Regulatory Classification Research Articles

The borderline range of toxicological methods: Quantification and implications for evaluating precision_suppl

Test methods to assess the skin sensitization potential of a substance usually use threshold criteria to dichotomize continuous experimental read-outs into yes/no conclusions. The threshold criteria are prescribed in the respective OECD test guidelines and the conclusion is used for regulatory hazard assessment, i.e., classification and labelling of the substance. We can identify a borderline range (BR) around the classification threshold within which test results are inconclusive due to a test method’s biological and technical variability. We quantified BRs in the prediction models of the non-animal test methods DPRA, LuSens and h-CLAT, and of the animal test LLNA, respectively. Depending on the size of the BR, we found that between 6% and 28% of the substances in the sets tested with these methods were considered borderline. When the results of individual non-animal test methods were combined into integrated testing strategies (ITS), borderline test results of individual tests also affected the overall assessment of the skin sensitization potential of the testing strategy. This was analyzed for the 2-out-of-3 ITS: Four out of 40 substances (10%) were con­sidered borderline. Based on our findings we propose expanding the standard binary classification of substances into “positive”/“negative” or “hazardous”/“non-hazardous” by adding a “borderline” or “inconclusive” alert for cases where test results fall within the borderline range.

The borderline range of toxicological methods: Quantification and implications for evaluating precision.

Test methods to assess the skin sensitization potential of a substance usually use threshold criteria to dichotomize continuous experimental read-outs into yes/no conclusions. The threshold criteria are prescribed in the respective OECD test guidelines and the conclusion is used for regulatory hazard assessment, i.e., classification and labelling of the substance. We can identify a borderline range (BR) around the classification threshold within which test results are inconclusive due to a test method's biological and technical variability. We quantified BRs in the prediction models of the non-animal test methods DPRA, LuSens and h-CLAT, and of the animal test LLNA, respectively. Depending on the size of the BR, we found that between 6% and 28% of the substances in the sets tested with these methods were considered borderline. When the results of individual non-animal test methods were combined into integrated testing strategies (ITS), borderline test results of individual tests also affected the overall assessment of the skin sensitization potential of the testing strategy. This was analyzed for the 2-out-of-3 ITS: Four out of 40 substances (10%) were considered borderline. Based on our findings we propose expanding the standard binary classification of substances into "positive"/"negative" or "hazardous"/"non-hazardous" by adding a "borderline" or "inconclusive" alert for cases where test results fall within the borderline range.

Development within the European Union of medical devices incorporating ancillary medicinal substances

In recent years, there has been a remarkable increase in the development and clinical use of Medical Devices (MDs). To date, about 500,000 different types of MDs are commercialised in the EU, with a global turnover of about 100 billion Euros. Increasingly frequently, manufacturers develop devices containing medicinal substances; i.e., a substance that used alone can be considered a Medicinal Product (MP) that help or integrate the main action of the MD (ancillary action). The correct regulatory classification of these MDs is often difficult and is a matter of discussion with the Competent Authorities (CAs). However, a correct classification is crucial for the development strategy and for the subsequent pre-clinical and clinical studies. In fact, the pre-clinical and clinical development plan, the size and number of studies, the reference guidelines and the competent authorities are different for MDs and Medicinal Products (MPs). In the present paper, we analyse and discuss the key phases of development of a MD incorporating an ancillary medicinal substance. Special attention is devoted to: i) the classification of the products according to the relevant European Guidelines; ii) the methodology for clinical evaluation; iii) the assessment procedure by the CA. Finally, we mention a possible approach to address the complexity of the procedure, through the implementation of development teams.

Recombinant Hemagglutinin of Avian Influenza Virus H5 Expressed in the Chloroplast of Chlamydomonas reinhardtii and Evaluation of Its Immunogenicity in Chickens.

Globally, avian influenza (AI) is a serious problem in poultry farming. Despite vaccination, the prevalence of AI in México highlights the need for new approaches to control AI and to reduce the economic losses associated with its occurrence in susceptible birds. Recombinant proteins from avian influenza virus (AIV) have been expressed in different organisms, such as plants. The present study investigated the feasibility of designing and expressing the HA protein of AIV in the transplastomic microalga Chlamydomonas reinhardtii as a novel approach for AIV control and taking advantage of culture conditions, its reproductive range, and safe use in consideration of the generally regarded as safe food ingredient regulatory classification. The results showed that the HA protein of AIV in C. reinhardtii presents antigenic activity by western blot test and through its application in chickens, demonstrating its feasibility as a recombinant antigen against AIV.

Topical preparations and their use in dermatology.

The challenges of everyday clinical routine require dermatologists to have a basic knowledge of the composition of topical preparations as well as the regulatory background associated with their prescription. Proper selection, prescription, and application of topical preparations, depending on the respective indication, are key to professional and responsible medical practice. Problems commonly arise with respect to regulatory classifications (medicinal products, medical devices, or cosmetics), eligibility for reimbursement by the statutory health insurances (GKV), and insufficient declaration of vehicle systems. Apart from selecting the appropriate active substance and its proper concentration, choosing a suitable pharmaceutical (galenic) formulation - and thus utilizing the intrinsic effects thereof - is pivotal in enhancing the intended therapeutic effects. When prescribing individual formulations, dermatologists should, to the greatest extent possible, always resort to standardized extemporaneous preparations. Given the multitude of potential ingredients available for pharmaceutical formulations as well as the complexity resulting therefrom, arbitrary changes in quality or quantity of individual components are associated with a high risk of instability, thus jeopardizing safety and the rationale behind any given formulation. Optimal use of topical preparations also requires basic knowledge in pharmacokinetics as well as evidence-based treatment planning.

Acute oral toxicity testing: Scientific evidence and practicability should govern Three Rs activities.

Acute oral toxicity is determined for regulatory hazard classification or non-classification. The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) recommends the following modules for acute oral toxicity testing: a) the use of the in vitro 3T3 Neutral Red Uptake (NRU) test to identify substances not requiring classification and to estimate starting doses for in vivo acute oral toxicity studies; and b) the use of data from sub-acute toxicity studies to identify substances not requiring classification. However, the application of these modules in a regulatory context would require a predefined, validated and formally accepted testing strategy and data interpretation procedure, which are not available. Furthermore, the application of the 3T3 NRU assay for starting dose estimations could in fact increase the number of animals used. Finally, only very few substances exist for which data from sub-acute or other repeated dose studies are available, but data from acute studies are not. Therefore, in practice, the prediction of acute toxicity by using sub-acute toxicity data is generally irrelevant. It could even lead to a risk of overdosing in the range-finding study, which may result in the death of many or all of the animals used.

A meta-analysis of biological variation in blood-based therapy as a precursor to bio-manufacturing

Currently cellular therapies, such as hematopoietic stem cell transplantation (HSCT), are produced at a small scale on a case-by-case basis, usually in a clinical or near-clinical setting. Meeting the demand for future cellular therapies will require a robust and scalable manufacturing process that is either designed around or controls the variation associated with biological starting materials. Understanding variation requires both a measure of the allowable variation (that does not negatively affect patient outcome) and the achievable variation (with current technology). The prevalence of HSCT makes it an ideal case study to prepare for more complex biological manufacturing with more challenging regulatory classifications. A systematic meta-analysis of the medical literature surrounding HSCT has been completed of which the key outcomes are the following: (i) the range of transplanted CD34+ cells/kg can be up to six orders of magnitude around the median for allogeneic procedures and four orders of magnitude for autologous procedures, (ii) there is no improvement in variation encountered over a period of 30 years and (iii) as study size increases, the amount of variation encountered also increases. A more detailed, stratified source from a controlled single-site clinical center is required to further define a control strategy for the manufacture of biologics.

Distinguishing between gaming and gambling activities in addiction research.

Background and AimsGambling and gaming activities have become increasingly recognised as sharing many common features at a structural and aesthetic level. Both have also been implicated as contributing to harm through excessive involvement. Despite this, relatively little attention has been given to the fundamental characteristics that differentiate these two classes of activity, especially in situations where the boundaries between them may be particularly hard to distinguish. This is evident, for example, in digital games that incorporate free and paid virtual currencies or items, as well as the capacity for wagering. Such overlaps create problems for regulatory classifications, screening, diagnosis and treatment. Is the problem related to the gambling or gaming content?MethodsIn this paper, we review the principal sources of overlap between the activity classes in terms of several dimensions: interactivity, monetisation, betting and wagering, types of outcomes, structural fidelity, context and centrality of content, and advertising.ResultsWe argue that gaming is principally defined by its interactivity, skill-based play, and contextual indicators of progression and success. In contrast, gambling is defined by betting and wagering mechanics, predominantly chance-determined outcomes, and monetisation features that involve risk and payout to the player. A checklist measure is provided, with practical examples, to examine activities according to features of design and function, which may inform guidelines for policy makers, researchers and treatment providers.Discussion and conclusionsWe suggest that, in some instances, using category-based nomenclature (e.g., “gambling-like game”) may be too vague or cumbersome to adequately organise our understanding of new gaming/gambling hybrid activities.

Regulatory requirements regarding cell-based medicinal products for human and veterinary use - a comparison

At present, there is no separate regulatory framework for cell-based medicinal products (CBMP) for veterinary use at the European or German level. Current European and national regulations exclusively apply to the corresponding medicinal products for human use. An increasing number of requests for the regulatory classification of CBMP for veterinary use, such as allogeneic stem cell preparations and dendritic cell-based autologous tumour vaccines, and a rise in scientific advice for companies developing these products, illustrate the need for adequate legislation. Currently, advice is given and decisions are made on a case-by-case basis regarding the regulatory classification and authorisation requirements.Since some of the CBMP - in particular in the area of stem-cell products - are developed in parallel for human and veterinary use, there is an urgent need to create specific legal definitions, regulations, and guidelines for these complex innovative products in the veterinary sector as well. Otherwise, there is a risk that that the current legal grey area regarding veterinary medicinal products will impede therapeutic innovations in the long run. A harmonised EU-wide approach is desirable. Currently the European legislation on veterinary medicinal products is under revision. In this context, veterinary therapeutics based on allogeneic cells and tissues will be defined and regulated. Certainly, the legal framework does not have to be as comprehensive as for human CBMP; a leaner solution is conceivable, similar to the special provisions for advanced-therapy medicinal products laid down in the German Medicines Act.

A feasibility study: Can information collected to classify for mutagenicity be informative in predicting carcinogenicity?

Carcinogenicity is a complex endpoint of high concern yet the rodent bioassay still used is costly to run in terms of time, money and animals. Therefore carcinogenicity has been the subject of many different efforts to both develop short-term tests and non-testing approaches capable of predicting genotoxic carcinogenic potential. In our previous publication (Mekenyan et al., 2012) we presented an in vitro–in vivo extrapolation workflow to help investigate the differences between in vitro and in vivo genotoxicity tests. The outcomes facilitated the development of new (Q)SAR models and for directing testing. Here we have refined this workflow by grouping specific tests together on the basis of their ability to detect DNA and/or protein damage at different levels of biological organization. This revised workflow, akin to an Integrated Approach to Testing and Assessment (IATA) informed by mechanistic understanding was helpful in rationalizing inconsistent study outcomes and categorizing a test set of carcinogens with mutagenicity data on the basis of regulatory mutagenicity classifications. Rodent genotoxic carcinogens were found to be correctly predicted with a high sensitivity (90–100%) and a low rate of false positives (3–10%). The insights derived are useful to consider when developing future (non-)testing approaches to address regulatory purposes.

Regulatory airport classification in the US: The role of international markets

In a context of debate over the future of the US Federal Aviation Administration's (FAA) funding model, this paper revisits the current system of airport classification used for the allocation of public funding for capacity developments. Previous papers have already addressed the limitations of the FAA's uni-dimensional method, and proposed new approaches that take into account the two dimensions of “hubbing” activity, i.e., traffic generation and connectivity. However, these studies are biased by the lack of detailed demand data on international connections. Using an MIDT dataset comprising a sample of domestic and international markets served by US airports during the first quarter of 2013, this paper aims at providing a full picture on the pitfalls of the existing FAA method, as well as addressing the impact of international connectivity in characterising the airports' hubbing profiles. Hierarchical clustering is used to provide alternative criteria for hub classification within the context of US National Plan of Integrated Airport Systems (NPIAS). This new typology of primary US airports can help to optimize AIP funding by allowing for further differentiation in the FAA allocation criteria.

“What Is the FDA Going to Think?”

The US National Institute of Health’s Human Microbiome Project aims to use genomic techniques to understand the microbial communities that live on the human body. The emergent field of microbiome science brought together diverse disciplinary perspectives and technologies, thus facilitating the negotiation of differing values. Here, we describe how values are conceptualized and negotiated within microbiome research. Analyzing discussions from a series of interdisciplinary workshops conducted with microbiome researchers, we argue that negotiations of epistemic, social, and institutional values were inextricable from the reflective and strategic category work (i.e., the work of anticipating and strategizing around divergent sets of institutional categories) that defined and organized the microbiome as an object of study and a potential future site of biomedical intervention. Negotiating the divergence or tension between emerging scientific and regulatory classifications also activated “values levers” and opened up reflective discussions of how classifications embody values and how these values might differ across domains. These data suggest that scholars at the intersections of science and technology studies, ethics, and policy could leverage such openings to identify and intervene in the ways that ethical/regulatory and scientific/technical practices are coproduced within unfolding research.

Do Banks Recognize Problem Loans Too Slowly? And, Could This Increase the Cyclicality Loan Loss Provisioning?

In this paper I analyze whether banks recognize problem loans loans with substandard and doubtful regulatory risk classifications in a timely manner. I argue that this is important to understand because substandard and doubtful rated loans are loans that should be evaluated for loan loss provisioning on a pooled and individual basis. In the analysis, I examine whether information on corporate loan interest rate spreads at origination and publicly available information on borrower risk forecast future downgrades to substandard and doubtful ratings. The results indicate that origination loan spreads and borrower risk factors forecast future ratings downgrades to substandard and doubtful regulatory risk classifications. I argue that this implies that banks recognize problem loans too slowy and that banks could improve the timeliness of their ratings by fully incorporating available information about borrower risk into their ratings when the information is observed. Furthermore, I find that banks recognize substandard and doubtful rated loans too slowly during business cycle expansions and banks that have has lower earnings and higher provisions in the past year also recognize these loans too slowly. Finally, I find that banks that recognize substandard and doubtful rated loans too slowly also have more cyclical loan loss provisions and allowance for loan and lease losses (ALLL).

A new standardised MedDRA query to address drug abuse-related safety signals

A new standardised MedDRA query to address drug abuse-related safety signals

Regulation of Cell-Based Therapeutic Products Intended for Human Applications in the EU

Recent developments in the field of cell-based therapeutic products (CBTPs) have forced the EU to revise its legislation on therapeutic products by enacting several new legal instruments. In this study, we investigate how CBTPs are regulated and what determines their regulatory classification. Furthermore, we compare the regulatory burden between CBTPs in different product categories. Product categories covering CBTPs were identified and characteristics critical for the regulatory classification of a CBTP were determined in each category. The effect of the critical characteristics on the classification was evaluated by constructing a decision tree that covers all possible combinations of the critical characteristics. Differences in the regulatory burden between CBTPs were evaluated by comparing regulations crucial for placing a therapeutic product on the EU market between the product categories. Regulation of CBTPs has been divided between the main product categories of the EU legal framework for therapeutic products on the basis of the characteristics of the cells that the CBTPs contain. The regulatory burden is lowest for CBTPs regulated as blood, cells or tissues, and highest for CBTPs regulated as medicinal products. CBTPs exist in all product categories of the EU legal framework for therapeutic products. However, the current framework does not cover all possible CBTPs. Furthermore, our results indicate that the regulatory burden of a CBTP is related to the risk it may pose to the health and safety of recipients.

Regulatorische Besonderheiten für Topika

Professional use of topical treatment in dermatological practice requires not only knowledge about the pharmacological properties, efficacy, safety and pharmaceutical quality of a preparation, but also about its regulatory classification. The latter essentially determines the physician's prescription practice and therapeutic freedom. The regulatory framework with which one is confronted unfortunately lacks transparency. It regulates not only the prescribability and reimbursability of proprietary medicinal products and extemporaneous preparations, but also the obligation to give information as well as the details of liability of both the prescriber (physician) and the manufacturer (pharmaceutical company or pharmacist). The prescriber needs to be aware of to what extent the pharmacist has the possibility and even obligation to change the prescribed preparation. In some cases this can directly affect the therapeutic concept of the physician and even impair the effectiveness and safety of the chosen therapy.

Improving enzyme regulatory protein classification by means of SVM-RFE feature selection

Enzyme regulation proteins are very important due to their involvement in many biological processes that sustain life. The complexity of these proteins, the impossibility of identifying direct quantification molecular properties associated with the regulation of enzymatic activities, and their structural diversity creates the necessity for new theoretical methods that can predict the enzyme regulatory function of new proteins. The current work presents the first classification model that predicts protein enzyme regulators using the Markov mean properties. These protein descriptors encode the topological information of the amino acid into contact networks based on amino acid distances and physicochemical properties. MInD-Prot software calculated these molecular descriptors for 2415 protein chains (350 enzyme regulators) using five atom physicochemical properties (Mulliken electronegativity, Kang-Jhon polarizability, vdW area, atom contribution to P) and the protein 3D regions. The best classification models to predict enzyme regulators have been obtained with machine learning algorithms from Weka using 18 features. K* has been demonstrated to be the most accurate algorithm for this protein function classification. Wrapper Subset Evaluator and SVM-RFE approaches were used to perform a feature subset selection with the best results obtained from SVM-RFE. Classification performance employing all the available features can be reached using only the 8 most relevant features selected by SVM-RFE. Thus, the current work has demonstrated the possibility of predicting new molecular targets involved in enzyme regulation using fast theoretical algorithms.

Is the transformation/dissolution protocol suitable for ecotoxicity assessments of inorganic substances such as silica fume?

Performing ecotoxicity tests on poorly water soluble substances and in particular metals, metalloids, and metal oxides such as silica fume, can be problematic. Such substances may not be directly toxic to aquatic organisms but often have high concentrations of impurities present, due to production processes, which may result in ecotoxicological effects. This combined with possibly testing above the limit of solubility further exacerbates the interpretation of ecotoxicity test results. One approach to overcome this is to perform a transformation/dissolution (T/D) test to determine the quantities of elemental impurities which will consequently be in solution. These data can subsequently be compared to existing data to determine if there is likely to be an effect on aquatic organisms. This paper highlights research into determining the T/D potential of 2 different grades of amorphous silica fume (low and high grade purity) with complementary chronic ecotoxicity tests of the 2 substances to validate this approach. The low grade silica fume test substance was identified in the T/D assessments as being of concern for the potential to cause acute toxicity to aquatic organisms and had levels of impurities (e.g. Pb and Zn) in the solutions which exceeded the effect limits identified in the open literature. Consequently, silica fume would be hazard classified as acute 2 according to regulatory classification schemes. However, the results of the ecotoxicity hazard validation assessments in a Daphnia magna reproduction test and the sediment dwelling organism Chironomus riparius indicated that low and high grade silica fumes are not acutely or chronically toxic up to and including an initial loading concentration of 100mg/L and 1000mg/kg respectively. Hence, using the T/D test data alone may have resulted in a false hazard classification of silica fume (low grade).

The Impact of Next Generation Television on Consumers and the First Amendment

Consumers have access to an ever increasing inventory of video content choices as a result of technological innovations, more readily available broadband, new business plans, inexpensive high capacity storage and the Internet’s ability to serve as a single medium for a variety of previously standalone services delivered via different channels. They increasingly have little tolerance for “appointment television” that limits access to a particular time, channel and device. Access to video content is becoming a matter of using one of several software-configured interfaces capable of delivering live and recorded content anytime, anywhere, to any device and via many different transmission and presentation formats. Technological and marketplace convergence eliminate the viability of judicial and regulatory models that apply varying degrees of First Amendment protection as a function of the medium delivering the content. With the Internet serving as a single conduit for a variety of information, communications and entertainment (“ICE”), ventures can offer a bundle of services that span two or more regulatory classifications, e.g., the ability of wireless handsets to make telephone calls, to receive video programming and to access the Internet. This paper will examine the ongoing migration from channels to software-configured platforms for accessing video content with an eye toward assessing the impact on consumers and the First Amendment. The paper identifies the need for significant amendment of the Communications Act of 1934 to provide a light-handed and limited, but explicit statutory basis for the FCC to resolve predictable disputes between stakeholders and to remedy anticompetitive practices.

Predicting how individuals approach enrichment: Regulatory focus in cotton-top tamarins (Sanguinus oedipus)

Evidence is mounting that personality is associated with health and well-being in humans and other animals. In a step towards increasing our understanding of this link, we applied regulatory focus theory, a motivational perspective from social psychology, to the behavior of zoo-housed cotton top tamarins. We tested whether regulatory focus "personality," that is stable differences in whether an individual is motivated by gains versus safety, would 1) produce individual differences in behavior and 2) predict how individuals interact with enrichment. First, we characterized individuals with respect to several key behaviors: eating in the open, hiding, and time spent near the front of the exhibit. The monkeys were consistent in their behavioral tendencies across the 6-month study, allowing regulatory focus classification. One monkey showed evidence of being a promotion-individual, that is, more motivated by gains than safety. One monkey showed evidence of being a prevention-individual, that is, more motivated by safety than gains. The other monkeys were stable in their behavior and showed evidence of being intermediate-individuals, that is, they favored neither gains nor safety. Using these characterizations, we predicted distinct patterns of individual-object interactions with enrichment. For example, we predicted that a promotion-individual (favoring gains over safety) would approach potential gains faster than a prevention-individual (favoring safety over gains). Counter-intuitively, however, we also predicted that a promotion-individual would approach non-gains slower than a prevention-individual concerned with safety. We found support for our predictions, which suggests that regulatory focus theory could be a useful tool for understanding how and why individuals interact with environmental enrichment.