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.

A descriptive study of healthcare-providers' experiences with the use and quality of oxytocin for the prevention of post-partum hemorrhage in Nigeria: A nation-wide survey.

BACKGROUND: Oxytocin is recommended as an affordable and effective drug in the prevention of postpartum hemorrhage-one of the leading causes of maternal morbidity and mortality in low- and middle-income countries, however, there are concerns about its proper use and quality. This study builds on earlier work conducted in a South-Western state in Nigeria. OBJECTIVE: The study assessed the knowledge around oxytocin, usage, storage practices and perceived quality of oxytocin used by healthcare providers that directly administer oxytocin for the prevention of postpartum hemorrhage across Nigeria. METHODS: This was a descriptive cross-sectional study that surveyed a representative sample of 6,299 healthcare providers who offer obstetrics and gynecological services and recruited from 1,894 healthcare facilities in Public and Private sectors in 12 states across Nigeria. Data were collected using an electronic questionnaire, analyzed using SPSS, and presented in frequencies and percentages. RESULTS: Only forty-six percent of respondents (52.8% in private; 40.0% in public sector) had proper knowledge that oxytocin storage is in the refrigerator. Proper knowledge also varied by professional cadre, doctors (71.2%); nurses (46.6%); Community Health Workers (28.4%) and by years of experience, less than 10 years (51.4%); more than 10 years (40.8%). Only 34% of the respondents (41% in private and 27.5% in public sector) reported good practices that oxytocin is stored in the refrigerator in their facilities. Most healthcare providers used oxytocin for prevention of PPH (77.9%). Oxytocin was also used for augmentation (66.7%) and induction of labor (52.6%). Half of respondents used above the WHO-recommended oxytocin dose of 10IU for prevention of PPH. Twenty-three percent of respondents reported experiencing oxytocin failure in PPH prevention of whom, 54.3% changed to another uterotonic and 37.1% doubled the dose of oxytocin for their patients. CONCLUSION: Our study findings should be used to establish clinical guidelines and trainings for healthcare providers to improve their knowledge and storage practices and use to safeguard the quality of these lifesaving medicines.

Importance of medicine quality in achieving universal health coverage.

OBJECTIVE: To assess the importance of ensuring medicine quality in order to achieve universal health coverage (UHC). METHODS: We developed a systems map connecting medicines quality assurance systems with UHC goals to illustrate the ensuing impact of quality-assured medicines in the implementation of UHC. The association between UHC and medicine quality was further examined in the context of essential medicines in low- and middle-income countries (LMICs) by analyzing data on reported prevalence of substandard and falsified essential medicines and established indicators for UHC. Finally, we examined the health and economic savings of improving antimalarial quality in four countries in sub-Saharan Africa: the Democratic Republic of the Congo (DRC), Nigeria, Uganda, and Zambia. FINDINGS: A systems perspective demonstrates how quality assurance of medicines supports dimensions of UHC. Across 63 LMICs, the reported prevalence of substandard and falsified essential medicines was found to be negatively associated with both an indicator for coverage of essential services (p = 0.05) and with an indicator for government effectiveness (p = 0.04). We estimated that investing in improving the quality of antimalarials by 10% would result in annual savings of $8.3 million in Zambia, $14 million in Uganda, $79 million in two DRC regions, and $598 million in Nigeria, and was more impactful compared to other potential investments we examined. Costs of substandard and falsified antimalarials per malaria case ranged from $7 to $86, while costs per death due to poor-quality antimalarials ranged from $14,000 to $72,000. CONCLUSION: Medicines quality assurance systems play a critical role in reaching UHC goals. By ensuring the quality of essential medicines, they help deliver effective treatments that lead to less illness and result in health care savings that can be reinvested towards UHC.

Registration timelines of antiretroviral medicines in Ghana and Kenya.

: This study examines registration timelines of antiretroviral medicines (ARVs) in Ghana and Kenya, to assess whether prior reviews by the US Food and Drug Administration Tentative Approval or WHO prequalification (WHO/PQP) affect in-country approval timelines. Data were collected from online and national databases. Median in-country review period in Ghana was 9 months compared with 25 months in Kenya. ARVs with Tentative Approval and WHO/PQP status did not benefit from shorter in-country review periods.

Clinical experiences with the use of oxytocin injection by healthcare providers in a southwestern state of Nigeria: A cross-sectional study.

BACKGROUND: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality in Nigeria and in most low- and middle-income countries. The World Health Organization (WHO) strongly recommends oxytocin as effective, affordable, and the safest drug of first choice in the prevention and treatment of PPH in the third stage of labor. However, there are concerns about its quality. Very high prevalence of poor-quality oxytocin, especially in Africa and Asia, has been reported in literature. Excessive and inappropriate use of oxytocin is also common in low-resource settings. OBJECTIVE: To assess clinical experiences with quality of oxytocin used by healthcare providers in Lagos State, Nigeria. METHODS: This was a descriptive cross-sectional study conducted in 2017, with 705 respondents (doctors and nurses) who use oxytocin for obstetrics and gynecological services recruited from 195 health facilities (public and registered private) across Lagos State. Data collection was quantitative, using a pretested self-administered questionnaire. Data analysis was performed with IBM SPSS version 21. Statistical significance was set at 5 percent (p<0.05). Ethical approval was obtained from Lagos University Teaching Hospital Health Research Ethics Committee. RESULTS: Only 52 percent of the respondents knew oxytocin should be stored at 2°C to 8°C. About 80 percent of respondents used oxytocin for augmentation of labor, 68 percent for induction of labor, 51 percent for stimulation of labor, and 78 percent for management of PPH. Forty-one percent used 20IU and as much as 10% used 30IU to 60IU for management of PPH. About 13 percent of respondents reported believing they had used an ineffective brand of oxytocin in their practice. Just over a third (36%) had an available means of documenting or reporting perceived ineffectiveness of drugs in their facility; of these, only about 12 percent had pharmacovigilance forms in their facilities to report the ineffectiveness. CONCLUSION: The inappropriate and inconsistent use of oxytocin, especially overdosing, likely led to the high perception of medicine effectiveness among respondents. This is coupled with lack of suspicion of medicine ineffectiveness by clinicians as a possible root cause of poor treatment response or disease progression. Poor knowledge of oxytocin storage and consequent poor storage practices could have contributed to the ineffectiveness reported by some respondents. It is necessary to establish a unified protocol for oxytocin use that is strictly complied with. Continuous training of healthcare providers in medicine safety monitoring is advocated.

Scarce quality assurance documentation in major clinical trial registries for approved medicines used in post-marketing clinical trials.

BACKGROUND: This research reviewed major Clinical Trial Registries (CTRs) and assessed the availability of fields on quality assurance for approved medicines used as Investigational Medicinal Products (IMPs) in phase IV clinical trials. METHODS: Two reviewers independently assessed CTRs of the International Committee of Medical Journal Editors (ICJME) and of World Health Organization (WHO) platforms. Each CTR was checked by two reviewers on availability of fields on brand name, manufacturer's name, approval status, approving authority, compliance with Good Manufacturing Practices, and quality testing. In case of discrepancy, consensus was sought between the two reviewers. RESULTS: Of 19 identified CTRs, 8 and 6 belonged to WHO and ICMJE, respectively, while 5 were equally part of both platforms. All CTRs had an 'intervention' field where data on IMPs and IMP comparators are captured. The Canadian CTR used 'drug name' rather than 'intervention'. The EU, Peruvian, and UK CTRs had fields for 'brand name'. However, only the EU CTR had fields for 'manufacturer's name', 'approval status', and 'approving authority'. None of the CTRs had fields on 'compliance with Good Manufacturing Practices' or 'quality testing'. CONCLUSION: This study demonstrates that none of the CTRs of ICMJE and WHO platforms has adequate fields to establish that the source of post-marketing IMPs is of assured quality. This is astonishing given the lengthy requirements in WHO and ICMJE guidelines. Considering the relation between IMP quality and safety of clinical trial participants, the gap of quality assurance fields should be bridged at CTRs concurrently to adjustments of WHO and ICMJE guidelines on CTRs. Specifically, IMP quality testing addressing issues on IMP appearance, impurities, microbial contamination, and dosing should be conducted and reported before, during, and after clinical trial conduct. Until adoption of these measures, the EU CTR should be preferred for registration of phase IV clinical trials conducted in countries lacking stringent regulatory capacities.

Expanding global access to essential medicines: investment priorities for sustainably strengthening medical product regulatory systems.

Access to quality-assured medical products improves health and save lives. However, one third of the world's population lacks timely access to quality-assured medicines while estimates indicate that at least 10% of medicine in low- and middle-income countries (LMICs) are substandard or falsified (SF), costing approximately US$ 31 billion annually. National regulatory authorities are the key government institutions that promote access to quality-assured medicines and combat SF medical products but despite progress, regulatory capacity in LMICs is still insufficient. Continued and increased investment in regulatory system strengthening (RSS) is needed. We have therefore reviewed existing global normative documents and resources and engaged with our networks of global partners and stakeholders to identify three critical challenges being faced by NRAs in LMICs that are limiting access to medical products and impeding detection of and response to SF medicines. The challenges are; implementing value-added regulatory practices that best utilize available resources, a lack of timely access to new, quality medical products, and limited evidence-based data to support post-marketing regulatory actions. To address these challenges, we have identified seven focused strategies; advancing and leveraging convergence and reliance initiatives, institutionalizing sustainability, utilizing risk-based approaches for resource allocation, strengthening registration efficiency and timeliness, strengthening inspection capacity and effectiveness, developing and implementing risk-based post-marketing quality surveillance systems, and strengthening regulatory management of manufacturing variations. These proposed solutions are underpinned by 13 focused recommendations, which we believe, if financed, technically supported and implemented, will lead to stronger health system and as a consequence, positive health outcomes.

Quality medicines in maternal health: results of oxytocin, misoprostol, magnesium sulfate and calcium gluconate quality audits.

BACKGROUND: The high level of maternal mortality and morbidity as a result of complications due to childbirth is unacceptable. The impact of quality medicines in the management of these complications cannot be overemphasized. Most of those medicines are sensitive to environmental conditions and must be handled properly. In this study, the quality of oxytocin injection, misoprostol tablets, magnesium sulfate, and calcium gluconate injections was assessed across the six geopolitical zones of Nigeria. METHOD: Simple, stratified random sampling of health facilities in each of the political zones of Nigeria. Analysis for identification and content of active pharmaceutical ingredient was performed using high-performance liquid chromatography procedures of 159 samples of oxytocin injection and 166 samples of misoprostol tablets. Titrimetric methods were used to analyze 164 samples of magnesium sulfate and 148 samples of calcium gluconate injection. Other tests included sterility, pH measurement, and fill volume. RESULTS: Samples of these commodities were procured mainly from wholesale and retail pharmacies, where these were readily available, while the federal medical centers reported low availability. Approximately, 74.2% of oxytocin injection samples failed the assay test, with the northeast and southeast zones registering the highest failure rates. Misoprostol tablets recorded a percentage failure of 33.7%. Magnesium sulfate and Calcium gluconate injection samples recorded a failure rate of 6.8% and 2.4%, respectively. CONCLUSION: The prevalence of particularly of oxytocin and misoprostol commodities was of substandard quality. Strengthening the supply chain of these important medicines is paramount to ensuring their effectiveness in reducing maternal deaths in Nigeria.

Cost benefit of investment on quality in pharmaceutical manufacturing: WHO GMP pre- and post-certification of a Nigerian pharmaceutical manufacturer.

BACKGROUND: Pharmaceutical companies in Africa need to invest in both facilities and quality management systems to achieve good manufacturing practice (GMP) compliance. Compliance to international GMP standards is important to the attainment of World Health Organization (WHO) prequalification. However, most of the local pharmaceutical manufacturing companies may be deterred from investing in quality because of many reasons, ranging from financial constraints to technical capacity. This paper primarily evaluates benefits against the cost of investing in GMP, using a Nigerian pharmaceutical company, Chi Pharmaceuticals Limited, as a case study. This paper also discusses how to drive more local manufacturers to invest in quality to attain GMP compliance; and proffers practical recommendations for local manufacturers who would want to invest in quality to meet ethical and regulatory obligations. METHOD: The cost benefit of improving the quality of Chi Pharmaceuticals Limited's facilities and system to attain WHO GMP certification for the production of zinc sulfate 20-mg dispersible tablets was calculated by dividing the annual benefits derived from quality improvement interventions by the annual costs of implementing quality improvement interventions, referred to as a benefit-cost ratio (BCR). RESULT: Cost benefit of obtaining WHO GMP certification for the production of zinc sulfate 20-mg dispersible tablets was 5.3 (95% confidence interval of 5.0-5.5). CONCLUSION: Investment in quality improvement intervention is cost-beneficial for local manufacturing companies. Governments and regulators in African countries should support pharmaceutical companies striving to invest in quality. Collaboration of local manufacturing companies with global companies will further improve quality. Local pharmaceutical companies should be encouraged to key into development opportunities available for pharmaceutical companies in Africa.

Actions of the National Regulatory Authorities in 10 Low- and Middle-Income Countries Following Stringent Regulatory Authority Safety Alerts on Rosiglitazone.

On September 23, 2010, the US Food and Drug Administration and the European Medicines Agency issued safety alerts for medicines containing rosiglitazone. The authors monitored the actions of national regulatory authorities (NRAs) from 10 low- and middle-income countries to identify the time lag between the issuance of safety alerts by these two stringent regulatory authorities and any actions by these select NRAs. Two NRAs outside Africa took regulatory actions related to safety of rosiglitazone within 2 weeks of stringent regulatory authority safety alerts. For the 7 of the 8 African NRAs where the authors could confirm the date of regulatory action, the median time lag before some regulatory action was 43 days, although there was considerable variability in time to regulatory action. Low- and middle-income countries should create or strengthen systems for timely consideration and management of emerging safety issues for products that they have registered.

A framework for assessing the economic value of pharmacovigilance in low- and middle-income countries.

Pharmacovigilance (PV) programs are an essential component of national healthcare systems. Well-functioning PV programs can improve population health by identifying and reducing medicines-related problems (MRPs). Many low- and middle-income countries lack functional PV systems, but this deficiency has not been described in terms of the potential economic value of strengthening PV systems. The assessment of economic value for PV can support rational decision making at the country level. We propose a framework for assessing the economic value of PV. We divide national PV systems into four levels: (1) no PV, (2) basic PV, (3) semi-functional PV, and (4) functional PV. These categories represent increasing levels of investment in PV capacity at the national or health facility level for all available medicines, including vaccines. The proposed framework can be used to estimate the costs of PV (including the value of investments to increase PV capacity and the costs of managing MRPs) and outcomes associated with PV (including improvements in morbidity, mortality, and quality of life as a result of the reduction in MRPs). The quantitative approach proposed for assessing costs and benefits uses a decision-analytic modeling framework that would estimate the value of the consequences of MRPs adjusted for their probability of occurrence. This allows the quantification of value using monetary outcomes (cost-benefit analysis), natural units (cost-effectiveness analysis), or mortality adjusted for quality of life or disability (cost-utility analysis). Evidence generated using this framework could assist policy makers, program managers, and donors in evaluating investments that aim to increase the capacity and efficiency of national and facility-level PV programs in low- and middle-income countries.

Pharmacovigilance and global HIV/AIDS.

PURPOSE OF REVIEW: This review focuses on current status, progress, challenges and opportunities in global pharmacovigilance for HIV/AIDS treatment. RECENT FINDINGS: Over 6 million HIV-infected individuals worldwide are on treatment with more than 150 innovator and generic antiretroviral drug products. This achievement is made possible through sponsorship of HIV/AIDS programs [The Global Fund to Fight AIDS, Tuberculosis and Malaria; the President's Emergency Program for AIDS Relief (PEPFAR)] and the availability of generic fixed-dose combination products. The WHO prequalifies generic drug products used by Global Fund programs; the US Food and Drug Administration tentatively approves generic products used by PEPFAR programs through a fast-track review process. Adequate national or regional quality and safety monitoring systems after drug distribution are lacking. The pharmaceutical sector, a significant player in pharmacovigilance in the developed world, has not been engaged. Innovative approaches based on collaboration and partnerships will be needed. Clinic-based or program-based cohort studies, randomized clinical trials and electronic medical records may contribute pharmacovigilance-relevant information. SUMMARY: Attention to drug quality and safety is obligatory for long-term program sustainability. Systematic approaches to regional pharmacovigilance that make use of diverse data sources, and collaborative partnerships between industry, clinical and/or research programs and national health authorities can potentially contribute to overall health system strengthening.

Records linkage of electronic databases for the assessment of adverse effects of antiretroviral therapy in sub-Saharan Africa.

PURPOSE: In 2009, the Ministry of Health and Social Services in Namibia decided to conduct a confirmatory assessment of the risk of anemia associated with zidovudine (AZT)-based highly active antiretroviral therapy (HAART) using records contained in three electronic databases. These records did not share a unique identifying number. The first step was to apply probabilistic record linkage methods to link records in the three databases. METHODS: Records of persons, aged 19-65 years, newly initiated on HAART between January 2007 and June 2008, were selected from a pharmacy electronic dispensing tool (EDT) and linked to an electronic medical records database (ePMS) and a laboratory database (MEDITECH). Using the paper-based clinical record as the gold standard, we measured the sensitivity of the starting HAART regimen, that is, proportion of AZT users in the clinical record correctly identified in electronic record, and specificity of severe anemia, that is, proportion of non-cases of severe anemia in the clinical records correctly identified in the electronic record. Kappa and intraclass correlation coefficients were used to determine reliability. RESULTS: A total of 12 358 records were selected from EDT. Seventy-six percent and 58% of EDT records were linked to ePMS and MEDITECH, respectively. The sensitivity of the starting HAART regimen was 98%, whereas specificity of severe anemia was 100%. The reliability scores for variables including weight, hemoglobin, and CD4 counts were moderate to perfect and ranged from 0.59 to 0.99. CONCLUSION: Probabilistic record linkage methods were effective for records linkage in this sub-Saharan African setting.

A situational analysis of pharmacovigilance plans in the Global Fund Malaria and U.S. President's Malaria Initiative proposals.

BACKGROUND: Pharmacovigilance programmes can monitor and help ensure the safe use of medicines that are critical to the success of global public health programmes. The widespread deployment of artemisinin-based combination therapy (ACT) by national malaria control programmes as part of the overall Global Malaria Action Plan for malaria control to elimination and eradication makes ACT an excellent candidate for pharmacovigilance activities. In 2008, The Roll Back Malaria partnership issued guidelines for inclusion of pharmacovigilance in Global Fund and other related proposals. In light of this recommendation and the rapid scale-up of ACT worldwide, an analysis of Global Fund Round 8 proposals and the President's Malaria Initiative (PMI) 2009 Malaria Operational Plans was conducted to assess if and how pharmacovigilance has been incorporated into countries' national malaria plans and donor budget requests. METHODS: The Global Fund-Malaria Round 8 proposals for the 26 countries and the PMI Malaria Operational Plans (MOPs) for fiscal year 2009 for the 15 countries that were approved and received funding from either the Global Fund-Malaria Round 8 or PMI were accessed through the programme websites. The analysis consisted of conducting word counts and key word in context analyses of each proposal and plan. RESULTS: Twelve out of 26 (46%) of the Global Fund proposals mentioned that established pharmacovigilance systems were present in their countries. Four of the fifteen PMI MOPs (27%) mentioned that established pharmacovigilance systems were present in their countries. Only seven of the 26 (27%) Global Fund proposals included a request for funding for new or current pharmacovigilance activities. Seven of 15 (47%) MOPs included a request for funding for pharmacovigilance activities. CONCLUSIONS: There were relatively few requests for funding for pharmacovigilance activities, demonstrating a lack of emphasis placed on pharmacovigilance systems in recipient countries. The findings stress the need for more active direction to strengthen active surveillance and passive adverse event reporting systems to augment the issuance of guidance documents.