Pharmacovigilance in low- and middle-income countries: A review with particular focus on Africa.

Low- and middle-income countries (LMIC) face unique challenges with regard to the establishment of robust pharmacovigilance systems capable of generating data to inform healthcare policy and practice. These include the limited integration and reliability of pharmacovigilance systems across LMIC despite recent efforts to harmonize pharmacovigilance rules and regulations in several regional economic communities. There are particular challenges relating to the need to translate reporting tools into numerous local languages and the low numbers of healthcare providers relative to number of patients, with very short consultation times. Additional factors frequent in LMIC include high uptake of herbal and traditional medication, mostly by self-medication; disruptive political conflicts jeopardizing fragile systems; and little or no access to drug utilization data, which makes it difficult to reliably estimate the true risks of medicines use. Pharmacovigilance activities are hindered by the scarcity of well-trained personnel with little or no budgetary support from national governments; high turnover of pharmacovigilance staff whose training involves a substantial amount of resources; and little awareness of pharmacovigilance among healthcare workers, decision makers and consumers. Furthermore, little collaboration between public health programmes and national medicines regulatory authorities coupled with limited investment in pharmacovigilance activities, especially during mass drug administration for neglected tropical diseases and mass vaccinations, produces major challenges in establishing a culture where pharmacovigilance is systematically embedded. Very low spontaneous reporting rates with poor quality reports hinders robust signal detection analyses. This review summarises the specific challenges and areas of progress in pharmacovigilance in LMIC with special focus on the situation in Africa.

Community Pharmacists' Views and Experiences with ADR Reporting for Complementary Medicines: A Qualitative Study in New Zealand.

INTRODUCTION: Detecting signals of safety concerns associated with complementary medicines (CMs) relies on spontaneous reports submitted by health professionals and patients/consumers. Community pharmacists are well placed to identify and report suspected adverse drug reactions (ADRs) associated with CMs, but pharmacists submit few CMs ADR reports. OBJECTIVES: The aim of this study was to explore New Zealand community pharmacists' views and experiences with ADR reporting for CMs. METHODS: Qualitative, in-depth, semi-structured interviews were undertaken with 27 practising community pharmacists identified through purposive and convenience sampling. Data were analysed using a general inductive approach. RESULTS: Participants were familiar with systems for reporting ADRs, believed ADR reporting for CMs important, and that pharmacists should contribute. However, few submitted reports of CMs ADRs and none encouraged patients/consumers to do so. Participants explained this was because they had never been informed by patients about ADRs associated with CMs. Participants said they would report serious ADRs; time pressures, lack of certainty around causality, lack of awareness of mechanisms for reporting CMs ADRs, and lack of remuneration were deterrents to reporting. Participants were aware of intensive-monitoring studies for prescription medicines, understood the rationale for considering this approach for CMs and recognised there would be potential practical difficulties. CONCLUSIONS: Participants used their knowledge of CMs safety concerns to minimise risk of harms to consumers from CMs use, but most had a passive approach to identifying and reporting ADRs for CMs. There is substantial potential for pharmacists to adopt proactive strategies in pharmacovigilance for CMs, particularly in recognising and reporting ADRs, and empowering CMs users to do the same.

Drug Safety Evaluation in China.

PURPOSE OF REVIEW: This review aimed to introduce the regulations management and current situations of drug safety evaluation in China. RECENT FINDINGS: The nationwide implementation of good laboratory practice and good clinical practice guarantees the quality of pre-marketing drug safety evaluation. In recent years, post-marketing drug safety monitoring is changing from passive mode to the combination of active and passive monitoring. A national adverse drug reaction monitoring sentinel alliance has been created to actively identify, report, and evaluate adverse reactions, with more than 1.4 million cases reported in 2017. But the quality of the reports is not optimal, with few reports from drug manufacturers, low rate of severe reports, and trend of lag reporting. Drug safety evaluation in China is transitioning from passive monitoring to a combination mode. Drug pharmacovigilance is a powerful tool for active monitoring, but participation by drug manufacturers would be essential to an effective drug safety evaluation system.

Vitamin B6 in Health Supplements and Neuropathy: Case Series Assessment of Spontaneously Reported Cases.

INTRODUCTION: In the literature, vitamin B6 has been linked to the development of polyneuropathy. Most often, these complaints were seen when taking high doses of vitamin B6 for a long time. Evidence as to whether a lower dosage range of vitamin B6 (< 50 mg/day) can also induce neuropathy is scarce. OBJECTIVE: We aim to comprehensively describe the cases of neuropathy associated with vitamin B6 received by the Netherlands Pharmacovigilance Centre Lareb and to assess the case series concerning the use of vitamin B6 and neuropathic complaints. METHODS: We describe the number and nature of the reported cases, including suspect product, dosage, duration of use, and vitamin B6 serum levels. In addition, we describe the causality for the individual cases (Naranjo Probability Scale) and for the entire case series (Bradford Hill criteria). RESULTS: In total, 90 reports on products containing vitamin B6 included at least one adverse drug reaction in the standardized Medical Dictionary for Regulatory Activities (MedDRA®) query (SMQ; broad) 'peripheral neuropathy'. The amount of vitamin B6 in the products varied between 1.4 and 100 mg per tablet. The serum vitamin B6 level was known in 36 cases (88-4338 nmol/l), and the mean serum vitamin B6 level was 907 nmol/l. However, no statistical correlation between dosage and vitamin B6 blood levels was found. DISCUSSION AND CONCLUSION: Causality assessment of the case series of 90 reports to Lareb shows it is plausible for the vitamin B6 supplements to have caused complaints such as neuropathies. This is especially the case with higher dosages and prolonged use, but dosages < 50 mg/day also cannot be excluded.

Adverse Events to Food Supplements Containing Red Yeast Rice: Comparative Analysis of FAERS and CAERS Reporting Systems.

INTRODUCTION: Food supplements containing red yeast rice (RYR) are proposed as an alternative in statin-intolerant patients, although they actually contain natural statin(s) and their safety in clinical practice is still incompletely characterized. We described and compared adverse events (AEs) associated with RYR products submitted to reporting systems maintained by the Food and Drug Administration (FDA), with a focus on liver and muscular events. METHODS: We extracted RYR-related AEs from the FDA Adverse Event Reporting System (FAERS) [first quarter (Q1)-2004 to Q2-2016], a drug-based archive, and the Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) (Q1-2004 to Q1-2017). Disproportionality via reporting odds ratio (ROR) with 95% confidence interval (CI) calculation and case-by-case inspection were performed, with a focus on muscular and hepatic AEs. RESULTS: One thousand three hundred AEs were extracted from FAERS (RYR mainly reported as a concomitant agent), whereas only 159 AEs were found in CAERS (RYR recorded mainly as a suspect agent). In FAERS, a large number of reports emerged for "general disorders and administration site conditions," whereas CAERS received also a high number of reports for "investigations" and "musculoskeletal and connective tissue disorders". Disproportionality analyses confirmed higher reporting of serious muscular and liver injuries: in FAERS, five cases of hepatic disorders (ROR = 13.71; 95% CI 5.44-34.57); in CAERS, 27 cases of rhabdomyolysis/myopathy (8.44; 5.44-13.10). CONCLUSIONS: Notwithstanding recognized limitations, these findings strengthen the importance of exploring multiple databases in safety assessment of RYR products, which should be monitored by clinicians for muscular and hepatic safety, and call for urgent review by policymakers to harmonize their regulatory status.

[Phytovigilance: A medical requirement and a legal obligation]. / La phytovigilance: impératif médical et obligation légale.

Phytovigilance consists in supervision of side effects and drug interactions consequential to use of herbal medicinal products, herbal food supplements, herbal cosmetics and/or medicinal plants. It includes thus pharmacovigilance applied to phytotherapy, nutrivigilance and cosmetovigilance but also addictovigilance in case of plants, which lead to drug addiction, and toxicovigilance in case of toxic plants. Becoming necessary owing to (acute or chronic) toxicity risks or to drug interactions risks (of pharmacocinetical or pharmacodynamical kind)--as far as it concerns interactions between several associated plants or between a plant and a chemical or biotechnological allopathic medicine--phytovigilance represents moreover a legal obligation. Pharmacovigilance--in case of herbal medicinal products--is indeed becoming mandatory according to title IX of the European directive 2001/83/EC, whereas nutrivigilance is imposed by the European Food Safety Agency (EFSA).

[Exploration of how to formulate guidelines on post-marketing traditional Chinese medicine surveillance].

Combining the world health organization's (WHO), the United States and the European union's relevant laws and guidelines on post-marketing drug surveillance to judge the status of post-marketing surveillance of traditional Chinese medicine(TCM) in China. We found that due to the late start of post-marketing surveillance of traditional Chinese medicine, the appropriate guidelines are yet to be developed. Hence, hospitals, enterprises and research institutions do not have a shared foundation from which to compare their research results. Therefore there is an urgent need to formulate such post-marketing surveillance guidelines. This paper has used as guidance various technical documents such as, "procedures to formulate national standards" and "testing methods of management in formulating traditional Chinese medicine standards" and has combined these to produce a version of post-marketing surveillance particular to Chinese medicine in China. How to formulate these guidelines is discussed and procedures and methods to formulate technical specifications are introduced. These provide a reference for future technical specifications and will assist in the development of TCM.

The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring.

CONTEXT: The increasing use of tyrosine kinase inhibitor therapy outside of the context of the clinical trial for treatment of advanced thyroid cancer has highlighted the need for a systematic approach to the clinical application of these agents in order to improve patient safety and monitoring promote consistency among providers, and ensure compliance with both institutional and industry standards. EVIDENCE: We reviewed professional thyroid cancer guidelines, the National Comprehensive Cancer Network task force reports, American Society of Clinical Oncology safety standards, review articles, and clinical trials published within the past 10 yr and also included relevant older studies. CONCLUSIONS: Review of available published data and the collective experience prescribing tyrosine kinase inhibitors at The University of Texas MD Anderson Cancer Center have highlighted the need for a systematic, comprehensive, and uniform approach to managing these patients. This paper discusses the approach adopted by the Department of Endocrine Neoplasia at the MD Anderson Cancer Center and illustrates practice patterns, experience, and our standardized approach related to prescribing commercially available tyrosine kinase inhibitors outside of the context of a clinical trial for patients with advanced thyroid cancer.

Safety monitoring of herb-drug interactions: a component of pharmacovigilance.

Adverse drug reactions, including those resulting from interactions between herbal medicines and conventional drugs, are a public health problem worldwide. The need for pharmacovigilance for herb-drug interactions (HDIs) is essential for the identification and assessment of risks of using herbal products (questionable safety, efficacy and quality), which are not always tested with rigor, or often not subject to approval by regulatory agencies. Spontaneous and active surveillance conducted by national pharmacovigilance centres permits a rapid detection of potentially harmful combinations of products. The incidence and prevalence of HDIs are difficult to predict because of the underreporting of adverse effects. It is important for health professionals, consumers, regulatory authorities and suppliers of herbal medicines to be aware of the possible adverse effects and drug interactions caused when herbal medicines are co-administered with conventional drugs. National pharmacovigilance centres continue to play a significant role in increasing awareness of drug safety, in this case with HDIs. The authors' objective for this paper is to provide awareness among policy makers responsible for the design of appropriate pharmacovigilance practices and therefore to highlight the importance of pharmacovigilance in the safety monitoring of HDIs.

[Interpretation of adverse drug reaction reporting and monitoring and significance of traditional Chinese medicine adverse drug reaction monitoring].

The newly revised Regulations for the Administration of Adverse Drug Reaction Reporting and monitoringhas been implemented since July 1, 2011. It is the most important regulation on adverse drug reaction (ADR) monitoring. This article will intensively read the regulation and analysis its significance on the traditional Chinese medicine adverse reaction monitoring, so as to make the revised content more clear and guide the ADR monitoring working better.

[Discussion on establishment of quality control system for intensive hospital monitoring on traditional Chinese medicine injections].

Hospital centralized monitoring is an important method to adverse drug reaction (ADR) of traditional Chinese medicine (TCM) injection. Nowadays, our hospital centralized monitoring to TCM injection is difficult to carry out normally, because of little attention that the medical staffs pay to, poor professional knowledge of researchers, unsound reporting system, unreasonable organization structures of ADR and so on. We hope to establish a quality control system of hospital centralized monitoring to TCM injection, by means of emphasizing the importance of ADR monitoring to TCM injection, establishing and perfecting the management mechanism, strengthening staff member training, building the four-steps inspecting rule, implementing barcode monitoring, to strengthen safety supervision of TCM injection, guarantee medication safety.

[Research on establishment of clinical safety intensive hospital monitoring net of traditional Chinese medicine injection].

The establishment of clinical safety monitoring net of traditional Chinese medicine (TCM) injection is the one of the key issues of the monitoring work. The monitoring net is including varieties of types of net, such as clinical monitoring net, multimedia network platform, the net of experts or talents. The paper will introduce the establishing method of clinical safety monitoring net, the establishing of clinical safety monitoring net, and the establishing of network based on the internet, the knowledge network construction of experts, the net construction of talents are all included, to assure the development for clinical safety monitoring work.

[Research and implementation of adverse reaction automatic warning algorithm on Chinese medicine injection].

OBJECTIVE: To provide analytical data and automatic method for more quickly and accurately discovering warning signals of adverse reactions of traditional Chinese medicine (TCM) injections from a large number of adverse reaction data. METHOD: Constructed the TCM injection adverse reaction monitoring system, integrated of multiple mining algorithms of warning signals of adverse reactions and automatically generate early warning analysis, and extended the algorithm to achieve better effect of warning and analysis. RESULT: By data validation, the system can provide consistent warning results with the actual situation. CONCLUSION: The established system has good scalability, it can provide warning analysis of adverse reaction data from multiple sources, and provide a basis for decision making to experts in the field.

[Principle of adverse drug reaction causality judgement and interpretation of causality assessment method both in China and abroad].

Adverse drug reaction (ADR) causality judgement is a routine procedure in pharmacovigilance, no unified judgement standard and categories standard are established. Temporal relations, consistency, specificity, intensity of reaction are the basic principle of ADR causality jugement we should abide by. There are many ADR causality assessment methods, which classifies standard algorithms, expert judgement, bayesian approches. The implicit definitions of some categories standard, incomplete information from case reports coupled with vast differences in the application of clinical judgements are the major problems facing ADR evaluation. Almost every kind of method shares certain common feature, that is, causal relationship of ADR is classified about five categories. However, causality assessment methods differ in basic principle, evaluation standard, specificity and sensitivity. There are some advantages and disadvantages among methods, but no causality assessment method can be applied to all ADR evaluation to date.

Herb induced liver injury presumably caused by black cohosh: a survey of initially purported cases and herbal quality specifications.

Herb induced liver injury (HILI) is a particular challenge that also applies to purported cases presumably caused by black cohosh (BC), an herb commonly used to treat menopausal symptoms. We analyzed and reviewed all published case reports and spontaneous reports of initially alleged BC hepatotoxicity regarding quality of case details and causality assessments. Shortcomings of data quality were more evident in spontaneous reports of regulatory agencies compared to published case reports, but assessments with the scale of CIOMS (Council for the International Organizations of Sciences) or its updated version revealed lack of causality for BC in all cases. The applied causality methods are structured, quantitative, and liver specific with clear preference over an ad hoc causality method or the liver unspecific Naranjo scale. Reviewing the case data and the reports dealing with quality specifications of herbal BC products, there is general lack of analysis with respect to authentication of BC in the BC products used by the patients. However, in one single regulatory study, there was a problem of BC authentication in the analysed BC products, and other reports addressed the question of impurities and adulterants in a few BC products. It is concluded that the use of BC may not exert an overt hepatotoxicity risk, but quality problems in a few BC products were evident that require additional regulatory quality specifications.

Risk management in dermatology: an analysis of data available from several British-based reporting systems.

BACKGROUND: The elimination or reduction of risk is a prime requirement of all healthcare workers. The matter has come to the fore in dermatological practice recently with the widespread use of effective drugs that have significant side-effects (e.g. retinoids, cytotoxic drugs, biologics), the increase in skin surgery, especially for skin cancer, and the extensive use of phototherapies. OBJECTIVES: To examine the available database from different agencies to which adverse events may be reported over at least a 5-year time frame, categorize the risks, look forward to where as yet unidentified risks might exist, and draw conclusions to improve the safety of dermatological practice. This work came about through a request from the National Patient Safety Agency [to the Joint Specialty Committee of the British Association of Dermatologists (BAD) and Royal College of Physicians] for information on risks to patients receiving treatment or investigation for skin disease. METHODS: Organizations in the U.K. that receive information about adverse events, whether caused by drugs or procedures in dermatological treatments, were approached for information about reported events over a 5-year (or, in one case, 10-year) time frame up to 2009. Data were received from the National Patient Safety Agency, the Medicines and Healthcare Products Regulatory Agency, the National Health Service Litigation Authority, the Medical Protection Society and the Medical Defence Union. In addition, the results of a survey conducted in 2010 by the BAD of its members concerning potential critical incident reporting were included. The received information was analysed according to category of event and conclusions drawn about how best to manage the risks that were identified. RESULTS: Adverse events were divided into the following categories, listed in order of the number of reports received: drug side-effects (biologics and retinoids), phototherapy dosage, drug monitoring (including initial screening), pregnancy prevention programmes, skin cancer follow-up (including acting on reports), dermatopathological reporting and conduct of dermatological surgery (including management of complications, equipment problems, use of lasers, cosmetic procedures and cryotherapy). Critical incidents reported by BAD members often concerned follow-up failures, e.g. of patients receiving systemic drugs or of those with skin cancer. CONCLUSIONS: Several of the reported adverse events concern systemic failures. Recommendations for risk reduction include the following points: better systems for drug monitoring (including regularity of attendance, provision of sufficient follow-up appointments, acting on results and adequacy of pregnancy prevention programmes); staff training and record keeping for phototherapy; acting on skin cancer multidisciplinary team meeting outcomes (including provision of sufficient follow-up appointments); and adequate training of staff in dermatological surgery including cryotherapy. Regular monitoring of the occurrence of such reports is needed to ensure safe practice and to identify early areas of new risk.

The Bradford Hill criteria and zinc-induced anosmia: a causality analysis.

OBJECTIVE: To apply the Bradford Hill criteria, which are widely used to establish causality between an environmental agent and disease, to evaluate the relationship between over-the-counter intranasal zinc gluconate therapy and anosmia. DESIGN: Patient and literature review applying the Bradford Hill criteria on causation. SETTING: University of California, San Diego, Nasal Dysfunction Clinic. PATIENTS: The study included 25 patients who presented to the University of California, San Diego, Nasal Dysfunction Clinic complaining of acute-onset anosmia after intranasal application of homeopathic zinc gluconate gel. MAIN OUTCOME MEASURES: Each of the 9 Bradford Hill criteria--strength of association, consistency, specificity, temporality, biological gradient (dose-response), biological plausibility, biological coherence, experimental evidence, and analogy--was applied to intranasal zinc gluconate therapy and olfactory dysfunction using published, peer-reviewed medical literature and reported clinical experiences. RESULTS: Clinical, biological, and experimental data support the Bradford Hill criteria to demonstrate that intranasal zinc gluconate therapy causes hyposmia and anosmia. CONCLUSIONS: The Bradford Hill criteria represent an important tool for scientifically determining cause between environmental exposure and disease. Increased Food and Drug Administration oversight of homeopathic medications is needed to monitor the safety of these popular remedies.

Improving reporting of adverse events and adverse drug reactions following injections of Chinese materia medica.

BACKGROUND: While reporting of adverse drug events (AE) and adverse drug reactions (ADR) following Chinese materia medica (CM) injection is becoming more common, the reporting quality is of concern. METHODS: A checklist about the reporting quality of AE/ADR was set up, and the ADR/AE reporting of Herba Houttuyniae injection was chosen as an example. Electronic databases Chinese Journal Net (1994-2009) and Chinese Science and Technological Journal Net (VIP) (1989-2009) were searched for target literature. RESULTS: Based on our search strategy, 210 articles were included, with 175 articles reporting single or several cases of ADR/AE following Herba Houttuyniae injection (type I report). There were seven reports from regional or national ADR monitoring centers (type II report), and 28 summary reports from a single hospital or medical center (type III report). All 210 papers mentioned "adverse effect,""safety" or related meaning words in their titles, but 199 articles did not have abstract. Patient demographic characteristics were not fully reported in these articles. In type I articles, only 97 cases (43.11%) mentioned whether patients had or did not have a history of allergies, whereas 128 cases (56.89%) in type II papers and 14 (50%) type III papers, did not mention allergic history of patients. Only three articles (3/210, 1.43%), all of them type I, mentioned the syndrome type in Chinese medicine. None of the papers gave clear indications of the type and grade of ADR/AE of patients. Most papers did not report details of the CM injection procedure, such as the drug company, product serial number, or the drug's validity period. Data about the occurrence time and management of ADR/AE was also inadequately reported. CONCLUSION AND RECOMMENDATIONS: The current reporting format of ADR/AE in clinical CM injections is not standardized. Much fundamental information of ADR/AE following CM injection is therefore missing. A standard reporting format for ADR should be developed, and should include the following: (1) a title mentioning adverse effects and safety; (2) a structured abstract including adequate information about the patient and the disease treated, the drug used, the specific ADR/AE, physician response to the ADR/AE, and result of management; (3) demographic characteristic of the patients (gender, age, etc.); (4) clinical characteristics of patients (disease, syndrome, etc); (5) allergic history of patients; (6) diagnosis and syndrome based on Chinese medicine theory; (7) detailed information about the CM intervention (the manufacturer of the drug, series number, valid dates, dosage, route of administration, menstruum, dripping speed, etc.); (8) concomitant drug use; (9) time and symptoms of ADR/AE; (10) type and grading of ADR/AE; (11) physiological systems affected by ADR/AE; (12) specific treatment and prognosis for ADR/AE; (13) evidence of the cause and effect of ADR/AE; and (14) any other possibility of ADR/AE. Also, a ADR/AE registration system should be established.