in any country in the supply chain affect all the countries downstream. This threatens global health security by increasing transmission, morbidity, mortality, and antimicrobial resistance, highlighting the need for a unified global effort to address the issue. In 2013, the WHO Global Surveillance and Monitoring System was launched to gather data, improve reporting, and strengthen regulatory capacity globally While this is an important first step, additional efforts to implement laws on drug quality and improve data sharing among stakeholders are essential to complement research and technical initiatives.

I want to call for an international convention on SF medicines, similar to the 1929 treaty that internationally criminalized counterfeit banknotes or the Framework Convention on Tobacco Control. Such a convention could (1) accurately define SF medicines, (2) require signatory countries to enact national laws (and consequent prosecution penalties) criminalizing intentional manufacture, trafficking, or selling of SF medicines, (3) provide a legal and institutional framework on convergent medicine regulation, and (4) provide LMICs with financial and technical assistance to effectively join local and regional SF medicine regulatory networks. Without such concerted global effort, the global supply chain, and thereby every country within it, remains vulnerable to SF medicines.

Finally, my observations suggest that SF essential medicines are a substantial and understudied problem in LMICs with high estimated economic impact. Reducing their prevalence is imperative to the Global Health Security Agenda, reaching the United Nations Sustainable Development Goals, and global efforts to curb antimicrobial resistance. Although the literature on prevalence continues to grow, methodological standards are needed to improve generalizability and facilitate comparison across studies. Precise, independent estimates are also needed to describe the health and economic effects of poor-quality medicines to build the evidence base for successful policy interventions to curb SF medicines in LMICs. Efforts to strengthen supply-chain management, surveillance, and regulatory capacity are essential to effectively control SF medicines. Globalization necessitates global coordination across national, regional, and sectoral stakeholders to improve the regulation, standardization, and surveillance of the quality of medicines worldwide.

The writer is Former Head, Department of Medical Sociology,

Institute of Epidemiology, Disease Control & Research (IEDCR) Dhaka, Bangladesh. E-mail: [email protected]

MK

 

The issue of substandard medicine

Precise, independent estimates are also needed to describe the health and economic effects of poor-quality medicines to build the evidence base for successful policy interventions to curb substandard medicines

Increasing access to essential medicines is integral to the effort to reduce global morbidity and mortality. While access and health outcomes have generally improved in recent decades, these efforts face a serious obstacle from the threat of substandard and falsified (SF) medicines. Poor-quality medicines increase risks of morbidity and mortality by prolonging illnesses and heighten the risk of treatment failure, poisoning, and adverse drug interactions. Circulation of SF medicines with little clinical effectiveness also places entire communities at risk of drug resistance, posing a threat to global treatment effectiveness, as well as undermining peoples overall trust in the health system and its legitimate health care professionals. Over time, diminished trust in licensed health care professionals may further encourage informal care-seeking and self-medication. Poor health outcomes can also erode trust in the manufacturers of genuine pharmaceutical products, which are often challenging to distinguish from SF ones without the use of verification technologies The risks posed by these medicines extend beyond health outcomes. Poor-quality medicines cause increased costs for patients and the health system. Some of these costs, such as resources wasted on ineffective therapies and treating additional complications, are borne primarily by consumers and health facilities. Others, such as decreased economic productivity resulting from prolonged illness, reduced sales and tax revenue, and costs of anticounterfeiting initiatives, are borne by governments, companies, the pharmaceutical industry, donors, and society as a whole. Furthermore, SF medicines purchased through the use of personal savings, sale of assets, or borrowing can lead people into poverty. Substandard and falsified medicines are a complex but critical global health issue. The World Health Organization (WHO) estimates that 10.5% of medicines worldwide are substandard or falsified. Furthermore, most of the burden falls on low- and middle-income countries (LMICs) because of poor pharmaceutical governance, weak technical capacity, and poor supply-chain management. Until recently, the efforts to combat SF medicines have been fragmented because of the complexity of the issue and intellectual property rights disputes. In 2017, in an effort to draw the issue away from intellectual property rights and reframe it solely as a public health issue, the World Health Assembly officially adopted the term substandard and falsified to replace the previous term, substandard/spurious/falsely labeled/falsified/counterfeit (SSFFC). Substandard medicines are officially defined as authorized medical products that fail to meet either their quality standards or specification, or both and may result through poor manufacturing, shipping or storage conditions, or when the drug is sold beyond the expiration date. Falsified medicines are defined as medical products that deliberately/fraudulently misrepresent their identity, composition or source. This issue not only has significant health and economic consequences, but directly threatens global health security and efforts to meet the United Nations Sustainable Development Goal 3.8, to achieve universal access to safe and effective essential medicines. Despite this, the full extent of the problem is unclear. Furthermore, research efforts to examine the issue have often faced poor methodological quality and exhibited high amounts of variability. To address these issues, we systematically reviewed and analyzed the existing evidence to assess the prevalence and estimated economic burden of SF essential medicines across LMICs. According to my systematic review and meta-analysis reveal that 13.6% of essential medicines tested in LMICs failed quality analysis. The highest prevalence of poor-quality medicines was observed in Africa, where 18.7% of samples were substandard or falsified. Deficiencies in quality were more prevalent among antimalarials (19.1%) than antibiotics (12.4%), while further studies are needed to understand the quality profile of other essential medicines. This review identified a significant amount of study heterogeneity and potential issues of quality of the prevalence data reported in publications. This is a significant issue as poor-quality prevalence data affect analyses of the health and economic effects of SF medicines as well as crucial policy and regulatory efforts to address the issue. Unfortunately, controversy over the role of industry in defining the problem of SF medicines has slowed global efforts to address this issue in recent decades. The International Medical Products Anti-counterfeiting Taskforce (IMPACT), established by the WHO in 2006, disbanded over perceived industry connections, and intellectual property concerns waylaid the agreement on the definition of SF medical products. There are concerns that anticounterfeiting efforts could adversely affect the legitimate generic drug industryessential for access to medicines in LMICshave been central to the debate. This dispute has distracted from the public health and socioeconomic consequences as well as efforts to accurately assess the scope of the issue. As a result, efforts have been disjointed, and numerous studies with small sample sizes that do not use rigorous randomization, collection, and analysis methods have been conducted. This review also identifies a significant gap in the literature on the economic burden of SF medicines due to the poor-quality of reported economic estimates and limited focus, primarily on market size. Robust economic analysis capturing the broader economic burden of SF medicines, such as additional costs of treatment and productivity losses, is critical to understanding the extent of the problem, raising awareness, developing intervention strategies, and fostering change. Future economic research is important to inform efforts to combat the falsification of medications and should be conducted following rigorous economic methods. As demonstrated in the results of our prevalence subgroup analysis, use of less rigorous research, analysis, and reporting methods is detrimental to efforts to assess the scope of the issue because of the number of biases they introduce. Studies aiming to support policy development should therefore follow rigorous standards of sampling, analysis, reporting, and disclosure. While metrics such as MEDQUARG exist to guide in the reporting of studies of the prevalence of SF medicines, greater effort and emphasis need to be placed on researching and standardizing international sampling, collection, and analysis protocols. Improving quality control and laboratory capacity in LMICs is also crucial as the GPHF-Minilab that is used in these settings in lieu of full pharmacopeial analysis has poor sensitivity to detect substandard medicines. Furthermore, to ensure that these efforts bear fruit, greater transparency is needed in the disclosure of industry-related potential conflicts of interest. This heterogeneity in findings serves to caution against extrapolating SF prevalence to other regions and across medicine categories. Countries with weak pharmaceutical governance and poor pharmacovigilance are at the greatest risk from SF medications. Weak regulatory capacity to license manufacturers, ensure good manufacturing practices, and perform quality control encourages the illicit manufacture and distribution of SF medications. Poor supply chain management and surveillance not only open the door to allow SF medicines to permeate the supply chain, but also cause stock-outs that drive patients to purchase medicines from unregulated markets. Therefore, efforts to improve supply-chain management, surveillance, and regulatory capacity in LMICs are essential to reduce the threat of SF medicines. The successes of the Promoting the Quality of Medicines and the WHO prequalified drug programs demonstrate that these efforts can reduce the prevalence of SF medicines.While the effects of SF medications disproportionately rest on LMICs, SF medicines originate from and are reported in every country worldwide. The global nature of the medicine supply chain implies that weaknesses in any country in the supply chain affect all the countries downstream. This threatens global health security by increasing transmission, morbidity, mortality, and antimicrobial resistance, highlighting the need for a unified global effort to address the issue. In 2013, the WHO Global Surveillance and Monitoring System was launched to gather data, improve reporting, and strengthen regulatory capacity globally While this is an important first step, additional efforts to implement laws on drug quality and improve data sharing among stakeholders are essential to complement research and technical initiatives. I want to call for an international convention on SF medicines, similar to the 1929 treaty that internationally criminalized counterfeit banknotes or the Framework Convention on Tobacco Control. Such a convention could (1) accurately define SF medicines, (2) require signatory countries to enact national laws (and consequent prosecution penalties) criminalizing intentional manufacture, trafficking, or selling of SF medicines, (3) provide a legal and institutional framework on convergent medicine regulation, and (4) provide LMICs with financial and technical assistance to effectively join local and regional SF medicine regulatory networks. Without such concerted global effort, the global supply chain, and thereby every country within it, remains vulnerable to SF medicines. Finally, my observations suggest that SF essential medicines are a substantial and understudied problem in LMICs with high estimated economic impact. Reducing their prevalence is imperative to the Global Health Security Agenda, reaching the United Nations Sustainable Development Goals, and global efforts to curb antimicrobial resistance. Although the literature on prevalence continues to grow, methodological standards are needed to improve generalizability and facilitate comparison across studies. Precise, independent estimates are also needed to describe the health and economic effects of poor-quality medicines to build the evidence base for successful policy interventions to curb SF medicines in LMICs. Efforts to strengthen supply-chain management, surveillance, and regulatory capacity are essential to effectively control SF medicines. Globalization necessitates global coordination across national, regional, and sectoral stakeholders to improve the regulation, standardization, and surveillance of the quality of medicines worldwide. The writer is Former Head, Department of Medical Sociology, Institute of Epidemiology, Disease Control Research (IEDCR) Dhaka, Bangladesh. E-mail: [email protected] MK