Regulatory Standpoint Research Articles

Roundtable Discussion: The Challenge of Developing Effective Sterilization and Reprocessing Instructions for Use.

Roundtable Discussion: The Challenge of Developing Effective Sterilization and Reprocessing Instructions for Use.

The World Small Animal Veterinary Association (WSAVA): List of Essential Medicines for Cats and Dogs.

The World Small Animal Veterinary Association (WSAVA): List of Essential Medicines for Cats and Dogs.

Nitrification in Premise Plumbing: A Review

Nitrification is a major issue that utilities must address if they utilize chloramines as a secondary disinfectant. Nitrification is the oxidation of free ammonia to nitrite which is then further oxidized to nitrate. Free ammonia is found in drinking water systems as a result of overfeeding at the water treatment plant (WTP) or as a result of the decomposition of monochloramine. Premise plumbing systems (i.e., the plumbing systems within buildings and homes) are characterized by irregular usage patterns, high water age, high temperature, and high surface-to-volume ratios. These characteristics create ideal conditions for increased chloramine decay, bacterial growth, and nitrification. This review discusses factors within premise plumbing that are likely to influence nitrification, and vice versa. Factors influencing, or influenced by, nitrification include the rate at which chloramine residual decays, microbial regrowth, corrosion of pipe materials, and water conservation practices. From a regulatory standpoint, the greatest impact of nitrification within premise plumbing is likely to be a result of increased lead levels during Lead and Copper Rule (LCR) sampling. Other drinking water regulations related to nitrifying parameters are monitored in a manner to reduce premise plumbing impacts. One way to potentially control nitrification in premise plumbing systems is through the development of building management plans.

Insights into toxicology, safety pharmacology, and drug dependence testing: The performance and predictive values of nonclinical tests

The pre-marketing testing of drugs and chemicals is now a paradigm of contribution to the safeguard of public health. As pointed out by the ICH concept paper E14/S7B, there is a need for science-based frameworks that allow a better design, conduction, and interpretation of nonclinical and toxicity tests, particularly, in order for those assays to influence nonclinical and clinical evaluations and decisions better. Critical issues related to the performance and predictive values of nonclinical testing were highlighted and discussed in this article, specifically, to help pharmacologists, toxicologists, and regulators in the evaluation of the reliability of such tests, and basing the prospective decisions on the true predictivity of selected screening tests. This review addressed two common mistakes in drug and chemical testing, namely, (a) the assumption of either sensitivity or specificity as automatically “predictive,” and (b) the reporting of the predictive values disregarding a truly representative prevalence. This review also discussed a statistical basis to apply for (industry standpoint) or grant (regulatory standpoint) authorization for the waiving of selected nonclinical tests. Furthermore, this review can be guiding for those who are entering into the field of drug and chemical testing. Through application, investigation, and enhancement of the conceptual framework discussed in this review, nonclinical testing is expected to provide a higher contribution to drug and chemical development, regulatory science, and public health.

Current Regulatory Standpoint on Evaluating the Bioequivalence of Different Classes of Generic Drugs - Is the Evaluation in the Right Direction?

The concept of evaluating bioequivalence has changed over a period of time. Currently, the Average Bioequivalence approach (ABE) is the gold standard tool for the evaluation of generics. Of late, many debates had arisen about employing ABE approach for the appraisal of all drug categories. This review aims to examine the limitations of ABE approach and the significances of Population Bioequivalence (PBE) and Individual Bioequivalence (IBE) approach, current regulatory thinking for assessing different categories of the drug, whether they are adequately assessed, and the evaluation is in the right direction. We carried out an organized search of bibliographic databases for peer-reviewed research literatures, regulatory recommendations, guidance documents using a focused review question and eligibility criteria. The standard tools were used to appraise the quality of retrieved documents and to make sure the authenticity of the data. In total 73 references were used in the review, the majority of the references (guidance documents) were from the different regulatory agencies and product-specific guidance. There were 29 product-specific guidance from USFDA and EMA. The limitations of the ABE approach were discussed in detail along with the significances of Population Bioequivalence (PBE) approach and Individual Bioequivalence (IBE) approaches. It is apparent from the review that IBE approach is a precise method for evaluating the drugs as it answers drug interchangeability (prescribability and switchability). IBE approach is followed by PBE approach and ABE approach for the evaluation of different categories of drugs in terms of precision.

Blockchain and insurance: a review for operations and regulation

Purpose The purpose of this paper is to examine the operational and regulatory positions of the employment of Blockchain in the insurance industry. Blockchain technology has attracted wide interest from various stakeholders. Many theorists are predicting that this technology will disrupt financial services, including insurance. As stated that the development of blockchain is dependent on regulatory acceptance of this technology, it is essential to establish the current state of play with regard to the application and use of blockchain from a commercial and regulatory standpoints. Design/methodology/approach This review encompasses a number of approaches to view the current status of Blockchain applications. From a commercial approach, this research lists the current applications of blockchain within the insurance industry. From a regulatory point of view, the current positions of the EU and national regulatory bodies are enquired upon to establish how they are examining FinTech and Blockchain technologies within their regulatory processes. Findings This review illustrates a number of Blockchain applications in situ from a commercial point of view. From a regulatory setting and following a call from international and EU levels, it appears that various regulatory bodies have begun the process of formulating testing processes for FinTech applications. There are two predominant types in operation, while others are forming points of contact for advice for FinTechs and a small amount who have not begun the process at all. Research limitations/implications This review illustrates the current state of play of blockchain in insurance from a commercial and regulatory point of view. While this has been observational, this review pulls together information from various sources to encapsulate the regulatory positioning of evaluating FinTech and Blockchain technologies for academia, regulatory and industry audiences. Originality/value This review offers a central resource of information with regard to the current state of blockchain technologies in operation and regulatory approaches to this and other FinTech developments.

Bayesian perspective in BEPU licensing analysis

The main objective of this paper is giving insights about the Bayesian formulation of Best-Estimate-Plus-Uncertainty (BEPU) methodologies of Nuclear Safety. It is written from a regulatory standpoint, focusing on the assessment and licensing process of this type of methodologies. The current use of Bayesian methods in Uncertainty Quantification (UQ) is summarized, distinguishing Forward and Inverse UQ. In Forward UQ, the most popular methods are frequentist and nonparametric. They are based on a minimum of assumptions, and this fact makes them simple to use and may expedite their assessment and licensing process, compared to other methods. Bayesian formulations, on the other hand, need to adequately justify the choice of prior distributions, to make sure that uncertainties are not estimated in an anticonservative fashion.Concerning Forward UQ, methods based on calculation of probabilities of exceeding regulatory limits (P-methods) are an alternative to standard methods based on quantile estimation (Q-methods). A frequentist P-method, the Clopper-Pearson interval, is basically equivalent to the noted Wilks’ method, and so it is extensively used in the BEPU realm. Bayesian framework has been typically overlooked in the realm of P-methods for licensing purposes. The possibility of using such formulation to implement prior information about previous BEPU analysis of similar plant designs, operational conditions and accident scenarios should be explored. Bayesian methodologies of this type are used in Reliability, and they combine specific data with generic data (in the form of priors) of component or system failures.In inverse UQ, the situation is opposite to forward UQ: Bayesian methodologies are preferred to frequentist ones. One of the main reasons may be that Bayesian formulation produce regularized (well-posed) solutions to inverse problems.

Canadian regulatory aspects of gene editing technologies.

The development of gene editing techniques, capable of producing plants and animals with new and improved traits, is revolutionizing the world of plant and animal breeding and rapidly advancing to commercial reality. However, from a regulatory standpoint the Government of Canada views gene editing as another tool that will join current methods used to develop desirable traits in plants and animals. This is because Canada focusses on the potential risk resulting from the novelty of the trait, or plant or animal product entering the Canadian environment or market place, rather than the process or method by which it was created. The Canadian Food Inspection Agency is responsible for the regulation of the environmental release of plants with novel traits, and novel livestock feeds, while Health Canada is responsible for the regulation of novel foods. Environment and Climate Change Canada, in partnership with Health Canada, regulates modified animals for entry into the environment. In all cases, these novel products may be the result of conventional breeding, mutagenesis, recombinant DNA techniques or other methods of plant or animal breeding such as gene editing. This novelty approach allows the Canadian regulatory system to efficiently adjust to any new developments in the science of plant and animal breeding and allows for risk-appropriate regulatory decisions. This approach encourages innovation while maintaining science-based regulatory expertise. Canadian regulators work cooperatively with proponents to determine if their gene editing-derived product meets the definition of a novel product, and whether it would be subject to a pre-market assessment. Therefore, Canada's existing regulatory system is well positioned to accommodate any new innovations or technologies in plant or animal breeding, including gene editing.

Preliminary Validation of Electroporation-Electrolysis (E2) for Cardiac Ablation Using a Parameterisable In-Vivo Model.

Atrial fibrillation is the most common arrhythmia, increasing the risk of stroke, heart failure and death, and a growing epidemic. Electroporation ablation is emerging in cardiac ablation for atrial fibrillation as a fast, tissue-specific and non-thermal alternative to existing technologies tied by their thermal action to shortcomings in efficacy, speed and risk. Studies so far have aimed to translate the success of irreversible electroporation from tumour treatment, with its kilovolt pulses, to cardiac ablation. However, these high voltages may be less appealing for cardiac ablation from clinical, technical and regulatory standpoints. A novel ablation technique combining electroporation and electrolysis in a single pulse E2 uses lower voltages. A custom E2 ablation system was developed and tested on an in vivo tissue model. Histopathological analysis showed lesions of clinically relevant depth, achieved without any acute complications or severe muscle contractions. Lesions were mapped onto a numerical model developed to refine further prototyping. This study provides preliminary prototype validation and the methodological foundation for dose optimisation towards endocardial application.

Technology and Analytics in the Wonderland of Risks Monitoring A Regulatory Standpoint

Technology has enabled a paradigm shift in the way banks and other financial institution work. Be it customer relationship or risk management, automation has completely changed the perspective and the scale of aggregation. But digitization should be taken with a pinch of salt as it has its own challenges like risk arising from third party vendors, model error & skillset required for Big data analytics, data privacy etc. Regulators have already started to analyze some of these issues.

Standards for Treatment and Control Regimens in Therapeutic Trials for Gonorrhea: Lessons From a “Failed” Trial

Standards for Treatment and Control Regimens in Therapeutic Trials for Gonorrhea: Lessons From a “Failed” Trial

Nonphysician Practice of Cosmetic Dermatology: A Patient and Physician Perspective of Outcomes and Adverse Events.

Nonphysicians are expanding practice into specialty medicine. There are limited studies on patient and physician perspectives as well as safety outcomes regarding the nonphysician practice of cosmetic procedures. To identify the patient (consumer) and physician perspective on preferences, adverse events, and outcomes following cosmetic dermatology procedures performed by physicians and nonphysicians. Internet-based surveys were administered to consumers of cosmetic procedures and physician members of the American Society for Dermatologic Surgery. Descriptive statistics and graphical methods were used to assess responses. Comparisons between groups were based on contingency chi-square analyses and Fisher exact tests. Two thousand one hundred sixteen commenced the patient survey with 401 having had a cosmetic procedure performed. Fifty adverse events were reported. A higher number of burns and discoloration occurred in the nonphysician-treated group and took place more often in a spa setting. Individuals seeing nonphysicians cited motivating factors such as level of licensure (type) of nonphysician, a referral from a friend, price, and the location of the practitioner. Improper technique by the nonphysician was cited most as a reason for the adverse event. Both groups agree that more regulation should be placed on who can perform cosmetic procedures. Recall bias associated with survey data. Patients treated by nonphysicians experienced more burns and discoloration compared with physicians, and they are encountering these nonphysicians outside a traditional medical office, which are important from a patient safety and regulatory standpoint. Motivating factors for patients seeking cosmetic procedures may also factor into the choice of provider. Both patients and physicians think more regulation should be in place on who can perform cosmetic procedures. More adverse events such as burns and discolorations occurred with patients seeing nonphysicians compared with those seeing physicians. In addition, for those seeing nonphysicians, a majority of these encounters took place in spa settings. Patient safety is of utmost concern when it comes to elective cosmetic medical procedures. More adverse events and encounters occurring outside traditional medical settings when nonphysicians performed these procedures call into question the required training and oversight needed for such procedures.

Regulatory gaps between LNG carriers and LNG fuelled ships

Given a number of marine vessels treating the liquefied natural gas either as cargo or fuel, this paper examined the regulatory gaps of two different international Codes – the International Code of the Construction and Equipment of Ships Carrying Liquefied Gases in Bulk and the International Code of Safety for Ships Using Gases or Other Low-flashpoint Fuels – from the regulatory standpoint. Results of the gap analysis have identified and discussed the key areas encountered with regulatory discrepancies or ambiguities that might interrupt the proper design, construction and operation of LNG carrier and LNG fuelled ship. A systematic investigation and harmonisation process across the Codes was proposed to mitigate the potential issues that may arise from the discordant regulations. Also, the International Maritime Organization was suggested to take proactive action to improve such dissonances while a general insight into the importance of filling those gaps was provided for rule-makers and stakeholders.

CRISPR/Cas9: A Novel Weapon in the Arsenal to Combat Plant Diseases.

Plant pathogens like virus, bacteria, and fungi incur a huge loss of global productivity. Targeting the dominant R gene resulted in the evolution of resistance in pathogens, which shifted plant pathologists’ attention toward host susceptibility factors (or S genes). Herein, the application of sequence-specific nucleases (SSNs) for targeted genome editing are gaining more importance, which utilize the use of meganucleases (MN), zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN) with the latest one namely clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The first generation of genome editing technologies, due to their cumbersome nature, is becoming obsolete. Owing to its simple and inexpensive nature the use of CRISPR/Cas9 system has revolutionized targeted genome editing technology. CRISPR/Cas9 system has been exploited for developing resistance against virus, bacteria, and fungi. For resistance to DNA viruses (mainly single-stranded DNA viruses), different parts of the viral genome have been targeted transiently and by the development of transgenic plants. For RNA viruses, mainly the host susceptibility factors and very recently the viral RNA genome itself have been targeted. Fungal and bacterial resistance has been achieved mainly by targeting the host susceptibility genes through the development of transgenics. In spite of these successes CRISPR/Cas9 system suffers from off-targeting. This and other problems associated with this system are being tackled by the continuous discovery/evolution of new variants. Finally, the regulatory standpoint regarding CRISPR/Cas9 will determine the fate of using this versatile tool in developing pathogen resistance in crop plants.

Target-independent high-throughput sequencing methods provide evidence that already known human viral pathogens play a main role in respiratory infections with unexplained etiology

ABSTRACT Despite the advanced PCR-based assays available, a fraction of the pediatric respiratory infections remain unexplained every epidemic season, and there is a perception that novel viruses might be present in these specimens. We systematically collected samples from a prospective cohort of pediatric patients with respiratory infections, that returned negative results by validated molecular RT–PCR assays, and studied them with a target-independent, high-throughput sequencing-based approach. We also included a matched cohort of children with no symptoms of respiratory infection, as a contrast study population. More than fifty percent of the specimens from the group of patients with unexplained respiratory infections were resolved. However, the higher rate of detection was not due to the presence of novel viruses, but to the identification of well-known viral respiratory pathogens. Our results show that already known viral pathogens are responsible for the majority of cases that remain unexplained after the epidemic season. High-throughput sequencing approaches that use pathogen-specific probes are easier to standardize because they ensure reproducible library enrichment and sequencing. In consequence, these techniques might be desirable from a regulatory standpoint for diagnostic laboratories seeking to benefit from the many advantages of these sequencing technologies.

Tangential headwinds when integrating industry-funded clinical trials into a US health care delivery system.

Although there are regulatory obligations put forth by the US Food and Drug Administration (FDA) that directly govern clinical trials and other investigational therapies, such activity does not occur in a vacuum. There are other regulations and administrative policies that are tangential to the operations of clinical trials in a health system that can have a direct or indirect effect. Regulations such as HHS's Common Rule and Right To Try have been rapidly evolving over the past couple of years. Also rapidly evolving in this timeframe are the federal government's administrative branch policies involving incentives and disincentives for electronic health records as well as how quality is measured electronically. All of this is occurring as the entire health care delivery sector is trying to reinvent itself with both existing and new unexpected players. Thus, while those interested in conducting industry‐funded clinical trials in their health system generally know to keep up with FDA, they must also be diligent to see how the greater system is forced to evolve to assure that they remain successful form a regulatory and operational standpoint.

The Identity Challenge in Finance: From Analogue Identity to Digitized Identification to Digital KYC Utilities

Identity is fundamental in finance. From a business standpoint, knowledge of clients’ identities is essential to protect against fraud and crime, and underpins all know-yourcustomer obligations, as well as being essential to providing quality services. From a risk management and regulatory standpoint, identity is essential to market integrity. At the same time, identification and KYC rules can be major barriers to accessing financial services, for individuals and small businesses in particular. This paper considers the various requirements for identification in the financial sector and the evolving nature of identity and its evolution from analogue to digitized to digital. We argue that technology presents an opportunity to solve this challenge through the development of digital identity infrastructure and related utilities. The establishment of such utilities for digital or electronic identification requires addressing design questions such as registration methods, data availability and crossjurisdiction recognitions. Yet, as with any reform, a balance between flow-through efficiency and cyber-security needs to be reached to ensure the objectives of financial inclusion and market integrity are not achieved at the detriment of financial stability.

Prevalence, Persistence, and Antimicrobial Resistance of Campylobacter spp. from Eggs and Laying Hens Housed in Five Commercial Housing Systems.

Husbandry practices for laying hens in commercial egg production is a topic of interest from a social, economic, and regulatory standpoint. Animal welfare concerns regarding the use of conventional cages have arisen and consumer perceptions of hen welfare have led to a higher demand for cage-free eggs. The aim of this study was to assess the impact of housing systems on prevalence, persistence, and antimicrobial resistance (AMR) of Campylobacter from laying hens and shell eggs. A total of 425 samples were collected over a 10-month period from the North Carolina Layer Performance and Management Test and Campylobacter isolates were identified by serological, biochemical, and molecular tests. Genetic variability was evaluated using pulsed-field gel electrophoresis (PFGE) and AMR testing was performed. Prevalence of Campylobacter spp. ranged from 11.1% in the enrichable cages to 19.7% in the conventional systems. A greater prevalence of Campylobacter was found in the fecal swab samples from free-range birds compared with those of birds housed in the more intensive housing systems (p > 0.05). Overall, 72 isolates were confirmed as Campylobacter spp. by PCR. More than 90% of the isolates (n = 66) were identified as Campylobacter jejuni, followed by Campylobacter coli (n = 6). C. jejuni isolates displayed high levels of resistance to tetracycline (67%). Genetic variability of Campylobacter was high, with more than 20 PFGE patterns identified. Pattern "a" comprised 42% of isolates from all housing systems and was also the most persistent. This study suggests that housing systems of laying hens used for commercial shell egg production may impact the rate of Campylobacter shedding by layers. Isolation rates and tetracycline resistance levels of this pathogen are still of concern, emphasizing the need for well-implemented biosecurity measures on the farm.

Influence of Different Acids on the Transport of CdSe Quantum Dots from Polymer Nanocomposites to Food Simulants.

We fabricated polymer nanocomposites (PNCs) from low-density polyethylene and CdSe quantum dots (QDs) and used these materials to explore potential exposure after long-term storage in different acidic media that could be encountered in food contact applications. While the low-level release of QD-associated mass into all the food simulants was observed, exposure to dilute acetic acid resulted in more than double the mass transfer compared to that which occurred during exposure to dilute hydrochloric acid at the same pH. Conversely, exposure to citric acid resulted in a suppression of QD release. Permeation experiments and confocal microscopy were used to reveal mechanistic details underlying these mass-transfer phenomena. From this work, we conclude that the permeation of undissociated acid molecules into the polymer, limited by partitioning of the acids into the hydrophobic polymer, plays a larger role than pH in determining exposure to nanoparticles embedded in plastics. Although caution must be exercised when extrapolating these results to PNCs incorporating other nanofillers, these findings are significant because they undermine current thinking about the influence of pH on nanofiller release phenomena. From a regulatory standpoint, these results also support current guidance that 3% acetic acid is an acceptable acidic food simulant for PNCs fabricated from hydrophobic polymers because the other acids investigated resulted in significantly less exposure.

Silencing Whistleblowers by Contract

In 2015 the corporate world was jolted as the Securities and Exchange Commission (SEC) commenced its first enforcement action against employer‐mandated confidentiality agreements to silence would‐be whistleblowers, imposing sanctions on KBR Inc. (KBR) for contractually restricting its employees from becoming whistleblowers. Lying dormant until this action, Dodd–Frank's Rule 21F‐17, which bars restrictions on SEC whistleblowing, now provides the SEC with an active enforcement mechanism through which the agency regularly penalizes noncompliant employers. Although it is now clear from a regulatory standpoint that such confidentiality agreements violate the law, Rule 21F‐17 is void of guidance or explanation as to a much thornier question—whether employers may restrict their employees from turning over to the SEC internal, confidential documents supporting their whistleblowing disclosures. While incorporating the results of a request by the author under the Freedom of Information Act pertaining to Dodd–Frank's whistleblower submission process, this article is the first scholarly attempt to fill this void in the law. By integrating law from related legal doctrines, including contract law, employment law, and precedent under the False Claims Act, this article proposes regulatory amendments to Rule 21F‐17 that balance the employer's concern of safeguarding confidential documents with the whistleblower's need for providing documentary support of his or her claims. Such clarifications to the law will not only provide the SEC and the courts a clear mechanism to determine the lawfulness of such transmissions, but will, most importantly, serve as advance guidance to whistleblowers as to the boundaries of relying on documentary support as they reveal wrongdoing.