Regulatory Applications Research Articles

Regulatory Science, and How Device Regulation Will Shape Our Future.

Pediatric medical device approvals lag behind adult approvals. Historically, medical devices have rarely been designed specifically for children, but use in children has most often borrowed from adult or general use applications. While a variety of social, economic, and clinical factors have contributed to this phenomenon, the regulatory process remains a fundamental aspect of pediatric device development and commercialization. FDA's Center for Devices and Radiological Health (CDRH) has established programmatic and technological areas of advancement to support innovation that serves the public health needs of children and special populations. We highlight four regulatory areas that have the potential to shape the future of pediatric cardiology: the CDRH Early Feasibility Study Program, advancements in 3D printing or additive manufacturing, computational modeling and simulation, and the use of real-world evidence for regulatory applications. These programs have the potential to impact all stages of device development, from early conception, design, and prototyping to clinical evidence generation, regulatory review, and finally commercialization. The success of these programs relies on a collaborative community of stakeholders, including government, regulators, device manufacturers, patients, payers, and the academic and professional community societies.

Adaptation for Regulatory Application: A Content Analysis of FDA Risk Evaluation and Mitigation Strategies Assessment Plans (2014-2018) Using RE-AIM.

Background: Risk Evaluation and Mitigation Strategies (REMS) are safety programs that U.S. Food and Drug Administration can require to ensure a drug's benefits outweigh its risks and can be considered public health interventions. FDA's 2019 draft Guidance for Industry on REMS Assessments encourages the development of “novel methods for assessing REMS [to] help advance the science of post-market assessment of effectiveness of risk mitigation strategies.”Objective: To characterize REMS assessment plans using RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework and identify areas for advancing methods for evaluating REMS programs. RE-AIM was selected for its wide application evaluating the translation of scientific advances into practice for public health impact.Methods: A content analysis of REMS assessment plans (N = 18) and measures(n = 540) was conducted for REMS programs approved by FDA between 1/1/2014–12/31/2018. Eligibility criteria were: a new drug application or biologic license application, included FDA-mandated mitigation strategies called elements to assure safe use (ETASU), and represented a single product REMS program. Assessment plans were collected from publicly available regulatory approval letters from REMS@FDA website. Blinded reviewers categorized each REMS assessment measure to a RE-AIM dimension, adjudicated their application (average IRR 75%), and refined the adapted dimensions' definitions. Dimensions were also mapped to REMS Assessment guidance categories.Results: The median number of assessment measures per REMS assessment plan was 31 (IQR: 21–36). Frequency of measures per RE-AIM criteria per REMS program was: Reach (median = 2; IQR: 2–4); Effectiveness (median = 2.5; IQR:1–4); Adoption (median = 3.5; IQR: 2–5); Implementation (median = 18; IQR: 15–24); Maintenance (median = 0; IQR: 0–1). Adoption (among prescriber, health system agents of implementation) was more commonly assessed than Reach (population-attributable number of patients affected). Assessment of heterogeneity of Adoption and Reach was generally absent. Implementation assessment measures were most common among drugs requiring evidence of safe-use conditions before dispensing or administering the drug. Patient-level Effectiveness and Maintenance assessments were most common among drugs requiring patient monitoring.Discussion: Implementation science frameworks, such as RE-AIM, can be applied to characterize REMS assessment measures and identify opportunities for standardizing and strengthening their evaluation. Methods to measure Maintenance are needed to provide real-world evidence of REMS integration into the healthcare system.

Towards the development of an omics data analysis framework

The use of various omics techniques for scientific research is increasing. While toxicogenomics studies have already produced substantial data on diverse omics platforms, to date there has been little routine application in regulatory toxicology. This is despite the promises and excitement of 20 years ago when it was widely speculated that omics methods would reduce or even replace animal use and allow a much enhanced understanding of hazard and susceptibility. One of the reasons for this has been a trepidation about relying on the produced data. It has been argued that omics outputs might not be sufficiently reliable for regulatory application because the techniques, bioinformatics and interpretation can vary. For these reasons the robustness of the obtained results is questioned. This reticence to trust omics data is further magnified by the lack of internationally agreed upon guidelines and protocols for both the generation and processing of omics data. One way forward would be to reach a consensus on an omics data analysis framework (ODAF) for regulatory application (R-ODAF) based on rigorous data analysis. The authors of this article are involved in a Long-Range Research Initiative (LRI) project that will propose an R-ODAF for transcriptomics data. The R-ODAF will then be reviewed and evaluated by the main regulatory agencies and consensus forums such as the Organization for Economic Co-operation and Development (OECD). This work builds on The MicroArray Quality Control work that developed standards for the generation of data from microarrays and sequencing but not for reporting or analysis.

Pharmaceutical Co-Crystallization: Regulatory Aspects, Design, Characterization, and Applications.

Pharmaceutical co-crystals are novel class of pharmaceutical substances, which possess an apparent probability of advancement of polished physical properties offering stable and patentable solid forms. These multi-component crystalline forms influence pertinent physicochemical parameters like solubility, dissolution rate, chemical stability, physical stability, etc. which in turn result in the materials with superior properties to those of the free drug. Co-crystallization is a process by which the molecular interactions can be altered to optimize the drug properties. Co-crystals comprise a multicomponent system of active pharmaceutical ingredient (API) with a stoichiometric amount of a pharmaceutically acceptable coformer incorporated in the crystal lattice. By manufacturing pharmaceutical co-crystals, the physicochemical properties of a drug can be improved thus multicomponent crystalline materials have received renewed interest in the current scenario due to the easy administration in the pharmaceutical industry. There is an immense amount of literature available on co-crystals. However, there is a lack of an exhaustive review on a selection of coformers and regulations on co-crystals. The review has made an attempt to bridge this gap. The review also describes the methods used to prepare co-crystals with their characterization. Brief description on the pharmaceutical applications of co-crystals has also been incorporated here. Efforts are made to include reported works on co-crystals, which further help to understand the concept of co-crystals in depth.

An evaluation framework for new approach methodologies (NAMs) for human health safety assessment

The need to develop new tools and increase capacity to test pharmaceuticals and other chemicals for potential adverse impacts on human health and the environment is an active area of development. Much of this activity was sparked by two reports from the US National Research Council (NRC) of the National Academies of Sciences, Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (2007) and Science and Decisions: Advancing Risk Assessment (2009), both of which advocated for “science-informed decision-making” in the field of human health risk assessment. The response to these challenges for a “paradigm shift” toward using new approach methodologies (NAMS) for safety assessment has resulted in an explosion of initiatives by numerous organizations, but, for the most part, these have been carried out independently and are not coordinated in any meaningful way. To help remedy this situation, a framework that presents a consistent set of criteria, universal across initiatives, to evaluate a NAM's fit-for-purpose was developed by a multi-stakeholder group of industry, academic, and regulatory experts. The goal of this framework is to support greater consistency across existing and future initiatives by providing a structure to collect relevant information to build confidence that will accelerate, facilitate and encourage development of new NAMs that can ultimately be used within the appropriate regulatory contexts. In addition, this framework provides a systematic approach to evaluate the currently-available NAMs and determine their suitability for potential regulatory application. This 3-step evaluation framework along with the demonstrated application with case studies, will help build confidence in the scientific understanding of these methods and their value for chemical assessment and regulatory decision-making.

Ответственность за оправдание геноцида, преступления против человечества, преступления против мира и военного преступления в уголовном законе Латвийской Республики

ccording to the Section 1 of the Council of European Union Framework Decision 2008/913/JHA on combating certain forms and expressions of racism and xenophobia by means of criminal law, each Member State shall take the measures necessary to ensure that the following intentional conduct is punishable: publicly condoning, denying or grossly trivialising crimes of genocide, crimes against humanity and war crimes. Section 74.1 ―Acquittal of Genocide, Crime against Humanity‖ of the Criminal Law provides for liability in the public glorification of genocide, crime against humanity, crime against peace or war crime or glorification, denial, acquittal or gross trivialisation of committed genocide, crime against humanity, crime against peace or war crime, including genocide, crime against humanity, crime against peace or war crime committed by the U.S.S.R. or Nazi Germany against the Republic of Latvia and its inhabitants. The article aims to initiate a debate on potential problems related to the application of the Section 74.1 ―Acquittal of Genocide, Crime against Humanity‖ of the Criminal Law. The author offers his vision of the regulatory framework application problems.

Mobility monitoring of two herbicides in amended soils: A field study for modeling applications

This paper reports the mobility and total balance of chlorotoluron (CTL), flufenacet (FNC) and bromide ion (Br−) throughout a sandy soil profile after the application of spent mushroom substrate (SMS) and green compost (GC). Obtaining mobility dataset is crucial to simulate the herbicides' fate under amended soil scenarios by application pesticide leaching models with regulatory application (FOCUS models). The application of organic residues is nowadays increased to improve the crop yields and there is a gap in the simulations of this kind of amended scenarios. A two-year field experiment involving unamended soil (S) and SMS- or GC-amended soil plots was conducted. CTL, FNC, and Br− were annually applied and their residual concentrations were determined in soil profiles (0–100 cm) regularly sampled. In all the treatments the order of mobility is followed as FNC < CTL < Br−. SMS and GC increased herbicide retention in the top 10 cm by the higher organic carbon (OC) content than the unamended soil, and their ability to increase the soil's water-holding capacity and to decrease water percolation. Simultaneously dissolved organic carbon (DOC) content facilitated herbicide transport being it favoured by the initial soil moisture content and the rainfall shortly after the chemicals' initial application. Over the first year, residual amounts (<2.6%) of Br−, CTL and FNC were leached down to 90–100 cm depth in the three treatments. However, over the second year low CTL and FNC amounts (<1.0%) reached the bottom layer only in S + SMS although high Br− concentrations did so in the three treatments (<20%). According to the total balance of Br−, CTL, and FNC in the soil profiles other processes (degradation, mineralisation, bound residues formation, and/or crop uptake) different from leaching below 1 m depth might play a key role in their dissipation especially in the amended soil profiles. SMS and GC are likely to be used as organic amendments to preserve the soil and water quality but in the case of SMS, its higher DOC content could imply a higher potential risk for groundwater contamination than GC.

Analysis of Bahrain’s anti-money laundering (AML) and combatting of terrorist financing (CTF) practices

PurposeThis paper aims to examine the level of anti-money laundering (AML) and combatting terrorist financing (CTF) practices incorporated within the legal framework of the Kingdom of Bahrain. The paper also studies the application of AML/CTF legislation in regulatory practice and implementation. Bahrain is an important state within the Middle-East region and is an integral part to the Gulf Cooperation Council (GCC). The paper analyzes Bahrain’s compliance to international AML/CTF standards and presents recommendations on remaining deficiencies.Design/methodology/approachThe paper studies the level of AML/CTF legislation enacted by the Kingdom of Bahrain by first examining the regulatory application, and then, the level of implementation. To understand the level of AML/CTF implementation, the paper uses literature on increased prosecution, penalties and reports for AML/CTF crimes in the Kingdom of Bahrain. In addition, the paper analyzes Bahrain’s compliance level to international standards of AML/CTF legislation and regulation.FindingsThe paper finds evidence of significant progress in the application of best practices of AML/CTF within the Kingdom of Bahrain. The paper also finds an increase in levels of implementation – i.e. suspicious transaction reports, investigations and prosecutions – with respect to AML/CTF violations. Additionally, the paper finds a limited number of deficiencies in Bahrain’s effort to establish strong reporting and enforcement mechanisms.Practical implicationsBahrain is an important member of the international trade network and one of the fastest growing non-oil economies in the region. The country sought to diversify the economy, with more industry- and service-intensive sectors. The level of AML/CTF implementation represents an important risk-averse approach to financial services in the country. Evidence of the country’s strengthening approach is an important factor in determining foreign investment confidence and the country’s policy on combatting terrorism financing.Originality/valueCommentators have previously recognized key deficiencies in Bahrain’s enactment and application of AML/CTF legislation. However, the analysis does not incorporate externalities arising from regulatory delay in domestic AML/CTF policy. The following paper studies the progress made by Bahrain since 2000-2001 and subsequent attempts at improving enforcement to maintain international compliance.

The value of avian gross pathology in identifying endocrine disrupting properties

The European Chemical Agency and European Food Safety Authority recommend that gross pathology findings, from avian reproduction studies, be used to support assessment of potential endocrine disrupting properties of active pesticidal and biocidal substances. In open literature, little information is available on the utility of gross pathology data for informing endocrine evaluations. Here the gross pathology data from historical control groups of 51 northern bobwhite and 51 mallard reproduction tests is analyzed to evaluate the utility of such information. Incidence of gross morphology findings in untreated birds may aid the interpretation of some gross abnormalities, potentially indicative of an endocrine interaction (e.g. reproductive condition). Statistical analysis of the historical control data indicates that gross pathology is not likely to be useful for detecting endocrine effects as abnormalities with relatively high increases in prevalence (more than 20–30%, depending on prevalence in controls) are reliably interpreted as a treatment response. Gross pathology changes are only indicative and not diagnostic of endocrine interactions making it difficult to distinguish gross pathology abnormalities, due to endocrine-mediated effects, from systemic toxicity. This work demonstrates the utility of using historical control analyses to establish the value and properties of selected endpoints for regulatory applications.

IRDFF-II: A New Neutron Metrology Library

High quality nuclear data is the most fundamental underpinning for all neutron metrology applications. This paper describes the release of version II of the International Reactor Dosimetry and Fusion File (IRDFF-II) that contains a consistent set of nuclear data for fission and fusion neutron metrology applications up to 60 MeV neutron energy. The library is intended to support: a) applications in research reactors; b) safety and regulatory applications in the nuclear power generation in commercial fission reactors; and c) material damage studies in support of the research and development of advanced fusion concepts. The paper describes the contents of the library, documents the thorough verification process used in its preparation, and provides an extensive set of validation data gathered from a wide range of neutron benchmark fields. The new IRDFF-II library includes 119 metrology reactions, four cover material reactions to support self-shielding corrections, five metrology metrics used by the dosimetry community, and cumulative fission products yields for seven fission products in three different neutron energy regions. In support of characterizing the measurement of the residual nuclei from the dosimetry reactions and the fission product decay modes, the present document lists the recommended decay data, particle emission energies and probabilities for 68 activation products. It also includes neutron spectral characterization data for 29 neutron benchmark fields for the validation of the library contents. Additional six reference fields were assessed (four from plutonium critical assemblies, two measured fields for thermal-neutron induced fission on 233U and 239Pu targets) but not used for validation due to systematic discrepancies in C/E reaction rate values or lack of reaction-rate experimental data. Another ten analytical functions are included that can be useful for calculating average cross sections, average energy, thermal spectrum average cross sections and resonance integrals. The IRDFF-II library and comprehensive documentation is available online at www-nds.iaea.org/IRDFF/. Evaluated cross sections can be compared with experimental data and other evaluations at www-nds.iaea.org/exfor/endf.htm. The new library is expected to become the international reference in neutron metrology for multiple applications.

Bank Failures, Capital Buffers, and Exposure to the Housing Market Bubble

We empirically document that banks with greater exposure to high home price-to-income ratio regions in 2005 and 2006 have higher mortgage delinquency and charge-off rates and significantly higher probabilities of failure during the last financial crisis even after controlling for capital, liquidity, and other standard bank performance measures. While high price-to-income ratios present a greater likelihood of house price correction, we find no evidence that banks managed this risk by building stronger capital buffers. Our results suggest that there is scope for improved measures of mortgage loan risk that could be considered for regulatory and risk management applications.

Electron transfer in the confined environments of metal-organic coordination supramolecular systems.

The incorporation of electron transfer pairs in both ground and excited states (including electron transfer pairs in excited states and hydrogen or oxygen transfer pairs in ground states) into redox-active hosts with electronic acceptor or donor guests has led to development of a novel method of mimicking the photophysical properties and redox reactions of naturally occurring enzymatic systems. This occurs within the confined microenvironments of metal-organic capsules and metal-organic frameworks. These two types of coordination supramolecular host-guest systems can dock and separate electronic donor-acceptor pairs via closed through-space separation. Electron transfer within confined cavities, which is mainly controlled by spatial and kinetic effects, does not utilize a through-bond electron transfer pathway. In this review, we provide an overview of significant progress in the photophysical and catalytic applications of supramolecular host-guest systems with electron-transfer processes in confined environments. Special emphasis is placed on the action modes and regulatory factors that affect electron transfer between different components to produce enhanced photophysical or redox catalytic performance. Finally, the prospects for confined-environment electron transfer, its application to photophysics and catalysis, and the remaining challenges in this field are highlighted.

Use of LUCS (Light-Up Cell System) as an alternative live cell method to predict human acute oral toxicity

LUCS (Light-Up Cell System) is a new live cell test that allows assessment of a cell’s homeostasis and its alteration by a toxic agent. To evaluate the effectiveness of LUCS as an alternative test method for acute oral toxicity, we compared EC50s determined in HepG2 cells treated with 53 chemicals selected from the ACuteTox EU database with corresponding human blood LC50s derived from human acute poisoning cases. Linear regression analysis showed that LUCS results predict human data to 69 %. Rodent oral LD50s and LUCS EC50s were then correlated to human LC50s using shared data sets. Linear regression analyses comparing LUCS and animal data clearly showed that LUCS always predicts human toxicity better than animal data do.These successful prediction values prompted us to simplify the LUCS test, adapting it to regulatory and high throughput applications, resulting in a new protocol with consistent dose-response profiles and EC50s.This study demonstrates that the LUCS test method could be relevant for assessing human acute oral toxicity with a simplified protocol adapted to commercially available fluorescence readers. We suggest that this new alternative method can be used for acute systemic toxicity testing in combination with other tests under European REACH and other regulations, wherever pertinent alternative methods are still lacking.

Evaluation of the global performance of eight in silico skin sensitization models using human data.

Allergic contact dermatitis, or the clinical manifestation of skin sensitization, is a leading occupational hazard. Several testing approaches exist to assess skin sensitization, but in silico models are perhaps the most advantageous due to their high speed and low-cost results. Many in silico skin sensitization models exist, though many have only been tested against results from animal studies (e.g., LLNA); this creates uncertainty in human skin sensitization assessments in both a screening and regulatory context. This project’s aim was to evaluate the accuracy of eight in silico skin sensitization models against two human data sets: one highly curated (Basketter et al., 2014) and one screening level (HSDB). The binary skin sen­sitization status of each chemical in each of the two data sets was compared to the prediction from eight in silico skin sensitization tools (Toxtree, PredSkin, OECD’s QSAR Toolbox, UL’s REACHAcross™, Danish QSAR Database, TIMES-SS, and Lhasa Limited’s Derek Nexus). Models were assessed for coverage, accuracy, sensitivity, and specificity, as well as optimization features (e.g., probability of accuracy, applicability domain, etc.), if available. While there was a wide range of sensitivity and specificity, the models generally performed comparably to the LLNA in predicting human skin sensitization status (i.e., approximately 70-80% accuracy). Additionally, the models did not mispredict the same com­pounds, suggesting there might be an advantage in combining models. In silico skin sensitization models offer accurate and useful insights in a screening context; however, further improvements are necessary so these models may be con­sidered fully reliable for regulatory applications.

Determination of bioavailable phosphorus in water samples using bioassay methods

The total phosphorus analyte (TP) has a long history of use in monitoring and regulatory applications relating to management of cultural eutrophication in freshwaters. It has become apparent, however, that the fraction of the TP analyte ultimately available to support algal growth varies significantly spatially (within a system), seasonally, and among systems. The algal bioassay methods described here provide an approach for determining the bioavailable fraction of the three operationally defined components of TP: soluble reactive phosphorus (SRP), dissolved organic phosphorus (DOP), and particulate phosphorus (PP) in effluents and tributaries discharging to lakes and reservoirs. Application of the technique facilitates a quantitative ranking and targeting of bioavailable phosphorus sources for management.•One congruent method to fractionate particulate and soluble phosphorus (found in aquatic samples) into bioavailable and unavailable fractions was developed based on compilation, adaptation and expansion of two methods from the late 1970s and early 1980s.•Detailed descriptions for culturing phosphorus-starved algae, sub-sampling schedules, kinetics determination, and data presentation are provided•Reproducibility is demonstrated by replication and closure of a mass balance on phosphorus.

Evaluation of the global performance of eight in silico skin sensitization models using human data_suppl

Allergic contact dermatitis, or the clinical manifestation of skin sensitization, is a leading occupational hazard. Several testing approaches exist to assess skin sensitization, but in silico models are perhaps the most advantageous due to their high speed and low-cost results. Many in silico skin sensitization models exist, though many have only been tested against results from animal studies (e.g., LLNA); this creates uncertainty in human skin sensitization assessments in both a screening and regulatory context. This project’s aim was to evaluate the accuracy of eight in silico skin sensitization models against two human data sets: one highly curated (Basketter et al., 2014) and one screening level (HSDB). The binary skin sen­sitization status of each chemical in each of the two data sets was compared to the prediction from eight in silico skin sensitization tools (Toxtree, PredSkin, OECD’s QSAR Toolbox, UL’s REACHAcross™, Danish QSAR Database, TIMES-SS, and Lhasa Limited’s Derek Nexus). Models were assessed for coverage, accuracy, sensitivity, and specificity, as well as optimization features (e.g., probability of accuracy, applicability domain, etc.), if available. While there was a wide range of sensitivity and specificity, the models generally performed comparably to the LLNA in predicting human skin sensitization status (i.e., approximately 70-80% accuracy). Additionally, the models did not mispredict the same com­pounds, suggesting there might be an advantage in combining models. In silico skin sensitization models offer accurate and useful insights in a screening context; however, further improvements are necessary so these models may be con­sidered fully reliable for regulatory applications.

Clinical Pharmacokinetics of Upadacitinib: Review of Data Relevant to the Rheumatoid Arthritis Indication.

Upadacitinib is a Janus kinase 1 inhibitor developed for treatment of moderate to severe rheumatoid arthritis (RA) and was recently approved by the US Food and Drug Administration for this indication in adults who have had an inadequate response or intolerance to methotrexate. Upadacitinib is currently under regulatory review by other agencies around the world. Ongoing trials are investigating the use of upadacitinib in other inflammatory autoimmune diseases. In this article, we review the clinical pharmacokinetic data available to date for upadacitinib that supported the clinical development program in RA and ultimately regulatory applications for upadacitinib in treatment of patients with moderate to severe RA.

Small Modular Reactor Control Room Workstation Demonstration

A control room simulator was designed to model the operation of a NuScale small modular reactor (SMR) nuclear power plant and provide enough fidelity to perform staffing validation studies for Nuscale’s Nuclear Regulatory Commission Design Certification Application. The simulator serves as a simulated control room with work stations to mimic the operation of an SMR module, turbine generator, and support systems using a proprietary human system interface (HSI) software package. The simulator, which includes all HSI screens, was designed by a team of Human Factors and Plant Operations staff to capitalize on best practices, lessons learned, and operating experience using the Agile development process. Finally, the design process included the development of plant operating procedures and training material as well as a training platform for future plant operators at an SMR nuclear power plant.

Governance of skilled migration and registration of internationally qualified health practitioners: an Australian policy perspective.

This paper presents a policy perspective on the topical issue of migration and registration of internationally qualified health practitioners (IQHPs), with a focus on international medical graduates and internationally qualified nurses and midwives. Current views, regulatory governance and recommendations affecting skilled migration and registration of IQHPs were examined, specifically whether current and proposed practices are transparent, consistent, equitable, robust, cost-effective and assist in ensuring IQHPs demonstrate the necessary qualifications and experience for protection of the Australian public. The complexity of the current regulatory and administrative application and approval processes for IQHPs seeking to live and work in the Australian healthcare setting provides significant opportunities for future research, particularly those areas of reform under consideration by the Health Ministers' Advisory Council.

Workshop Report

Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.