Safety monitoring of herbal medicines in Nigeria: worrying state of pharmacovigilance system based on WHO core pharmacovigilance indicators

Introduction Traditional medicine is increasingly gaining global recognition among rural and urban populations especially in Africa, Asia and Latin America (1). It is an integral part of the health care system in these regions, where an estimated 80% of the population considered traditional medicine as a source of primary health care (2). Traditional medicine practitioners treat various illnesses using herbal medicines (HMs), which are mainly prepared from medicinal plants and other natural substances (1,3). Previous reports have provided comprehensive lists of medicinal plants used as HMs (3-5) and the preparation techniques used by the traditional practitioners (6). The efficacies of HMs have been demonstrated in the treatment of various infectious http://www.herbmedpharmacol.com doi: 10.34172/jhp.2021.22


Introduction
Traditional medicine is increasingly gaining global recognition among rural and urban populations especially in Africa, Asia and Latin America (1). It is an integral part of the health care system in these regions, where an estimated 80% of the population considered traditional medicine as a source of primary health care (2). Traditional medicine practitioners treat various illnesses using herbal medicines (HMs), which are mainly prepared from medicinal plants and other natural substances (1,3). Previous reports have provided comprehensive lists of medicinal plants used as HMs (3)(4)(5) and the preparation techniques used by the traditional practitioners (6). The efficacies of HMs have been demonstrated in the treatment of various infectious and non-infectious diseases such as malaria (7), bacterial infections (8), diabetes mellitus (9), and hypertension (10), among others. These therapeutic activities are attributable to the presence of pharmacologically active phytochemicals in plants (4). The increased popularity of HMs in Africa is due to several factors, including abundance of medicinal plants, tradition, drug resistance, cost and side effects of orthodox drugs and the perceived efficacy and safety of HMs (11).
Despite the therapeutic effects of HMs, they can potentially induce toxicological effects (12), which are also associated with the active phytochemical constituents. For instance, saponins are known to have bitter taste, haemolytic, cytotoxic and antinutritional effects (13), while alkaloids may possess hepatoxic, cardiotoxic, and neurotoxic properties (14). In addition, contaminants such as microbes and heavy metals may be mistakenly introduced into the HMs during preparation (15,16). Previous studies have reported adverse effects resulting from irrational consumption of HMs (17)(18)(19). This emphasizes the need for rigorous safety monitoring of HMs similar to what is obtainable with orthodox drugs. Thus, the WHO recommends safety as a fundamental principle in providing HMs for health care, and as a vital element of quality control (20).
Pharmacovigilance (PVG), the science of safety monitoring, initially focused on conventional medicines but the product spectrum has expanded to include HMs (21) due to concern of HMs safety (1). The WHO established guidelines for safety monitoring of HMs with provisions for reporting process, signal detection, causality assessment, scope of the herbal products, extent of what to be reported and probable challenges (20). In order to ascertain the functionality of PVG system in different settings, WHO developed PVG indicators that are used to measure the preparedness of the system for effective safety monitoring of drugs, HMs and other relevant products. The indicators provide scientific information on baseline situation and progress in systems and the assessment of services and interventions. They are categorized into core and complementary indicators with each category comprising structural, process, and outcome core or complementary indicators. The core indicators are the elements that are highly relevant and vital to achieving the objectives of PVG (21).
In Nigeria, the National Pharmacovigilance Centre (NPC), a unit of the National Food and Drug Administration and Control (NAFDAC) is statutorily responsible for PVG activities (22). NPC has conducted several safety monitoring activities including cohort event monitoring of drugs (23), however, the efforts on HMs are considered inadequate. Similarly, few studies have evaluated the PVG system in Nigeria using the WHO indicators with a focus on conventional medicines (24). Thus, the present study assessed the state of preparedness of PVG system in Nigeria for safety monitoring of HMs using WHO core PVG indicators.

Materials and Methods
The study was conducted at the Department of Clinical Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Medical Sciences, University of Maiduguri, Maiduguri, Nigeria, between January and June 2019 with participants enrolled across the country. Sixty individuals with expertise in PVG were invited to participate in the study. However, 39 invitees consented and enrolled in the study. The inclusion criteria were: (i) expertise in PVG, (ii) relevant professional background, (iii) residence in Nigeria, (iv) current involvement in PVG activities such as teaching, practice and research, and (v) informed consent. Expertise in PVG was operationally defined as individuals with relevant professional backgrounds, involving in PVG activities such as teaching, research and practice.
The data were collected using data collection form for PVG indicators as described by WHO (21) with a minor modification. The form was used to obtain data on the demographic characteristics of the participants (Section A) and the state of PVG system in Nigeria for safety monitoring of HMs based on core structural indicators (CSIs) [Section B], core process indicators (CPIs) [Section C] and core outcome indicators (COIs) [Section D]. CSIs assessed the availability of essential basic infrastructure, systems, relevant policies, funds, and regulatory framework for safety monitoring of HMs using ten structural indicators. CPIs evaluated the level of HMs-related PVG activities such as collection, collation, analysis, and evaluation of adverse reactions due to HMs using nine process indicators. COIs measured the extent of realization of PVG objectives using the eight elements of outcome indicators (21). The participants were requested to independently and objectively score the state of PVG system in Nigeria in respect to safety monitoring of HMs based on CSIs, CPIs, and COIs on the scales of 3, 2, 1, and 0 for adequate, fairly adequate, inadequate, and uncertain states, respectively. Then, the CSIs index (CSII), CPIs index (CPII) and COIs index (COII) were determined using the formula below:

Mean Score CSIs CPIs COIs CSII CPII COII Total Obtainable Score CSIs CPIs COIs =
The data obtained were analyzed using Statistical Package for Social Science (SPSS) window version 16.0. The data were presented as mean ± standard deviation (SD) and percentage where applicable. The means of the CSIs, CPIs, and COIs were compared using analysis of variance (ANOVA) and CSII, CPII, and COII were compared using chi-square. Significance difference was inferred at P<0.05. Table 1 presents the characteristics of the 39 experts who participated in the study. The mean ± SD age of the participants was 43.6 ± 10.3 years, and mean ± SD work experience was 15.3 ± 9.3 years. The majority of the participants had a doctoral degree (35.9%; P >0.05) as the highest qualification and were medical doctors (28.2%; P >0.05) by profession. Collectively, 12 of the 27 indicators scored at least 2.0 and CSIs, CPIs and COIs accounted for 75.0% (9/12), 0.0% (0/12) and 25.0% (3/12), respectively (P <0.05) as shown in Figure 1. Out of the ten elements of CSIs evaluated, nine indicators had a mean score above 2.0 with seven indicators having the highest obtainable score of 3.0. However, CSIs-5 recorded a mean score ± SD of 1.7 ± 0.8 ( Table 2). None of the nine elements of CPIs assessed had a mean score upto 2.0 with CPIs-8 having the highest mean score ± SD of 1.2 ± 0.4 while CPIs-1 and CPIs-4 with the least score of 0.7 ± 0.4 (Table 3). Similarly, the perception of the state of PVG system in respect of HMs based on CPIs was generally poor. Only three of the indicators scored at least 2.0. COIs-6 and COIs-7 received the highest mean score of 2.1 ± 0.6 while COIs-1, COIs-3, COIs-4, and COIs-5 had the least mean score of 0.9 ± 0.3 (Table 4). In addition, the perception of the state of PVG system in Nigeria for safety monitoring of HMs was compared using CSII, CPII, and COII. The results showed that CSII had the highest index of 91.0% (P <0.05), indicating the adequate state of the system for safety monitoring of HMs based on structural elements ( Figure 2).

Discussion
The WHO has established guidelines for safety monitoring of HMs in PVG systems (20) and developed PVG indicators for assessing the state of the PVG systems for effective safety monitoring of medical devices, prophylactic and therapeutic agents including HMs (21). In Nigeria, previous studies have identified some challenges in reporting adverse reactions due to HMs (17) and the state of PVG system (24) in some parts of the country. Thus, the present study investigated the state of PVG system with respect to safety monitoring of HMs in Nigeria using the WHO core PVG indicators -CSIs, CPIs, and COIs.
CSIs are used to evaluate availability and adequacy of basic infrastructure, systems, and policies required for the optimum discharge of PVG activities in a setting (20). With the CSII of 91%, the present finding suggests that PVG system in Nigeria has infrastructure, system, policies, and regulatory bodies adequate for safety monitoring of HMs used in Nigeria. This is evident by existence of NPC, NAFDAC, yellow form (22), National Drug Policy in Nigeria (25), National PVG Policy and Implementation Framework (22), and annual budgetary allocations by the Government (26). Previous studies have also demonstrated adequacy of PVG system in Nigeria considering the structural indicators (24). However, the low score for CSIs-5 indicates that available human resources may not be adequate to operate the available infrastructure; hence, the need for urgent training of individuals to complement the existing workforce. This is in accordance with studies within and outside Nigeria that have reported inadequacy of experienced professionals to ensure effective implementation of PVG activities (27-     CPIs-2 Current herbal medicine adverse drug reactions reports in the national, regional or local database 0.9 ± 0.

30)
. Also noteworthy is the moderate score obtained by CSIs-8 that assesses the extent of incorporation of PVG into national educational curricula. Thus, the National Universities Commission in Nigeria is hereby urged to review the undergraduate curricula of Medicine, Dentistry, Pharmacy, Pharmacology, Veterinary Medicine and other relevant disciplines to accommodate PVG. Another important indicator is CPIs, which measures the level of PVG activities, including collection, collation, analysis, and evaluation of adverse drug reactions (21). Based on process indicators, the PVG system appears not adequately prepared for the safety monitoring of HMs in Nigeria. Specifically, the records of HMs adverse reactions, ineffectiveness, and medication errors reported in 2018 and the causality assessment and active surveillance related to HMs conducted in 2018 were grossly insufficient. However, these are not surprising because previous studies have shown poor reportage of harmful effects of HMs (17,31) and orthodox drugs (28,30) in Africa even among the health care professionals. This could be partly due to the perceived general safety of HMs (11) and unawareness of the inclusion of HMs among the products covered by PVG (unpublished data). Similarly, records have shown that most of the active surveillance of safety monitoring conducted in 2014 -2018 focused on antimalarial drugs (23,24). Thus, the NPC needs to improve on her activities such as (i) active surveillance of efficacy and safety of HMs, (ii) causality assessment of HMs-related reports, and (iii) awareness campaign and education of the public and relevant professionals on the need to report adverse reactions due to HMs.
The outcome or impact indicators, COIs, assess actualization of PVG objectives, which primarily ensure the patients' safety (21). The findings from the present study suggest that the PVG system in Nigeria is marginally prepared for safety monitoring of HMs as indicated by the COII of 46.7%. There is dearth of adequate data on cost of treating adverse reactions due to HMs, number of admitted patients, and duration of hospitalization in line with a previous study that has reported inadequate data for outcome or impact indicators analysis (24). This may be a reflection of the poor HMs-related PVG activities conducted in the last few years as earlier discussed. Thus, the NPC should also direct adequate resources towards detecting HMs-related signals, taking appropriate regulatory actions when necessary, and collecting data on number of admission, cost of treatment of adverse reactions, duration of hospitalization, and mortality resulting from HMs consumption. These could be achieved through adequate training of health care professionals and traditional practitioners on scope and methods of PVG, and public campaign on the need to report adverse reactions following self-medication with HMs.

Conclusion
It could be concluded that the state of PVG system in Nigeria is adequate for safety monitoring of HMs considering the existence of basic infrastructure, national drug policy, PVG policy, and financial provision, among other structural indicators. However, deliberate systematic efforts targeting process and outcome indicators are required to position the PVG system in a better operational state for optimum outcomes. The present findings provide baseline scientific data on the state of PVG system and could contribute to the effective use and safety monitoring of HMs.