Igho J. Onakpoya

Many terms have been used to describe interventions that do not involve the use of pharmacological products in the setting of communicable diseases. Terminology has varied, and terms have included physical, non-pharmaceutical, non-drug, non-pharmacologic, and non-pharmacological interventions, as well as public health measures and public health and social measures. The recent COVID-19 pandemic has highlighted the importance of non-pharmacological interventions (NPIs), and the term is now recognized globally. The use of the terms public health measures or public health and social measures has variably been inclusive of the use of vaccines, which would be considered pharmacological products. Given this background and confusion over terminology and descriptions, we have reviewed this topic to provide clarity regarding nomenclature, taxonomy, and definitions, with the aim of ensuring an explicit shared understanding of any interventions that do not involve pharmacological products, given the importance of conducting NPI evaluations for future epidemics and pandemics.

Background: Complex multiple long-term conditions (C-MLTC) are commonly defined as the presence of four or more long-term conditions, and their prevalence is projected to increase significantly over the next decade. Methods: We conducted a scoping review of the literature to identify available evidence on risk factors for C-MLTC and map potential clusters. We focused on a subset of 18 chronic conditions because they are among the most commonly reported and prevalent in the general population. For guidelines, we searched the NICE Clinical Knowledge Summaries (CKS), and for systematic reviews, we searched PubMed, Google Scholar, and the TRIP database. Results: We found 53 risk factors associated with 18 long-term conditions. Sixteen of these are linked to C-MLTC, of which 11 are modifiable. Although we reviewed 55 systematic reviews, inconsistent reporting made it difficult to quantify the risk factors and conditions associated with C-MLTC. Diabetes mellitus was a risk factor for most other conditions (n=10), followed by coronary heart disease, hypertension, and chronic kidney disease (each associated with eight long-term conditions). Additionally, depression and anxiety were commonly associated with long-term conditions. Conclusion: Several risk factors and conditions contribute to the development of multimorbidity. Anxiety and depression are associated with nearly all long-term conditions. Reporting problems in the existing evidence and a lack of clear definitions prevent adequate quantification of the risks associated with C-MLTC.

Hundreds of herbal medicines are currently marketed for the management of acute respiratory infections (ARIs). However, there is uncertainty about their benefits and harms, and clinical guidance remains unclear. Our objective was to evaluate the benefits and harms of herbal medicines for preventing and treating ARIs using the evidence from published systematic reviews. We conducted electronic searches in MEDLINE, Embase, CINAHL, and the Cochrane Library. We also searched Google Scholar and the bibliography of relevant studies. We included reviews of herbal medicines or herbal medicine combinations for the prevention or treatment of ARIs. Our primary outcomes were infection rates, symptom resolution, symptom duration, and symptom severity. We used AMSTAR‐2 criteria to assess the quality of included reviews. Two reviewers independently screened abstracts, assessed quality, and extracted the data. We included 18 reviews evaluating the effectiveness of 16 different herbal medicines. A total of 13 were rated high quality, and five were rated moderate quality. Seven reviews of ginseng, ivy leaf extract, echinacea, eucalyptus, and black elderberry showed some benefits in the management of ARIs. The evidence from the remaining 11 reviews was either insufficient or inconclusive. No serious adverse events were reported; however, adverse events were likely underreported. Herbal medicines show modest benefits for managing ARIs, but the evidence remains limited by methodological flaws in the primary studies. While some treatments appear promising, current data are insufficient for strong clinical recommendations. High‐quality, large‐scale RCTs are needed to confirm efficacy, assess safety, and guide clinical use.

Introduction Medicinal product information documents (PIDs) detail clinical characteristics and instructions for monitoring, preventing, and mitigating adverse drug reactions (ADRs). They vary across countries, but there have been no recent international comparisons. We have therefore quantified and compared the completeness of the information given in drug labelling from different countries. Methods From the websites of 35 regulatory agencies, we retrieved the PIDs of medicinal products that were involved in signals communicated by regulators in 2014–2019. We developed a data extraction framework based on the Dose-relatedness, Time course, Susceptibility (DoTS) clinical classification of ADRs and used its implications for prevention and mitigation to score the completeness of related instructions in PIDs. To extract and classify monitoring instructions, we used a modified Systematic Instructions for Monitoring (SIM) method. PIDs had sufficiently complete instructions for prevention when the DoTS score was ≥ 5/12, and sufficiently complete monitoring instructions when the SIM score was ≥ 3/6. We used proportions of PIDs having a score ≥ 1 to determine the relative availability of clinical characteristics or instructions in a country, compared with all other countries. We quantified their pairwise disagreements using Jaccard’s distance and identified clusters with similar patterns of completeness using agglomerative hierarchical clustering. Results PIDs were available on the websites of 18 of 35 regulatory agencies. They concerned 364 distinct medicinal products, which were involved in 627 signals. Across all countries, the instructions for prevention or mitigation met sufficient completeness for a median of 30% of PIDs (IQR 28–33%), while instructions for monitoring were sufficiently complete for a median of 22% (IQR 19–25%). The information given by the European Union (EU) and Canada had the highest relative availability of clinical characteristics and prevention or mitigation instructions, with a proportion of 0.86. Canadian and EU PIDs also had the highest relative availability of monitoring instructions, with proportions of 0.79 and 0.70. Two clusters of countries showed low disagreements: Malaysia and Singapore; Australia and New Zealand. Conclusions This study suggests that PIDs often do not contain complete instructions for prevention, mitigation, and monitoring of ADRs. Extending existing regulatory cooperation globally would enable regulators to access clinical characteristics and instructions from different regions.

Introduction: There is uncertainty about the quantification, viability and infectivity of SARS-CoV-2 in air samples. Our objective was to systematically review the evidence for air sample virus infectiousness with high-level confirmatory studies. Methods: We conducted literature searches in LitCovid, medRxiv, PubMed, the WHO Covid-19 databases, and Google Scholar. We included studies that assessed viral infectiousness in the air using viral culture or serial qRT-PCR with or without genomic sequencing. Our primary outcome was the proportion of culture-positive air samples of SARS-CoV-2. Secondary outcomes explored the relationship between infectiousness and Cycle threshold (Ct). We used published methods for assessing quality, and R software for meta-analysis. Results: We included 26 studies that used viral culture to assess air sample positivity of SARS-CoV-2. The overall reporting quality was moderate. The overall pooled frequency of positive viral cultures was 14% (95% CI 7–17, I ² = 52.3%; p = 0.001). The data were not sufficient to compute a threshold for infectivity, or to explore the relationship between distance and infectiousness. Conclusions: The proportion of positive SARS-CoV-2 viral cultures following positive RNA samples in the air is low, suggesting that while viral RNA may be present, the likelihood of detecting culturable, infectious viruses is substantially lower. Our findings underscore the need for standardized guidelines to assess and report the infectivity and potential for transmissibility of airborne viruses, including the consistent reporting of Ct values and methods to mitigate bias.

Background To date, signals of adverse reactions to herbal medicines have not been systematically reviewed, limiting pharmacovigilance of herbal medicines because of a lack of data. Objectives We sought to analyse the available evidence on signals involving herbal medicines and to determine to what extent they had been documented at the European Union (EU) level and in the USA. Methods We used the results of a published scoping review of interventional and non-interventional studies that reported signals of adverse reactions to drugs. We assigned Anatomical Therapeutic Chemical classification to all drugs, and identified herbal medicines when they fell under the Anatomical Therapeutic Chemical V90. We ascertained the presence of the adverse reaction, or related adverse reactions, for each signal in reference documents for healthcare professionals: the US Botanical Safety Handbook and the EU monographs and US Dietary Supplement Fact Sheets; and in those for consumers: the US Dietary Supplement Label Database. We summarised the data descriptively, treating US documents as one and comparing harms across pairs of US and EU documents by signal. Documents were deemed concordant if they both included the same or related adverse reactions, or if neither did. We also compared adverse reactions across US documents for healthcare professionals with those for consumers. Results Of the 10,861 signals covered by the scoping review, 53 (0.49%) concerned herbal medicines, all based on case reports. Reference documents from both the US and EU were available for 37 signals. Most of the documents were concordant (73%), and ten (27%) were discordant: six adverse reactions were mentioned only in US documents, three only in EU monographs, and one was warned against in US documents but not in EU documents. Twenty-one signals could be followed up in the Botanical Safety Handbook and Dietary Supplement Fact Sheets. Most (68%) US documents for healthcare professionals were concordant. When the Botanical Safety Handbook and Dietary Supplement Fact Sheets did not include an adverse reaction, neither did the Dietary Supplement Label Database. However, when they did, only 20% of the labels for consumers did too. The proportion of labels mentioning adverse reactions otherwise available in documents intended for healthcare professionals ranged widely, reflecting differences across multiple labels for the same products. Conclusions Very few signals of adverse reactions from the wider scoping review concerned herbal medicines, and were all based on case reports. Information was mostly concordant across documents in the EU and USA. As manufacturers are solely responsible for the contents of the Dietary Supplement Label Database, regulatory oversight may be required to ensure that consistent and comprehensive information on the harms of herbal medicines is made available to consumers in the USA.

We define clinical study reports (CSRs) as standardized full reports of the protocols, results, and other pertinent details of clinical studies that are typically submitted by pharmaceutical companies to regulatory authorities when they apply for marketing authorization. In this systematic review we searched various databases (Clarivate Web of Science, EMBASE and Ovid Medline, Google Scholar, and PubMed) for publications containing the term “clinical study report/s”, without restrictions. In the first part of this review we discussed the history of CSRs, their contents and structure, definitions, and relevant terminology. In this second part we discuss the uses of CSRs, concentrating on the individual benefits and harms of pharmacological interventions, and thus the benefit to harm balance. We also discuss adherence to interventions, prepublication of protocols of clinical trials, and how CSRs are written, factors that can all affect estimation of the benefit-harm balance. When clinical trial data from CSRs are compared with the data in published trial reports, the apparent benefits of pharmacological interventions are less impressive, and more information emerges about harms they can cause. Both of these effects change how the benefit-harm balance of a pharmacological intervention is estimated, generally making it less favourable than was otherwise thought. For more accurate assessment of the benefit-harm balance of an intervention, full, not abbreviated or synoptic, clinical study reports should continue to be made publicly available by regulatory authorities and manufacturers. Authorities that do not currently make them available should do so. CSRs should be introduced for assessment of surgical operations, therapeutic devices, and other non-pharmacological interventions in clinical trials.

Clinical study reports (CSRs) are standardized full reports of the protocols, results, and other pertinent details of clinical studies that are typically submitted by pharmaceutical companies to regulatory authorities, as part of the drug approval process. Their recommended contents and structure were described in 1995 in a document of the International Conference on Harmonisation, ICH E3, although companies can choose how to present the data. Until 2015, such reports were not readily available to the public, but since then some regulatory authorities have made them available, as have some pharmaceutical companies, albeit often in abbreviated or redacted versions. The apparent benefits of pharmacological interventions are not as impressive when they are calculated using data from clinical study reports compared with published trial reports, and more information emerges about harms the interventions can cause. Our methods are described in Part 2 of this systematic review with thematic synthesis, in which we have summarized the uses of CSRs, as described in 349 publications of various sorts, including analyses of clinical trials, data analyses, commentaries, and official documents. We have specifically concentrated on how CSRs affect assessments of benefits, harms, and the benefit-to-harm balance, and other factors that affect it. In Part 1, we discuss the history of the development of CSRs, their contents and structure, definitions of CSRs and qualifying terms, and relevant terminology (including the availability of CSRs, data sharing systems, and transparency and confidentiality). Our conclusions are listed in Part 2 of this review.

Introduction: Product information is intended to be a reference for healthcare professionals to verify instructions for monitoring and preventability of adverse drug reactions (ADRs), among other things. International comparisons of these documents, using the Systematic Information for Monitoring (SIM) method, have highlighted discrepancies in the instructions for monitoring, but there has been no comparison of preventability instructions. Objectives: To quantify and compare, across different countries, the completeness of instructions for monitoring and preventability provided to healthcare professionals in medicinal product information. Methods: We shall retrieve information included with medicinal products that have been involved in signals communicated by regulators, in 2014–2019 and based on clinical assessments of reports of ADRs, from the websites of 35 regulatory agencies. We shall evaluate the completeness of instructions for monitoring using a modified version of the SIM method; a score of 67% will qualify a monitoring instruction as sufficiently complete. To evaluate the completeness of instructions for preventability, we have derived a framework from the Dose-responsiveness-Temporality-Susceptibility (DoTS) classification of ADRs and related implications, comprising domains and items/implications. We shall iteratively develop a threshold to define the sufficiency of completeness of instructions based on data distribution across DoTS domains. We shall present descriptive statistics by country for each item of the framework and by total scores, using tables, or figures where necessary. Outcomes: Our target audience is regulators, and the results should highlight gaps in the level of information available to healthcare professionals. This study may also provide some insights into how suspicions of causality that arise from clinical assessments of reports of ADRs translate into actionable recommendations in clinical practice.