key: cord-0334776-yoir7nlb authors: Orubu, E. S. F.; Samad, M. A.; Rahman, M. T. T.; Zaman, M. H.; Wirtz, V. J. title: The integrity of the antimicrobial supply chain in Bangladesh: assessing the regulatory environment and contextual challenges date: 2021-10-30 journal: nan DOI: 10.1101/2021.10.28.21265605 sha: a9e877ae9312027b02daa63ef753c4f3770f0415 doc_id: 334776 cord_uid: yoir7nlb Poor-quality medicines lead to large individual, health systems and national economic losses. Most low- and middle-income countries (LMICs) lack the robust regulatory quality assurance system necessary to contain the spread of poor-quality medicines. Innovations in regulatory systems strengthening are needed to protect public health. In this study, we assessed the integrity of the antimicrobial supply chain in Bangladesh and suggest innovations. We employed a qualitative methodology comprising a policy content analysis, and literature and database reviews. Bangladesh was chosen as a model LMIC because of its pharmaceuticals production capacity. Using a framework modified from the World Health Organization's and the United States Pharmacopoeia's, the Bangladesh National Drug Policy (BNDP) was evaluated for provisions on quality assurance mechanisms that match regulatory functions. Newspaper, peer-reviewed and post-marketing surveillance reports were used to assess the extent of poor-quality antimicrobials in circulation. There are provisions for quality assurance in the BNDP. Newspaper reports identified the circulation of substandard antimicrobials and reported on actions by the government to seize fraudulent/falsified and expired products. Only six peer-review studies testing antimicrobial product quality were identified; the three studies with the larger sample size (over 10 samples tested) reported results of out-of-specifications products. This assessment found evidence of regulatory actions against poor-quality antimicrobials as well as news reports and studies suggesting quality concerns, but no current rigorous assessment of the extent in Bangladesh. We suggest a multi-pronged approach to regulatory system strengthening comprising three strategies: community-based surveillance, task-shifting, and technology-enabled consumer participation. Maintaining the integrity of the pharmaceutical supply chain to prevent the entry of poor-quality medicines continues to be a regulatory challenge for many countries. In 1995, a The WHO defines poor-quality medicines as those that are SF. A substandard medicine is one that is out-of-specification, or fails to meet quality checks, while a falsified medicine is one that deliberately misleads as to content, or manufacturer (7). The impacts of poor-quality medicines extend beyond the individual to health systems and economies (8). Poor-quality antimicrobials contribute to antimicrobial resistance (AMR) with transnational impacts, reinforcing the need for stringent regulatory controls to ensure product integrity in the supply chain (9,10). In many countries, the duty of ensuring the quality of medicines in the supply chain rests with the national medicines regulatory authority (NMRA), which is a public body with the technical . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint 4 and constitutional authority to provide an oversight function. However, most LMICs have limited regulatory capacity to perform all the functions necessary to protect the medicine supply chain against the entry of SF medicines (11). Current approaches to regulatory systems strengthening focus on improving capacity at the NMRA. However, the persistence of the problem of SF medicines in LMICs calls for further innovations in regulatory medicine quality assurance. The aim of this study, as part of a broader Social Innovation on Drug Resistance program, was to assess the integrity of the antimicrobial supply chain in Bangladesh to understand the regulatory environment and contextual challenges. Understanding local contexts including the prevalence of SF medicines and gaps in regulatory approaches is important to any initiative to address challenges (12). While the WHO report gives a global prevalence of SF medicines, there are scant reports from other WHO geographical regions, including the WHO Southeast Asian region. Bangladesh, located in the WHO Southeast, has a large human and animal population and was selected as a model because of its pharmaceutical production capacity. The objectives were to: (i) evaluate the regulatory policies, and other mechanisms, for assuring the quality of antimicrobials in Bangladesh; (ii) identify any reports or publications on the prevalence of SF medicines. The study employed a qualitative methodology comprising document, literature, and database reviews to assess regulatory policies and any quality issues in the antimicrobial supply chain in Bangladesh. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) To evaluate the policy, we modified the regulatory functions frameworks of the WHO and the United States Pharmacopoeia, USP (14,15) to construct a framework covering pre-marketing authorization to post-marketing surveillance mechanisms for oversight of the five tiers of the pharmaceutical supply chain (Table 1 ). This framework grouped regulatory mechanisms into four: current Good Manufacturing Practice (cGMP); Good Distribution Practices (GDP); Good Pharmacy Practice (GPP) guidelines; and pharmacovigilance. The four mechanisms comprised 10 functions. The relevant sections of the policy document corresponding to these grouped functions were identified and described. Additionally, any other quality assurance mechanism specific for antimicrobials identified from practice experience or knowledge were noted and described. Market surveillance and quality issues: To map reports and publications on SF medicines and market surveillance activities, we conducted a combined literature and database review as detailed: 1. Literature review for reports on SF medicines: To identify media reports of SF medicines in circulation/supply chain and/or market surveillance, we performed a literature search for grey literature (non-peer reviewed newspaper reports). Literature from 2017-2020 were reviewed. The literature search was conducted twice in December 2018 and April 2020. The search strategy and extracted data are described in the Appendix. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) For the first two databases, a keyword search was performed using "Bangladesh". Any report of a poor-quality medicine was noted. For the DGDA database, reports of any post-marketing surveillance were retrieved. These results present a composite view of the regulatory environment (policies and postmarketing surveillance) and media and peer-reviewed reports and publications respectively on the quality of antimicrobials in the pharmaceutical supply chain in Bangladesh. Four documents laying out government's policies for ensuring medicine quality in Bangladesh were identified as: • Drug (Control) Ordinance 1982. • The Drug (Control) (Amendment) Ordinance 1984. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We identified 10 mechanisms for the quality assurance of medicines in Bangladesh in the NDP covering all four pre-defined areas as well as a new provision for environmental protection against antimicrobial run-offs from manufacturing plants ( Table 2) . Media reports: Out of 200 listed reports in The Daily Star newspaper of Bangladesh, 27 met the inclusion criteria. Of these, 12 reports were on SF medicines. In three of these reports, antimicrobials were expressly mentioned, and these were evaluated ( Table 3) . Two of evaluated reports were on falsified antibiotics in private facilities, which were seized, and the perpetuators arrested and/or fined (19,20). In one case up to seven different antibiotics were falsified, with most (57%, 4/7) being cephalosporins (20). The third was on expired anthelmintic distributed to a public facility. Reports on medicine quality: The search on Google Scholar retrieved six studies on the quality evaluation of antibiotics marketed in Bangladesh ( Table 4 ). The EMBASE search retrieved three . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Overall, the six studies tested between 1-6 different antibiotics from different manufacturers; the smallest study tested 3 different generics and the largest 39, where studies with larger samples found more out-of-specification results. Importantly, Faruque (2018) et al testing 39 samples of six antibioticscefixime, cephradine, ciprofloxacin, metronidazole, amoxicillin, and azithromycinfound all six evaluated antibiotics to be falsified, with no API content for five, and a low out-of-specification content for azithromycin. This study also suggests that SF medicines may be more prevalent in rural areas (21). Uddin (2017) found that 40% (4/10) different ciprofloxacin brands tested did not meet the dissolution specifications in the USP (or Ciprofloxacin was the most commonly (67%, 4/6) evaluated antibiotic in all six studies. In three of these studies, the ciprofloxacin samples were substandard with out-of-specification dissolution profiles. The link between AMR and SF medicine was investigated by Islam et al (2019), as one arm of a three-part study investigating resistance of selected bacteria to commonly used antibiotics and compliance. Even though half the samples failed one of the two tests for quality, the authors commented that products were generally of sufficient quality and that AMR should not be attributed to SF antimicrobials, but to the low rates (18%, n=300) of patients' compliance. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint Post-marketing surveillance: The MQDB and MQMG, as at the time of the study, did not hold records of any poor-quality antimicrobial from Bangladesh, apart from a WHO Alert on falsified oral cholera vaccine circulating in Bangladesh on MQMG. We found no current reports from the DGDA's website. In 2011, Bangladesh reported a failure rate of 0.04% of medicines assessed for quality as part of its pharmacovigilance activities (24). In this study, we reviewed regulatory medicine quality assurance policies, media and postmarketing surveillance reports as well as antimicrobial quality studies in Bangladesh to provide an understanding of the local context and to suggest approaches to regulatory system strengthening. This assessment of the integrity of the antimicrobial supply chain in Bangladesh highlights the existence of regulations but a significant knowledge gap on the extent of SF antimicrobials. At the same time, it also highlights innovations and existing structures that could be leveraged to improve regulatory oversight in Bangladesh. This analysis shows that all iterations of the Bangladesh NDP recognize the need to ensure medicine quality throughout the supply chain and emphasize the need for manufacturers to fully comply with the WHO GMP guidelines. This is in consonance with other countries who have also incorporated these guidelines in their quality assurance mechanisms (25). The NDP also includes GDP guidelines for storage conditions as well as GPP guidelines. In enforcing the drug laws, Bangladesh leverages other players including security and justice personnel. There is a standing Rapid Action Battalion (RAB) composed of DGDA personnel and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Bangladesh, in addition to meeting 98% of its pharmaceutical needs, exports medicines to over a hundred countries (32,33). Its annual pharmaceutical exports is expected to cross the $1 billion mark in the next two years (34). Recently, the country produced its own remdesivir in a demonstration of its pharmaceutical manufacturing capacity (35). Our analysis suggests some challenges with the antimicrobial supply chain in Bangladesh for the study period 2017-2020. Indeed, ever since the first report of poor-quality medicine in the 1980s of contaminated paracetamol, there has been recurrent reports in the newspapers of actions by RAB involving SF medicinesmostly falsified products or expired drugs (36-44). The reports we described above found in the mass media are complemented by laboratory studies we identified from our literature review investigating the quality of antibiotics in circulation in Bangladesh and exploring the impact or implications. The findings are troubling considering that . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint capacity challenges to medicine quality assurance of antimicrobials for human and veterinary use, apart from infrastructural, including human resources (29,49). There is also need for a comprehensive evidence base on the prevalence and spatial distribution of SF antimicrobials to guide targeted and effective regulatory actions using this limited regulatory force. The government, or development partners, could commission a nation-wide quality audit of selected most consumed or marketed antimicrobials available for sale to the public. This would help to identify possible hot-spots for the manufacture, entry, distribution, or sale of SF antimicrobials for a risk-based approach to medicine quality assurance. Bangladesh could address existing policy implementation gaps and further strengthen the integrity of the antibiotic supply chain by three approaches. Firstly, the use of existing community-based structures as a tool to strengthening medicine quality assurance. Interestingly, there are NGOs advocating for stricter actions on SF medicines, signifying public awareness and concern. For example, the Organization of Social and Environment Changes instituted a suit against the government in 2015 at the High Court questioning government's apparent inaction to control the production of counterfeit medicines (50). These organizations may be leveraged to help with inspections of demand points, especially in hard-to-reach rural areas where SF medicines tend to proliferate, using a checklist created by the DGDA. This checklist which would be based on visual analysis by package inspection could include product licensing status and expiry date. Similar checklists have been proposed and studied (51,52). They could also help create community awareness on SF medicines. Interventions utilizing community-based approaches to improving health outcomes have been demonstrated in Bangladesh for reproductive health and TB management, for examples (53, 54) . Thus, this strategy could be a useful tool to explore in the context of pharmacovigilance and regulatory inspections. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint 13 Secondly, task-shifting approaches using designated academic institutions performing regular surveys on behalf of the DGDA may be another way to expand capacity. To strengthen output measures among several different research institutions, the WHO Guidelines on the conduct of Medicine Quality Assurance Survey could be adopted for uniformity in methodology and reporting (55). Mandating such independent analyses to be shared with the NMRA could provide synergies to improve the integrity of the supply chain in LMICs. While we found that the Bangladesh NDP mentions the use of third-partly medicine quality assessors, the extent to which this is utilized to complement efforts by the DGDA within Bangladesh is not known. Taskshifting has been widely used to address workforce capacity challenges in the health sector in many different countries, including high-income settings (56). There may be the need to extend pharmacovigilance also to the veterinary sector, using veterinarians and para veterinarians in the first instance to flag any suspected poor-quality veterinary medicines for follow-up action by the DGDA. The establishment of a separate veterinary medicines agency as is the case with Ethiopia may be another approach at capacity building (57) . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint leveraging information technology and a >80% mobile phone ownership in its population to provide services to the public. Track and trace technologies already exist in its significant fisheries/aquatic livestock sector (66). Thus, leveraging on a combination of end-user participation and technology could be one approach to improving supply chain integrity. This study found the existence of regulation and regulatory actions against poor-quality antimicrobials as well as news reports and peer-reviewed studies on poor-quality antimicrobials, but no current rigorous assessment of the extent of poor-quality antimicrobials. We suggest a multi-pronged diffuse approach to regulatory system strengthening comprising three strategies: community-based surveillance, task-shifting, and technology-enabled consumer participation. These approaches could expand capacity to provide a more robust surveillance of the antimicrobial supply chain. Ethical approval: Not required (as the study included only document and literature review and was not human subject related, there was no need for ethics). Innovation on Drug Resistance (SIDR) Postdoctoral Program to ESFO. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint "Drugs and Therapeutic committee to be formed in all public and private hospitals to ensure rational use of drugs including antibiotics" Pharmacovigilance Pharmacovigilance at demand points, drug manufacturers, drug marketing organizations, and patients (4.13) 1. Regulatory reliance is a mechanism whereby one national MRA accepts products licensed in countries with stringent MRAS without the requirement for additional product registration in-country. 2. Not an integral function of MRAs. However, this mechanism is informed by AMR containment strategies. 3. Good Pharmacy Practices (GPP) considered together as one distinct mechanism. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint Fatal renal failure caused by diethylene glycol in paracetamol elixir: the Bangladesh epidemic POISONING: A CLINICAL AND EXPERIMENTAL CORRELATION: FINAL REPORT Epidemic of Pediatric Deaths From Acute Renal Failure Caused by Diethylene Glycol Poisoning Lessons Learned From Yet Another Episode of Diethylene Glycol Poisoning: It Happened Before and It Happened Again Strengthening Regulatory Systems To Improve Medical Product Quality in Low-and Middle-Income Countries: Promoting the Quality of Medicines (PQM) program [Internet] Drug Seller Provision Practices and Knowledge of Misoprostol in Bangladesh. Int Perspect Sex Reprod Health Community-Based Treatment for Drug-Resistant Tuberculosis: Bangladesh Program Experience. Glob Health Sci Pract Veterinary Drug and Animal Feed Administration and Control Authority of Ethiopia Veterinary Drug and Animal Feed Administration & Control Authorigy Chevaux T. National Guideline on the Pharmacovigilance System in Bangladesh | SIAPS Program [Internet] . [cited 2020 Apr 8]. Available from:. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint 24 http://siapsprogram.org/publication/national-guideline-on-the-pharmacovigilance-system-in- . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Market surveillance and quality issues: To map reports of SF medicines and market surveillance activities, we conducted a combined literature and database review as detailed:Literature review for reports on SF medicines: The search strategy is as described:Google was searched for "online Bangladesh English language newspapers", retrieving 21 (72).Of these, that with the largest print circulationthe Daily Starwas purposively selected. The search term was "medicine". Following a preliminary scan to identify local descriptors of poorquality medicines, headlines/titles/captions and "abstracts", or "one-liners" were then searched for any containing the following keywords: "fake", "adulterated", "substandard", "closure", "illegal", "counterfeit", "unwholesome", "banned" or "expired". Reports meeting these criteria were assessed for eligibility. Inclusion criteria were antimicrobial(s)/ antibiotic/ antihelminth(ic).Editorials and commentary pieces were excluded. Also excluded were reports on non-allopathic medicines including herbal and homeopathic medicines. Data was extracted in the form of the following variables: facility type (manufacturer, hospital or medicine outlet, trader, other) where SF medicines were found; location of facility; category of SF medicine; and whether medicine indicated for use in human or animals. Data were entered into an Excel spreadsheet for analysis.Reporting on quality testing: BANGLAJOL: The search on Banglajol was conducted using the search terms "medicine quality" and "drug quality". Titles were screened for the same key words used in the literature search on Google above in addition to "quality". Exclusion criteria were any study outside Bangladesh, studies on non-pharmaceutical substances including food and water.. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. on May 18-19, 2020. The search term was "drug quality Bangladesh". Retrieved articles were screened for relevance. Titles and abstracts containing "quality" AND/OR "Bangladesh" and describing a laboratory analysis were collated into a reference manager software. Laboratory analyses were identified by any, or combinations of, the following terms: "in vitro", "HPLC", "dissolution", "potency", "assay", "pharmacopeial", "evaluation", "analysis", or "release".Articles were then assessed for eligibility for evaluation using the following criteria: . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)The copyright holder for this preprint this version posted October 30, 2021. ; https://doi.org/10.1101/2021.10.28.21265605 doi: medRxiv preprint