International Regulatory Agencies Research Articles

Multicenter Randomized Controlled Trial of Surveillance Versus Endoscopic Therapy for Barrett’s Esophagus With Low-grade Dysplasia: The SURVENT Trial: Study Rationale, Methodology, Innovation, and Implications

Multicenter Randomized Controlled Trial of Surveillance Versus Endoscopic Therapy for Barrett’s Esophagus With Low-grade Dysplasia: The SURVENT Trial: Study Rationale, Methodology, Innovation, and Implications

Validating multi-dimensional model of financial literacy using confirmatory factor analysis

PurposeThe purpose of this paper is to validate the measurement model of financial literacy in which financial literacy is a second-order construct with financial knowledge, financial attitude and financial behavior as lower-order constructs.Design/methodology/approachThe study is based on the primary data collected from 536 adult respondents of Punjab, India. Confirmatory factor analysis (CFA) has been used in the study.FindingsFinancial knowledge, financial attitude and financial behavior have significant correlation with each other and they converge to form a second-order construct–Financial Literacy. The model of financial literacy as a second-order construct (using CFA) is the perfect fit. The study also highlights that the financial literacy level of people differ significantly depending upon the age, gender, marital status, area of residence, qualification, monthly family income, employment status.Practical implicationsThe study has major implications for policymakers. It confirms the claim that financial literacy is a combination of three components–financial knowledge, financial attitude and financial behavior. The national as well as international regulatory agencies working to promote financial literacy should realize that the overall financial literacy of people can be improved by imparting financial knowledge along with inculcating positive financial attitude and financial behavior among the masses.Originality/valueThe present study is the first study to validate financial literacy as a multidimensional model in the context of India to the best of our knowledge. The study contributes to the extant literature in the field of financial literacy by providing a strong framework for future research.

Development and Evaluation about "2nd-wave" COVID-19 Vaccines

To tackle the pandemic of the novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2), the international society, including Japan, has been actively promoting vaccination for SARS-CoV-2. To effectively utilize these vaccines, clinical trials have been conducted to evaluate their safety and efficacy. For efficacy evaluation, prevention rate of symptomatic novel coronavirus infections (corona virus disease 2019; COVID-19) between placebo groups and investigational vaccine groups has been the key parameter to evaluate the novel COVID-19 vaccines. This approach is based on a consensus among international regulatory authorities. Compared to several months ago, the public vaccination campaign for COVID-19 has substantially progressed in many countries. This makes it difficult to conduct clinical trials, which have placebo control arms, anywhere in the world because of ethical problems in administering a placebo during a pandemic. Therefore, the new international consensus among regulatory authorities is that immunogenicity bridging studies between the new COVID-19 vaccines that are being developed and approved COVID-19 vaccines may be needed when placebo-controlled studies are no longer feasible. In the future, the number of unvaccinated people worldwide is expected significantly decrease; thus, the issue of how to evaluate additional immunization for those who have completed the initial immunization remains to be addressed. This would require new international convergence. The development of COVID-19 vaccines and their evaluation would have to be updated, considering the social situation and vaccine coverage.

Evaluation of EFSA training courses on principles in chemical and biological risk assessment

This report evaluates the training courses delivered under the contract OC/EFSA/SCER/2017/01 - Lot 1. Within the period of January 2018 to February 2022 a total of 21 training courses were provided, eight on-site training courses in Parma at EFSA, six virtual training courses during the Covid-19 pandemic and seven eLearning courses comprising various numbers of modules. The courses covered different aspects of chemical and biological risk assessment and related tools, namely i) harmonisation of risk assessment methodologies for human health and ecological risk assessment of combined exposure to multiple chemicals (mixture assessment), ii) risk assessment of the application of nanoscience and nanotechnologies in agro/food/feed (nanotoxicity); iii) science-based criteria for identifying endocrine disruptors in the context of EU legislation on pesticides and biocides (endocrine disruption); iv) principles on genotoxicity on scientific assessment (genotoxicity) and v) computational toxicology approaches and tools (in silico). All tutors were experts in their field and had previously performed training courses on these topics. The target participants of the training courses were members of EFSA’s Scientific Committee/Panels and their working groups as well as employees from national and international regulatory agencies associated with risk assessment of feed and food compounds. Members of the EFSA Networks as well as EFSA scientific staff also participated in the training courses. Courses were evaluated based on the feedback of participants and continuously improved also by integrating updated or new EFSA guidance documents.

Sustainable development roadmap of Chinese antimalarial products

As the first country that has been certified malaria-free in the WHO Western Pacific Region for more than 3 decades, China should share its successful experiences of malaria control and provide globally recognized anti-malaria products by making full uses of its advantages in provision and production capacity of artemisinin raw materials, to fill the gaps of international demands for mosquito nets, rapid diagnostic reagents and antimalarial compounds. Increasing the investment of research and development of antimalarial products, building overseas bases for artemisinin raw material production, establishing international regulatory authority and promoting the local production of antimalarial products are needed to further promote the internationalization of Chinese antimalarial products, so as to achieve the equity and accessibility of Chinese antimalarial products in highburden regions for malaria.

Convergence or divergence: next frontiers toward globalization of current- and next-generation cell and gene therapies.

The last decades have seen a massive transformation in the field of advanced therapies, culminating in the marketing approval of different cutting-edge gene, cell- and tissue engineering-based therapies across different regions of the world. Although this success is promising, the global clinical development pathway of such therapies is often hindered by unique manufacturing, preclinical and clinical regulatory challenges; with different expectations, sometimes linked with divergence in opinions between international regulatory authorities. Such technologies call for a science-based approach and an early regulatory dialogue to set the key elements of quality, safety and efficacy for the next generation cell and gene therapies that can be harmonized across different regional jurisdictions, hence speeding up patient access to innovative therapies across the globe.

Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review.

In 2011, we published a paper providing an overview about the bioavailability, efficacy, and regulatory status of creatine monohydrate (CrM), as well as other “novel forms” of creatine that were being marketed at the time. This paper concluded that no other purported form of creatine had been shown to be a more effective source of creatine than CrM, and that CrM was recognized by international regulatory authorities as safe for use in dietary supplements. Moreover, that most purported “forms” of creatine that were being marketed at the time were either less bioavailable, less effective, more expensive, and/or not sufficiently studied in terms of safety and/or efficacy. We also provided examples of several “forms” of creatine that were being marketed that were not bioavailable sources of creatine or less effective than CrM in comparative effectiveness trials. We had hoped that this paper would encourage supplement manufacturers to use CrM in dietary supplements given the overwhelming efficacy and safety profile. Alternatively, encourage them to conduct research to show their purported “form” of creatine was a bioavailable, effective, and safe source of creatine before making unsubstantiated claims of greater efficacy and/or safety than CrM. Unfortunately, unsupported misrepresentations about the effectiveness and safety of various “forms” of creatine have continued. The purpose of this critical review is to: (1) provide an overview of the physiochemical properties, bioavailability, and safety of CrM; (2) describe the data needed to substantiate claims that a “novel form” of creatine is a bioavailable, effective, and safe source of creatine; (3) examine whether other marketed sources of creatine are more effective sources of creatine than CrM; (4) provide an update about the regulatory status of CrM and other purported sources of creatine sold as dietary supplements; and (5) provide guidance regarding the type of research needed to validate that a purported “new form” of creatine is a bioavailable, effective and safe source of creatine for dietary supplements. Based on this analysis, we categorized forms of creatine that are being sold as dietary supplements as either having strong, some, or no evidence of bioavailability and safety. As will be seen, CrM continues to be the only source of creatine that has substantial evidence to support bioavailability, efficacy, and safety. Additionally, CrM is the source of creatine recommended explicitly by professional societies and organizations and approved for use in global markets as a dietary ingredient or food additive.

Preclinical safety evaluation of levonadifloxacin, a novel anti-methicillin-resistant Staphyloccocus aureus benzoquinolizine fluoroquinolone by intravenous and oral administration.

Fluoroquinolone (FQ) antibacterials have drawn heightened attention from various international regulatory agencies due to their class-specific side effects. Levonadifloxacin is a novel broad spectrum benzoquinolizine FQ active against methicillin-resistant Staphyloccocus aureus (MRSA). Owing to FQ-associated safety concerns, extensive preclinical safety pharmacology (central nervous system and cardiac safety) and toxicology studies (subacute repeat-dose toxicity, genotoxicity, phototoxicity and chondrotoxicity) of levonadifloxacin were performed at relatively high doses. Intravenous (IV) and oral studies were conducted using WCK 771 (l-arginine salt of levonadifloxacin) and WCK 2349 (l-alanine ester prodrug of levonadifloxacin), respectively. Safety pharmacology studies following single dose revealed no adverse effects on central nervous system (including seizure) in mice and cardiovascular system (hERG and monkey telemetry). In repeat-dose toxicity studies, except for IV bolus dosing related effects in rat (hyperactivity, mild convulsion, polypnoea and injection site irritation) and dog (emesis and salivation), no other adverse findings limiting the dosing duration were observed. No major biochemical, haematological, gross or histopathological changes suggestive of damage to vital organs were observed in either WCK 771- or WCK 2349-treated groups. WCK 771 and WCK 2349 were found to be nongenotoxic; however, they showed weak phototoxicity that was comparable with levofloxacin. WCK 771 showed chondrotoxicity in the Beagle dog pups on repeat-dose administration; however, the severity level was lower than ofloxacin. Overall, preclinical safety studies helped establish wider safety margin for WCK 771 and WCK 2349 that supports administration of higher therapeutic doses in humans by both IV and oral routes, thereby enabling safe anti-MRSA treatment.

Determination and validation of spectrophotometric analytical method for quantification of total flavonoids in the leaves of Azadirachta indica A. Juss. (Meliacease) and optimization of the ultrasound-assisted extraction conditions

Azadirachta indica A. Juss. (Meliaceae) is a plant whose leaves present several pharmacological activities, among them: antioxidant, antimicrobial and hypoglycemic. The present work aims to determine and validate a spectrophotometric analytical method for quantification of total flavonoids, expressed as rutin, in A. indica leaves and to optimize the extraction conditions of these flavonoids. For the selection of the spectrophotometric method, four analytical methods were investigated. The method selected as the most efficient, simple, fast and sustainable has been validated and optimized. The validation was performed according to criteria of national and international regulatory agencies. Box Behnken design (33) and the response surface methodology (RSM) were used to estimate the best extraction conditions. The analytical method that met the study criteria consisted of ultrasound-assisted extraction (UAE) of the plant material in hydroethanolic solution, at a temperature of 60 ºC, for 30 minutes, followed by filtration, dilution of the extract in ethanol/0.02 M acetic acid solution (99:1) and absorbance reading in a spectrophotometer at 364nm. In the validation stages, this method was shown to be linear (linear interval - 20 to 80 μg/mL), precise (intraday and interday), accurate (mean recovery of 120.8%), robust and selective (absence of matrix effect). The best conditions for the UAE process were: Ethanol content 30% (p/p), plant material/solvent ratio 0.2 g/mL and extraction time of 33 minutes. The spectrophotometric method and the UAE conditions determined in this study are suitable for use in the quality control of plant drugs and ethanol extracts from the leaves of Azadirachta indica.

Journey to the Market: The Evolution of Biodegradable Drug Delivery Systems

Biodegradable polymers have been used as carriers in drug delivery systems for more than four decades. Early work used crude natural materials for particle fabrication, whereas more recent work has utilized synthetic polymers. Applications include the macroscale, the microscale, and the nanoscale. Since pioneering work in the 1960’s, an array of products that use biodegradable polymers to encapsulate the desired drug payload have been approved for human use by international regulatory agencies. The commercial success of these products has led to further research in the field aimed at bringing forward new formulation types for improved delivery of various small molecule and biologic drugs. Here, we review recent advances in the development of these materials and we provide insight on their drug delivery application. We also address payload encapsulation and drug release mechanisms from biodegradable formulations and their application in approved therapeutic products.

Collagen-associated side effects of fluoroquinolones: aneurysm and aortic dissection (systematic review)

Well known for fluoroquinolones cause the development of collagen-associated side effects tendopathies with the risk of tendon rupture and retinal detachment, which is associated with the damaging effect and degradation of type I and type III collagen. The aorta is also rich in collagen type I and type III up to 8090%, which has the potential to play a role in the development of aortopathies in cases of fluoroquinolone use. Since 2015, the first publications of research results on the collagen-associated effect of fluoroquinolones on the development of aneurysm and aortic dissection, often called aortopathy, began to appear. A systematic review of observational studies and 5 meta-analyzes of the development of a novel side effect of fluoroquinolones is presented. An absolute incidence of this side effect of 1.1% and a twofold increased relative risk of developing aneurysm/aortic dissection (RR 2.042.23), aortic aneurysm (RR 1.742.83), and aortic dissection (RR 1.882.79). When analyzing age subgroups, an increase in the risk of aneurysm/aortic dissection was noted already from the age of 35 years and was more significant in elderly patients (over 65 years). Analisys of the course duration of fluoroquinolone use (314 days or 14 days) was carried out in two studies and showed an increase in the risk of aneurysm/aortic dissection with increasing duration of fluoroquinolone therapy (RR 1.72 versus RR 1.92). The risk of developing a fluoroquinolone-associated aortopathy was highest during the first 30 days after the course use of fluoroquinolones, with a slight decrease within 6090 days after the course. The signal was confirmed by the FDA pharmacovigilance system (USA) during the analysis of cases of aneurysm/aortic dissection against the background of fluoroquinolones use. International regulatory authorities (FDA and EMA) have announced official documents warning of an increased incidence of rare but serious cases of aortic dissection or ruptured aortic aneurysm with oral fluoroquinolones. Fluoroquinolones should not be given to patients at increased risk unless other treatment options are available. The increased risk category includes patients with a history of aortic or other blood vessel aneurysm, high blood pressure, and the elderly.

Comparison of international guidelines for early-phase clinical trials of cellular and gene therapy products.

Cellular and gene therapies (CGT) are promising fields that are bringing significant clinical benefits to patients by directly targeting the underlying cause of disease. In line with this trend, regulatory agencies in every country have been making efforts to accelerate CGT product development. For acceleration, it is necessary to increase the efficiency of clinical trials, thus the early-phase clinical trials for CGT products should be elaborate and productive. The guidelines of international regulatory agencies were compared and analyzed to examine the considerations for the design of early-phase CGT products. The guidelines described a safety evaluation, preliminary evidence of effectiveness gathering, dose exploration, and a feasibility assessment as common objectives of early-phase clinical trials for CGT products. In addition, the considerations for the design of early-phase CGT products included pretreatment effects and problems in the manufacturing and administration process. The guidelines also covered selection of a study population, control group/blinding, and dose/regimen planning. There were differences in the degree of detail, description, and the scope of the content covered by each guideline. The guideline published by FDA was the most specific. However, when compared with the previous guidelines for designing early-phase clinical trials for small molecules and biologics, the current guidelines need to be revised to suggest more detailed and practical principles and rules.

A Comprehensive Review of Quantifications, Profiling, and Regulations of Pharmaceutical Impurities

In the past few decades impurity profiling has continuously gained the attention of regulatory bodies due to the rise in the number of drugs frequently entering the market. International regulatory agencies like ICH, FDA, Canadian Drug and Health Agency emphasize carrying out impurity profiling of drugs in strict compliance with the regulatory guidelines that have been laid down intending to ensure production of high quality and safe pharmaceutical drugs to serve mankind. Simple impurities can be easily evaluated by conventionally available methods whereas impurities present within complex matrix structure pose significant challenges to the analyst and require a more sophisticated approach. The work has been carried out with great efforts to make the study possible distinctively and comprehensively.

Does external assurance on CSR reporting contribute to its higher quality? Empirical evidence from China

This paper examines the difference that the assurance brings to the quality of CSR reports in the Chinese institutional setting, in particular, the difference in quality (proxy – RKS ranking) of assured and unassured CSR reports, as well as whether the high ownership concentration and corresponding to it “entrenchment effect” obstruct the positive impact the assurance exerts on the quality of CSR reports. The paper examines CSR reports on 2,292 firm-year observations of large Chinese companies over three years (2015–2018). The hypothesis development process predicates on the signaling and stakeholder theories, whilst this study applies regression analysis to test the hypotheses. Consistent with the predictions of signaling and stakeholder theories, the paper finds that assurance contributes to the higher quality of CSR reports. Moreover, the study finds that assured CSR reports have higher sub-scores in all four aspects of RKS ranking. However, as ownership concentration exceeds 50 per cent and reaches the majority, it thwarts the advancement in the quality of CSR reports through its assurance. The paper provides an initial empirical account of the role of assurance in the emerging CSR reporting practice in China. The paper contributes to the modest body of empirical research on the function of external assurance in the CSR area by explicating the role played both by the accounting (external assurance) and corporate governance (ownership concentration) infrastructure to ensure high quality of CSR reporting. The paper briefs local, international regulatory authorities and the business community about the importance of external assurance for the CSR reporting quality.

ANMCO Position paper: Prescription appropriateness of direct oral anticoagulants for stroke and systemic thromboembolis with non-valvular atrial fibrillation

The prescription appropriateness of direct oral anticoagulants (DOACs [dabigatran, rivaroxaban, apixaban, and edoxaban]) is carefully regulated, taking into account the criteria established in phase III trials and listed in the summary of the product characteristics of the four DOACs. In clinical practice, prescriptions are not always in compliance with established indications. In particular, the use of doses lower than those recommended in drug data sheets is relatively frequent. Literature data show that the inappropriate prescription of DOAC doses causes drug underexposure and an up to three-fold increase in the risk of stroke/transient ischemic attack, systemic thromboembolism, and hospitalizations. Possible causes of the deviation between the dose that should be prescribed and that actually employed may include erroneous prescriptions, an overstated bleeding risk perception, and the presence of frail patients, who were not included in pivotal trials. For these reasons, we summarize DOAC indications and contraindications and suggest the appropriate use of DOACs in common clinical scenarios, in accordance with what international guidelines and national and international health regulatory agencies recommend.

A comparative evaluation of dietary exposure to glyphosate resulting from recommended U.S. diets

Since its commercial introduction in 1974, national and international regulatory agencies have consistently reported no human health concerns associated with the herbicide glyphosate when used according to label directions. However, in 2015, the International Agency for Research on Cancer (IARC) classified glyphosate as a probable human carcinogen. Despite IARC being the sole outlier in its conclusion, dietary exposure to glyphosate remains a health concern to some members of the public. While glyphosate residues have been detected in foods, it is unclear whether a specific eating pattern substantially contributes to glyphosate exposure. Therefore, dietary glyphosate intake was determined for three eating patterns recommended in the U.S. The 95th percentile of glyphosate ingestion at 2,000 calories/day for adults for the U.S.-Style, Mediterranean-Style, and Vegetarian eating patterns ranged from 38 to 960, 39 to 1100, and 39 to 880 μg/day, respectively. No significant differences were observed in glyphosate intake between the dietary styles, and the 95th percentile glyphosate intakes were well below the current U.S. EPA chronic oral reference dose (RfD) of 0.1 mg/kg/day. Our data demonstrate that ingestion of certain high residue foods, particularly grains and legumes, is a driver of total dietary glyphosate body burden regardless of dietary style.

Vaccine-induced immune thrombotic thrombocytopenia: definition, risks with different vaccines, and regulatory responses

After the vaccination campaign initiation in Europe and the UK, reports of rare cases of atypical thrombosis, including sinus vein thrombosis and splanchnic venous thrombosis, began to appear in association with the use of vector vaccines AstraZeneca (ChAdOx1) and Johnson & Johnson/Janssen. The syndrome called VITT (vaccine-induced immune thrombotic thrombocytopenia) manifested as thrombosis simultaneously with a decrease in platelet count, a significant increase in D-dimer levels and a detection of factor 4 platelet (PF4) antibodies. We present a detailed review of the epidemiology, pathogenesis, clinical presentation, diagnostics and treatment of VITT, which is by its nature an immune complication, similar to the processes occurring in heparin-induced thrombocytopenia (HIT). All international and national organizations and regulatory authorities, including experts in the field of thrombosis and hemostasis and the VITT expert council recommend continuing the prompt mass vaccination against COVID-19 as the only method that can reduce the incidence of severe cases, stop the spread of COVID-19 infection and the emergence of new dangerous mutations in the viral genome. Failure to vaccinate poses an incomparably greater risk of fatal thrombotic and inflammatory complications associated with infections, compared with the risks of extremely rare adverse events that can occur after vaccination. It should be noted that information on VITT, described as a sporadic phenomenon of an abnormal immune response to some variants of vaccines against COVID-19, cannot be translated to other vaccines (including registered in the Russian Federation) and even more cannot be a reason for refusal to use them.

Expecting the Unexpected: How Regulators Can Prepare for Serious Events

Expecting the Unexpected: How Regulators Can Prepare for Serious Events

Safety assessment of natural products in Malaysia: current practices, challenges, and new strategies.

The belief that natural products are inherently safe is a primary reason for consumers to choose traditional medicines and herbal supplements for health maintenance and disease prevention. Unfortunately, some natural products on the market have been found to contain toxic compounds, such as heavy metals and microbes, as well as banned ingredients such as aristolochic acids. It shows that the existing regulatory system is inadequate and highlights the importance of thorough safety evaluations. In Malaysia, the National Pharmaceutical Regulatory Agency is responsible for the regulatory control of medicinal products and cosmetics, including natural products. For registration purpose, the safety of natural products is primarily determined through the review of documents, including monographs, research articles and scientific reports. One of the main factors hampering safety evaluations of natural products is the lack of toxicological data from animal studies. However, international regulatory agencies such as the European Food Safety Authority and the United States Food and Drug Administration are beginning to accept data obtained using alternative strategies such as non-animal predictive toxicological tools. Our paper discusses the use of state-of-the-art techniques, including chemometrics, insilico modelling and omics technologies and their applications to the safety assessments of natural products.

Unexpected (123I)FP-CIT SPECT findings: SWIDD, SWEDD and all DAT.

Although the diagnosis of Parkinson's disease (PD) is essentially clinical, the implementation of imaging techniques can improve diagnostic accuracy. While some techniques (e.g. magnetic resonance imaging-MRI, computerized tomography-CT) are used to exclude secondary syndromes, presynaptic dopaminergic imaging including imaging of dopamine transporter (DAT)-can help the Neurologist in the differential diagnosis between neurodegenerative parkinsonian syndromes and parkinsonism without dopamine deficiency. DAT imaging can be useful in cases in which the clinical picture is not univocal, as in case of overlapping clinical features in patients with early disease, atypical syndromes or unsatisfying response to therapy. Currently, (123I)FP-CIT ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) (trade name DaTSCAN) is the only agent approved by international regulatory agencies for this purpose. With the increasing use of this technique, some unexpected findings have been reported, including patients clinically diagnosed with PD with a normal SPECT scan [e.g. Scans Without Evidence of Dopaminergic Deficit (SWEDD)]; PD patients with a greater dopaminergic deficit in the striatum ipsilateral to the clinicallymore affected side [e.g. Scans With Ipsilateral Dopaminergic Deficit (SWIDD)]; as well as some artifacts. Moreover, the neurologist must remember that structural lesions and administration of some drugs might alter the result of DAT imaging. Unexpected findings, artifacts, and misinterpretation of imaging findings can lead to an erroneous diagnosis and inappropriate therapy, neglect of other medical conditions that might explain the clinical picture, and undermine the selection phase in clinical trials. The aim of the present review is to bring clarity on these controversial (and sometimes erroneous) results, in order to informof these possibilities the clinicians requesting a DaTSCAN in clinical practice.