Regulatory Science Research Research Articles

Development and Piloting Testing of an Experimental Tobacco and Nicotine Product Marketplace.

We describe the development and pilot testing of the experimental tobacco and nicotine product marketplace (ETM)-a method for studying tobacco and nicotine product (TNP) choices and use behavior in a standardized way. The ETM resembles an online store populated with TNPs. Surveillance activities and data from a US representative survey and consumer reports were used to determine the most popular TNPs for inclusion in the ETM. Standardized information and videos demonstrating how to use the TNPs were provided. To test the feasibility of using the ETM, smokers (n = 119) underwent monitoring of usual brand cigarette smoking and other TNP use (Baseline Phase) followed by access to the ETM (ETM Phase) that included their usual brand cigarettes, e-cigarettes, moist snuff, snus, and nicotine replacement therapy. During the ETM Phase, participants were provided points based on their baseline TNP consumption to exchange for TNPs in the ETM. Participants were advised to exchange points for enough TNPs to last until their next visit and to refrain from using TNPs not obtained in the ETM. A subset of the participants (n = 62) completed a survey on their experience with the ETM. The majority of the participants stated they were comfortable with navigating the ETM (97%), it was easy to determine product characteristics (89%), and they were satisfied with the products included in the marketplace (85%). The ETM was well received by the vast majority of the participants and can be utilized by researchers to investigate a variety of TNP policy and regulatory science research questions. Patterns of TNP use are complex due to greater availability, marketing, and promotion of a diverse array of TNPs. Innovative methods are needed to experimentally study TNP choices and patterns. Through describing the development of the ETM, we provide researchers with a tool that can be readily adapted to studying a variety of phenomena challenging public health.

An Integrated Bioinformatics and Quantitative Modeling Approach to Investigate Potential Claims of Oral Generic Drug Product Bioinequivalence: Introduction.

An Integrated Bioinformatics and Quantitative Modeling Approach to Investigate Potential Claims of Oral Generic Drug Product Bioinequivalence: Introduction.

Decision Science for Generic Drug Development and Review.

Decision Science for Generic Drug Development and Review.

A review of tobacco regulatory science research on vulnerable populations

In 2013 the U.S. Food and Drug Administration and National Institutes of Health established fourteen Tobacco Centers of Regulatory Science (TCORS) to advance scientific knowledge relevant to conducting evidence-based tobacco regulation. This report reviews TCORS-funded research with adult vulnerable populations. The literature search included a list of all TCORS-funded publications compiled by the TCORS coordinating center; all TCORS were requested to share publications not in the coordinating-center's list. Only TCORS-funded reports describing an empirical study with an adult vulnerable population published in a peer-reviewed journal between September 2013 and June 2018 were included. 71 reports met inclusion criteria; 39% (28/71) examined tobacco use among those with mental health and medical comorbidities, 34% (24/71) socioeconomic disadvantage, 31% (22/71) women of reproductive age, 30% (21/71) racial/ethnic minorities, 18% (13/71) rural residents, and 3% (2/71) each among active military/veterans and sexual/gender minorities. Regarding scientific domains, 63% (45/71) investigated behavior, 37% (26/71) addiction, 24% (17/71) health effects, 20% (14/71) impact analyses, 18% (13/71) toxicity, 8% (6/71) marketing influences, and 7% (5/71) communications. Totals exceed 100% because some reports addressed multiple populations/domains. TCORS funding has generated a substantial, multidisciplinary body of new scientific knowledge on tobacco use in adult vulnerable populations. However, considerable variability was noted in the amount of research conducted across the various vulnerable populations and scientific domains. Most notably, relatively few studies focused on active military/veterans or sexual/gender minorities, and the scientific domains of marketing influences and communications were conspicuously underrepresented. These are important knowledge gaps to address going forward.

3017 Regulatory Science in Translational and Regenerative Medicine Biomedical Education: A Pilot Course

OBJECTIVES/SPECIFIC AIMS: INTRODUCTION: Many of the innovative therapies used in regenerative medicine, such as additive manufacturing and stem cell engineering, rely on novel technologies and techniques for which standards for safety, efficacy, and quality have not been fully explored and established. As these therapies and technologies develop at a rapid pace, there is a need for the development of scientifically-based metrics to assess whether new treatments are effective and safe for clinical translation. Research and development of such standards is known as “regulatory science,” and is needed by the United States Food and Drug Administration (FDA) to support the creation of the evidence-based guidances and regulations that are used in review of product submissions. As outlined by the FDA’s description of their Centers for Excellence in Regulatory Science and Innovation (CERSIs) and the Association for Clinical and Translational Science’s (ACTS) Regulatory Science Working Group, here is a need to train investigators and clinicians to conduct regulatory science research to support successful clinical translation of regenerative treatments. OBJECTIVE: To develop a course to expose scholars to regulatory science concepts, to empower them to apply these concepts to their personal areas of research, and to challenge them to engage in the dialogue surrounding regulatory science on a national level. METHODS/STUDY POPULATION: METHODS: The “Introduction to Regulatory Science” course was developed jointly by the Yale-Mayo CERSI and the Mayo Clinic Center for Clinical and Translational Science (CCaTS) in 2017 as a didactic in-person survey course. The course objectives included exposing scholars to the ideas of regulatory science and affairs; reviewing the FDA’s Priority Areas for Advancing Regulatory Science; and determining what safety, quality, and efficacy concerns may need to be addressed when using new technologies, such as those used in regenerative medicine research. To meet these intended learning objectives, the course addressed one FDA Priority area each week, with a team of experts providing one-hour of lecture and discussion each class session. Regenerative medicine-related topics included a bioethics of stem cell therapy development, evaluation of additive manufacturing as an emerging technology, and the application of cGMPs to the manufacture of new therapies. Assignments and assessments included a quiz each week, which served as a knowledge check of that week’s lecture content, and a final paper analyzing regulatory concerns associated with a technology or product of the scholar’s choosing. RESULTS/ANTICIPATED RESULTS: RESULTS: The course was first delivered as an elective in 2017, with an enrollment of 8 scholars and 3 auditors. Scholars enrolled included 7 trainees and established investigators from Mayo Clinic Rochester and one from Arizona. Of the 8 scholars enrolled, 7 completed the post-course survey. Scholars strongly agreed that the “course objectives were met” (7/7) and that the “course was well worth the effort I put into it” (7/7). Five scholars stated that they learned “a lot” during the course; two said they learned “an incredible amount.” Scholars unanimously gave the course a grade of “A.” Qualitative feedback was positive, indicating that the team-taught and in-person course design choices were highlights for trainees. The course is currently in its second delivery (2018), with an enrollment of 16 scholars across Mayo Clinic Rochester, Arizona, and Florida. DISCUSSION/SIGNIFICANCE OF IMPACT: CONCLUSIONS: The developed course was successfully piloted and well-received. Scholars reported that they agreed that the course aims were achieved, and indicated that they would like to see additional coursework to continue to learn how to engage in regulatory science. Next steps include utilizing course feedback to iterate on the current course, expanding course delivery to include scholars at the Yale site of the Yale-Mayo CERSI, and the creation of a second course.

A Vision for Eye-tracking Research in Tobacco Regulatory Science.

The purpose of this compendium of recent research in this themed issue is to heighten awareness of eye-tracking methodology and its application in tobacco regulatory science to advance knowledge of consumer understanding of the diversity of advertising, marketing, and other communications about tobacco products. Eye-tracking provides an objective and direct measure of attention that cannot be obtained through self-reported measures. The 7 papers selected for this special issue contribute to scientific knowledge and this editorial provides a synthesis to help guide readers and offer insights for future eye-tracking research. These elegantly designed studies apply eye-tracking methods to 3 major topics related to tobacco products: health warnings, advertising, and constituent information. The application of eye tracking methodology to tobacco regulatory science research has the potential to increase understanding of the impact of tobacco communication and marketing on consumers.

Emerging technologies for food and drug safety

Emerging technologies are playing a major role in the generation of new approaches to assess the safety of both foods and drugs. However, the integration of emerging technologies in the regulatory decision-making process requires rigorous assessment and consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) in partnership with the Brazilian Health Surveillance Agency (ANVISA) hosted the seventh Global Summit on Regulatory Science (GSRS17) in Brasilia, Brazil on September 18–20, 2017 to discuss the role of new approaches in regulatory science with a specific emphasis on applications in food and medical product safety. The global regulatory landscape concerning the application of new technologies was assessed in several countries worldwide. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the development, application and review of emerging technologies. The need for advanced approaches to allow for faster, less expensive and more predictive methodologies was elaborated. In addition, the strengths and weaknesses of each new approach was discussed. And finally, the need for standards and reproducible approaches was reviewed to enhance the application of the emerging technologies to improve food and drug safety. The overarching goal of GSRS17 was to provide a venue where regulators and researchers meet to develop collaborations addressing the most pressing scientific challenges and facilitate the adoption of novel technical innovations to advance the field of regulatory science.

Cigarette Management System: An operating procedures guide to obtaining and managing investigational tobacco products for regulatory science research.

Investigational tobacco products, specifically variable nicotine content research cigarettes (SPECTRUM), are available through the National Institute of Drug Abuse Drug Supply Program. Randomized controlled trials using research cigarettes are intended to support tobacco regulatory science research. The current paper provides an in-depth look into managing research cigarettes for two multi-site clinical trials and the design of a computer-based Cigarette Management System (CMS). The paper provides guidance intended for any investigator using similar products on the operating procedures under Good Clinical Practice standards and describes features of the CMS. The CMS and procedures described have been field tested for the past three years and have dispensed over 160,000 cigarette packs to participants. The CMS can accommodate a range of practical issues with real-world study implementation making it a robust application that is scalable to any study.

Competitive docking model for prediction of the human nicotinic acetylcholine receptor α7 binding of tobacco constituents.

The detrimental health effects associated with tobacco use constitute a major public health concern. The addiction associated with nicotine found in tobacco products has led to difficulty in quitting among users. Nicotinic acetylcholine receptors (nAChRs) are the targets of nicotine and are responsible for addiction to tobacco products. However, it is unknown if the other >8000 tobacco constituents are addictive. Since it is time-consuming and costly to experimentally assess addictive potential of such larger number of chemicals, computationally predicting human nAChRs binding is important for in silico evaluation of addiction potential of tobacco constituents and needs structures of human nAChRs. Therefore, we constructed three-dimensional structures of the ligand binding domain of human nAChR α7 subtype and then developed a predictive model based on the constructed structures to predict human nAChR α7 binding activity of tobacco constituents. The predictive model correctly predicted 11 out of 12 test compounds to be binders of nAChR α7. The model is a useful tool for high-throughput screening of potential addictive tobacco constituents. These results could inform regulatory science research by providing a new validated predictive tool using cutting-edge computational methodology to high-throughput screen tobacco additives and constituents for their binding interaction with the human α7 nicotinic receptor. The tool represents a prediction model capable of screening thousands of chemicals found in tobacco products for addiction potential, which improves the understanding of the potential effects of additives.

<b>4. Frontier of the Regulatory Science Research; Evaluation of the Efficacy and Safety of the Molecular Targeted Drug by Analyzing the Biomarker</b>

<b>4. Frontier of the Regulatory Science Research; Evaluation of the Efficacy and Safety of the Molecular Targeted Drug by Analyzing the Biomarker</b>

Generic drug device combination products: Regulatory and scientific considerations

Complex regulatory and scientific considerations exist for drug-device combination products submitted under an Abbreviated New Drug Application. The Agency has published several guidances to aid industry in the development of a generic drug-device combination product: providing recommendations on the types of studies necessary to establish bioequivalence, providing considerations on product quality and performance for certain types of device constituents, and most recently, providing tools to assess the proposed user interface when compared to the user interface of the Reference Listed Drug.In addition, the Office of Generic Drugs11The Office of Generic Drugs is in the Center for Drug Evaluation and Research (CDER) in the United States Food and Drug Administration. has established a regulatory science research program intended to support projects that examine scientific questions relating to the development of generic combination products and their associated regulatory review. Several research examples are described within this article, which demonstrate how equivalence can be evaluated when the function of the device could potentially impact drug delivery. Moreover, this article provides an overview of regulatory recommendations and ongoing scientific research efforts to further develop guidances and ultimately improve public access to generic combination products.

In silico weight of evidence assessment of drug-induced liver injury in humans

Emerging technologies are playing a major role in the generation of new approaches to assess the safety of both foods and drugs. However, the integration of emerging technologies in the regulatory decision-making process requires rigorous assessment and consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) in partnership with the Brazilian Health Surveillance Agency (ANVISA) hosted the seventh Global Summit on Regulatory Science (GSRS17) in Brasilia, Brazil on September 18–20, 2017 to discuss the role of new approaches in regulatory science with a specific emphasis on applications in food and medical product safety. The global regulatory landscape concerning the application of new technologies was assessed in several countries worldwide. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the development, application and review of emerging technologies. The need for advanced approaches to allow for faster, less expensive and more predictive methodologies was elaborated. In addition, the strengths and weaknesses of each new approach was discussed. And finally, the need for standards and reproducible approaches was reviewed to enhance the application of the emerging technologies to improve food and drug safety. The overarching goal of GSRS17 was to provide a venue where regulators and researchers meet to develop collaborations addressing the most pressing scientific challenges and facilitate the adoption of novel technical innovations to advance the field of regulatory science.

The need for consumer science and regulatory science research on functional foods with health claims - What should we do to harmonize science and technology with society?

BackgroundAccording to the Codex Alimentarius of the foods with health claims (FHCs), two major factors play a significant role in the ability for consumers to select functional foods and utilize them appropriately for health maintenance (Codex Alimentarius, 1997). These are: 1) food labeling based on scientific evidence that consumers are able to understand; and 2) standardized criteria for obtaining scientific evidence. Scope and approachWe discuss the regulatory system for foods with health claims in the world and the need for consumer science and regulatory science research through reviewing the history and recent topics about the regulation on FHCs in Japan. Key findings and conclusionsThere are some differences in regulations on FHCs among countries participating in the Codex, which have been said sometimes to cause some troubles. These are: 1) despite of the lack of renewal system, Japan experienced the first revocation event regarding the approved Foods for Specified Health Uses category of FHCs in 2016; and 2) global export barriers. Therefore, the introduction of mutual recognition rules among countries has been desired in Japan for further international harmonization. However, its feasibility seems to be low because of the complexity caused by such differences on regulations among countries. When it happens, we expect that the global regulatory climates on FHCs may be better regulated by involving neutral academic researchers and the trained experts in the field of consumer and regulatory science of functional foods. As Japan is the first country to establish the FHCs regulatory system in the world, it should lead to discuss the introduction of mutual recognition rules with other countries immediately.

Evaluation of transporters in drug development: Current status and contemporary issues.

Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The drug interaction guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated drug-drug interactions. Regulatory science research continues to assess the prediction performances of various criteria as well as to examine the strength and limitations of each prediction criterion to foster discussions related to harmonized decision criteria that may be used to facilitate global drug development. This review discusses the role of transporters in drug development with a focus on methodologies in assessing transporter-mediated drug-drug interactions, challenges in both in vitro and in vivo assessments of transporters, and emerging transporter research areas including biomarkers, assessment of tissue concentrations, and effect of diseases on transporters.

The Leading-edge Drug Formulation Technology “Nanotechnology” and Challenges for the Regulatory Science Research

The Leading-edge Drug Formulation Technology “Nanotechnology” and Challenges for the Regulatory Science Research

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.

A Roadmap for Regulatory Science Research for Next Generation Sequencing Informatics

A Roadmap for Regulatory Science Research for Next Generation Sequencing Informatics

Accelerating Regulatory Science Initiatives for the Development of Drugs for Alzheimer’s Disease in Japan

PurposeThe Ministry of Health, Labour and Welfare (MHLW) of Japan launched a regulatory science research project in which the aim is to promote the establishment of guidelines for the development of innovative drugs thorough interactions between academia and Japan’s regulatory agency, the Pharmaceuticals and Medical Devices Agency (PMDA). In this project, a research system with the aim of developing a guideline for the clinical evaluation of drugs intended for the treatment of Alzheimer’s disease (AD) was established. MethodsTwo research groups were set up: (1) the Biomarker and Clinical Evaluation Group to establish biomarker-based criteria for the clinical evaluation of drugs for AD, and (2) the Modeling and Simulation (M&S) Group to create a disease model of AD using M&S techniques based on data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Furthermore, a human resource exchange between the University of Tokyo Hospital and the PMDA is conducted to establish a guideline that is suitable for regulatory use. FindingsAs an interim report of this project, issues that require consideration for the clinical evaluation and development were summarized, including topics such as the use of biomarkers in the inclusion criteria, the efficacy endpoint, and the clinical data package required for application in Japan. ImplicationsAs the result of collaboration between the University of Tokyo Hospital and PMDA, this document is the first to summarize perspectives on the development of drugs for AD in Japan.

Recent advances in medical device triage technologies for chemical, biological, radiological, and nuclear events.

In 2010, the US Food and Drug Administration (Silver Spring, Maryland USA) created the Medical Countermeasures Initiative with the mission of development and promoting medical countermeasures that would be needed to protect the nation from identified, high-priority chemical, biological, radiological, or nuclear (CBRN) threats and emerging infectious diseases. The aim of this review was to promote regulatory science research of medical devices and to analyze how the devices can be employed in different CBRN scenarios. Triage in CBRN scenarios presents unique challenges for first responders because the effects of CBRN agents and the clinical presentations of casualties at each triage stage can vary. The uniqueness of a CBRN event can render standard patient monitoring medical device and conventional triage algorithms ineffective. Despite the challenges, there have been recent advances in CBRN triage technology that include: novel technologies; mobile medical applications ("medical apps") for CBRN disasters; electronic triage tags, such as eTriage; diagnostic field devices, such as the Joint Biological Agent Identification System; and decision support systems, such as the Chemical Hazards Emergency Medical Management Intelligent Syndromes Tool (CHEMM-IST). Further research and medical device validation can help to advance prehospital triage technology for CBRN events.

Genomics in the land of regulatory science

Genomics science has played a major role in the generation of new knowledge in the basic research arena, and currently question arises as to its potential to support regulatory processes. However, the integration of genomics in the regulatory decision-making process requires rigorous assessment and would benefit from consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) hosted the fourth Global Summit on Regulatory Science (GSRS2014) to discuss the role of genomics in regulatory decision making, with a specific emphasis on applications in food safety and medical product development. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the analysis, interpretation and reporting of genomics data with an emphasis on transparency, traceability and “fitness for purpose” for the intended application. It was recognized that there is a need for a global path in the establishment of a regulatory bioinformatics framework for the development of transparent, reliable, reproducible and auditable processes in the management of food and medical product safety risks. It was also recognized that training is an important mechanism in achieving internationally consistent outcomes. GSRS2014 provided an effective venue for regulators andresearchers to meet, discuss common issues, and develop collaborations to address the challenges posed by the application of genomics to regulatory science, with the ultimate goal of wisely integrating novel technical innovations into regulatory decision-making.