Prediction of Acute Oral Systemic Toxicity Using a Multifingerprint Similarity Approach.

The implementation of nonanimal approaches is of particular importance to regulatory agencies for the prediction of potential hazards associated with acute exposures to chemicals. This work was carried out in the framework of an international modeling initiative organized by the Acute Toxicity Workgroup (ATWG) of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) with the participation of 32 international groups across government, industry, and academia. Our contribution was to develop a multifingerprints similarity approach for predicting five relevant toxicology endpoints related to the acute oral systemic toxicity that are: the median lethal dose (LD50) point prediction, the "nontoxic" (LD50 > 2000 mg/kg) and "very toxic" (LD50<50 mg/kg) binary classification, and the multiclass categorization of chemicals based on the United States Environmental Protection Agency and Globally Harmonized System of Classification and Labeling of Chemicals schemes. Provided by the ICCVAM's ATWG, the training set used to develop the models consisted of 8944 chemicals having high-quality rat acute oral lethality data. The proposed approach integrates the results coming from a similarity search based on 19 different fingerprint definitions to return a consensus prediction value. Moreover, the herein described algorithm is tailored to properly tackling the so-called toxicity cliffs alerting that a large gap in LD50 values exists despite a high structural similarity for a given molecular pair. An external validation set made available by ICCVAM and consisting in 2896 chemicals was employed to further evaluate the selected models. This work returned high-accuracy predictions based on the evaluations conducted by ICCVAM's ATWG.

Biocompute Objects-A Step towards Evaluation and Validation of Biomedical Scientific Computations.

The unpredictability of actual physical, chemical, and biological experiments due to the multitude of environmental and procedural factors is well documented. What is systematically overlooked, however, is that computational biology algorithms are also affected by multiplicity of parameters and have no lesser volatility. The complexities of computation protocols and interpretation of outcomes is only a part of the challenge: There are also virtually no standardized and industry-accepted metadata schemas for reporting the computational objects that record the parameters used for computations together with the results of computations. Thus, it is often impossible to reproduce the results of a previously performed computation due to missing information on parameters, versions, arguments, conditions, and procedures of application launch. In this article we describe the concept of biocompute objects developed specifically to satisfy regulatory research needs for evaluation, validation, and verification of bioinformatics pipelines. We envision generalized versions of biocompute objects called biocompute templates that support a single class of analyses but can be adapted to meet unique needs. To make these templates widely usable, we outline a simple but powerful cross-platform implementation. We also discuss the reasoning and potential usability for such concept within the larger scientific community through the creation of a biocompute object database initially consisting of records relevant to the U.S. Food and Drug Administration. A biocompute object database record will be similar to a GenBank record in form; the difference being that instead of describing a sequence, the biocompute record will include information related to parameters, dependencies, usage, and other information related to specific computational instance. This mechanism will extend similar efforts and also serve as a collaborative ground to ensure interoperability between different platforms, industries, scientists, regulators, and other stakeholders interested in biocomputing.

Regulatory bioinformatics for food and drug safety.

"Regulatory Bioinformatics" strives to develop and implement a standardized and transparent bioinformatic framework to support the implementation of existing and emerging technologies in regulatory decision-making. It has great potential to improve public health through the development and use of clinically important medical products and tools to manage the safety of the food supply. However, the application of regulatory bioinformatics also poses new challenges and requires new knowledge and skill sets. In the latest Global Coalition on Regulatory Science Research (GCRSR) governed conference, Global Summit on Regulatory Science (GSRS2015), regulatory bioinformatics principles were presented with respect to global trends, initiatives and case studies. The discussion revealed that datasets, analytical tools, skills and expertise are rapidly developing, in many cases via large international collaborative consortia. It also revealed that significant research is still required to realize the potential applications of regulatory bioinformatics. While there is significant excitement in the possibilities offered by precision medicine to enhance treatments of serious and/or complex diseases, there is a clear need for further development of mechanisms to securely store, curate and share data, integrate databases, and standardized quality control and data analysis procedures. A greater understanding of the biological significance of the data is also required to fully exploit vast datasets that are becoming available. The application of bioinformatics in the microbiological risk analysis paradigm is delivering clear benefits both for the investigation of food borne pathogens and for decision making on clinically important treatments. It is recognized that regulatory bioinformatics will have many beneficial applications by ensuring high quality data, validated tools and standardized processes, which will help inform the regulatory science community of the requirements necessary to ensure the safe introduction and effective use of these applications.

FDA's Activities Supporting Regulatory Application of "Next Gen" Sequencing Technologies.

Applications of next-generation sequencing (NGS) technologies require availability and access to an information technology (IT) infrastructure and bioinformatics tools for large amounts of data storage and analyses. The U.S. Food and Drug Administration (FDA) anticipates that the use of NGS data to support regulatory submissions will continue to increase as the scientific and clinical communities become more familiar with the technologies and identify more ways to apply these advanced methods to support development and evaluation of new biomedical products. FDA laboratories are conducting research on different NGS platforms and developing the IT infrastructure and bioinformatics tools needed to enable regulatory evaluation of the technologies and the data sponsors will submit. A High-performance Integrated Virtual Environment, or HIVE, has been launched, and development and refinement continues as a collaborative effort between the FDA and George Washington University to provide the tools to support these needs. The use of a highly parallelized environment facilitated by use of distributed cloud storage and computation has resulted in a platform that is both rapid and responsive to changing scientific needs. The FDA plans to further develop in-house capacity in this area, while also supporting engagement by the external community, by sponsoring an open, public workshop to discuss NGS technologies and data formats standardization, and to promote the adoption of interoperability protocols in September 2014. LAY ABSTRACT: Next-generation sequencing (NGS) technologies are enabling breakthroughs in how the biomedical community is developing and evaluating medical products. One example is the potential application of this method to the detection and identification of microbial contaminants in biologic products. In order for the U.S. Food and Drug Administration (FDA) to be able to evaluate the utility of this technology, we need to have the information technology infrastructure and bioinformatics tools to be able to store and analyze large amounts of data. To address this need, we have developed the High-performance Integrated Virtual Environment, or HIVE. HIVE uses a combination of distributed cloud storage and distributed cloud computations to provide a platform that is both rapid and responsive to support the growing and increasingly diverse scientific and regulatory needs of FDA scientists in their evaluation of NGS in research and ultimately for evaluation of NGS data in regulatory submissions.

Legal issues for chem-bioinformatics models.

Chem-Bioinformatic models connect the chemical structure of drugs and/or targets (protein, gen, RNA, microorganism, tissue, disease...) with drug biological activity over this target. On the other hand, a systematic judicial framework is needed to provide appropriate and relevant guidance for addressing various computing techniques as applied to scientific research in biosciences frontiers. This article reviews both: the use of the predictions made with models for regulatory purposes and how to protect (in legal terms) the models of molecular systems per se, and the software used to seek them. First we review: i) models as a tool for regulatory purposes, ii) Organizations Involved with Validation of models, iii) Regulatory Guidelines and Documents for models, iv) Models for Human Health and Environmental Endpoint, and v) Difficulties to Validation of models, and other issues. Next, we focused on the legal protection of models and software; including: a short summary of topics, and methods for legal protection of computer software. We close the review with a section that treats the taxes in software use.

Regulatory issues in management of chemicals in OECD member countries.

The chemical risk assessment is determinant for the approval of any kind of chemical. Each aspect of chemical is taken into consideration for the new chemical legislation registration, evaluation, and authorization of chemicals (REACH). However, some improvements can be made in order to select and authorize a chemical. QSAR techniques have been used for the study of several kind of toxicological properties in order to realize a deeper study concerning to risk assessment. For this reason, this work is focused into present a review of chemical legislation policies in the European Union (EU) and in Russia, and changes in chemicals regulations to meet the requirement of REACH. Also, we reported the used of several approaches and chemo- bioinformatics tools applied to QSAR methodologies for the several parameters relative to toxicity and how they can be used for regulatory purposes in risk assessment.

Regulatory use of computational toxicology tools and databases at the United States Food and Drug Administration's Office of Food Additive Safety.

Over 10 years ago, the Office of Food Additive Safety (OFAS) in the FDA's Center for Food Safety and Applied Nutrition implemented the formal use of structure-activity relationship analysis and quantitative structure-activity relationship (QSAR) analysis in the premarket review of food-contact substances. More recently, OFAS has implemented the use of multiple QSAR software packages and has begun investigating the use of metabolism data and metabolism predictive models in our QSAR evaluations of food-contact substances. In this article, we provide an overview of the programs used in OFAS as well as a perspective on how to apply multiple QSAR tools in the review process of a new food-contact substance.

Patent prosecution strategies for stem cell related applications.

Stem cell research and the intellectual property derived from it, because of its potential to completely transform health care, demand an especially high level of consideration from business and patent prosecution perspectives. As with other revolutionary technologies, ordinary risks are amplified (e.g., litigation), and ordinarily irrelevant considerations may become important (e.g., heightened level of both domestic and foreign legislative risk). In the first part of this article, general strategies for patent prosecutors such as several prosecution considerations and methods for accelerating patent prosecution process are presented. In the second part, patent prosecution challenges of stem cell-related patents and possible solutions are discussed. In the final part, ethical and public policy issues particular to stem cell-related and other biotechnological inventions are summarized.