Regulatory Science Research Articles

Regulating Between the Notes: The US FDA and the Evolution of the Patient Voice Through Twenty-First Century Regulatory Science.

Regulating Between the Notes: The US FDA and the Evolution of the Patient Voice Through Twenty-First Century Regulatory Science.

Describing competency requirements for competency-based regulatory sciences education in sub-Saharan Africa – A qualitative systematic review

Background: Competency-based regulatory sciences education could expand the workforce of regulatory scientists in sub-Saharan Africa. A competency framework is foundational to developing competency-based education. Objective: To identify the entry-level competency requirements of regulatory scientists in sub-Saharan Africa. Method: This research was a systematic review of the literature based on a pre-registered protocol. The research used the "framework synthesis" systematic review model to deductively identify competencies and code them into clusters with NVivo 12 software. Result: Three broad clusters of competencies were identified – enabling behaviours, knowledge, and skills. The knowledge and skills clusters were further subdivided into sub-clusters: the knowledge cluster into administrative, regulatory governance/framework, and scientific knowledge, and the skills cluster into functional and technical skills. Conclusion: The identified competencies will assist in developing an entry-level competency framework required for competency-based regulatory sciences education in sub-Saharan Africa.

Transforming Evidence Generation for Drug Label Changes: A Case Study.

Computer Modeling and Simulation (CM&S) provides the opportunity to drastically reduce clinical trial patient burden and advance regulatory decision making. At the suggestion of the US Food and Drug Administration (FDA), MannKind Corporation and Nudge BG submitted an application to the FDA Model-Informed Drug Development (MIDD) pilot program to support a label change for the initial dose of Afrezza® (insulin human), a novel inhalable insulin with a rapid pharmacokinetic and pharmacodynamic profile. The MIDD pilot program demonstrates the FDA's commitment to advancing regulatory science through the adoption of evidence generated by CM&S. A simulation framework was developed based on empirical data. It was used to generate evidence to support the label change. Briefing packages and presentations were prepared for two meetings with the FDA, over a period of four months. The model was thoroughly characterized, determined to be low risk for the question of interest, and submitted along with additional clinical evidence for validation. The FDA found the simulation framework to be helpful in providing insights into the question of interest and provides reasonable glycemic outcome predictions. At the conclusion of the MIDD paired meetings, FDA personnel from the Center for Drug Evaluation and Research review team accepted the simulation and requested additional, traditional clinical evidence to support the proposed label change. In the post-meeting comments, the FDA invited MannKind to submit a proposal for a data package including the CM&S evidence in a Type C meeting for further discussion on the label change. This MIDD pilot experience suggests that CM&S is a credible method for evidence generation. Collaboration between sponsor organizations as well as all stakeholders in the FDA, including proponents of CM&S, can further support regulatory decision-making. The learnings from early participants will allow the program to reach its full potential and thereby ultimately benefit patients, sponsors, and FDA.

The effects of oral and vaporized cannabis alone, and in combination with alcohol, on driving performance using the STISIM driving simulator: A two-part, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory protocol.

The legalization of cannabis for medicinal and non-medicinal purposes, and the corresponding increase in diversity of cannabis products, has resulted an urgent need for cannabis regulatory science. Among the most pressing needs is research related to impairment due to cannabis exposure, especially on driving performance. The present project was designed to evaluate the impact of oral and vaporized cannabis, when administered alone or in combination with alcohol, on simulated driving performance (STISIM driving simulator), cognitive/psychomotor ability, and field sobriety performance. Healthy adults will complete two, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory studies, one with oral cannabis (16 men/16 women) and the second with vaporized cannabis (16 men/16 women). In each study, participants will complete seven experimental sessions during which acute doses of placebo or high Δ9-THC cannabis containing 0, 10, or 25 mg Δ9-THC will be administered both alone and in combination with placebo or alcohol-containing beverages (target breath alcohol concentrations, BAC, of 0.0% or 0.05%). A positive control session (i.e., alcohol at target BAC of 0.08% with placebo cannabis) will also be completed. Simulated driving performance tests (available for download; see Methods), field sobriety assessments, subjective drug effect questionnaires, a mobile device impairment test (DRUID app), and collection of whole blood specimens will be completed repeatedly during each session. Linear mixed models will be used to test for differences across experimental conditions and a priori planned comparisons will be used to determine differences between conditions of interest (e.g., cannabis alone vs cannabis with alcohol). This research is designed to extend prior studies of cannabis and alcohol on driving performance by using oral and vaporized routes of cannabis administration. By increasing understanding of impairment associated with co-use of alcohol and these novel forms of cannabis, this research could inform impairment detection standards for cannabis and alcohol and have important implications for law enforcement, public policy decisions regarding accessibility of these substances, and education of the general population who may use cannabis and/or alcohol. Lastly, this manuscript provides interested researchers with access to the simulated driving scenarios and data extraction tools developed for this study as a means of facilitating future cross-study comparisons, which is important given the heterogeneity in methods used across laboratories in prior research.

S-13-04 The changing testing paradigm and its potential impact on regulatory science

S-13-04 The changing testing paradigm and its potential impact on regulatory science

Special Section on New Era of Transporter Science: Unraveling the Functional Role of Orphan Transporters–Editorial

In the current issue of Drug Metabolism and Disposition (DMD) , Dr. Kathleen M. Giacomini, a world-renowned leader in membrane transporter biology, pharmacogenomics, and regulatory sciences, along with and several of her former trainees contribute a special section titled, “New Era of Transporter

Who shapes the CJEU regulatory jurisprudence? On the epistemic power of economic actors and ways to counter it

AbstractWhat role does the Court of Justice of the European Union (CJEU) play in holding European Union (EU) regulatory science, ie the science underpinning public regulation, to account for its epistemic quality? Since Pfizer, CJEU case law has strengthened the role of science in both EU risk regulation and litigation, whilst intensifying judicial scrutiny of scientific reasoning based on procedural standards. Scholars often welcome this approach as striking an adequate balance between effective judicial protection and institutional competence. Some praise the Court as an ‘information catalyst’ promoting procedures, in which epistemic quality is ensured through diligent consideration of and deliberation among all relevant voices. These debates, however, overlook the role of economic actors as information providers, in and challengers of EU risk regulation. This paper re-evaluates the modern post-Pfizer approach from a new, socio-legal perspective by studying, for the first time, the interactions between judicial review and the epistemic power of economic actors, ie their relative ability to influence what EU regulators know at the expense of other actors. We combine an epistemologically informed comparative institutional analysis with doctrinal critique of CJEU case law. Our findings show the need to rethink both legal standing and procedural review in EU risk regulation. Instead of catalysing inclusive procedures that open regulatory science to public scrutiny, the modern approach fosters an exclusive bilateral information exchange between the administration and the regulated industry. The Court reduces the function of process values, such as duty of care and reason-giving, to the protection of a small circle of actors, neglecting the public interest dimension of such values. Thus, the modern approach fails to address, and instead further entrenches the epistemic power imbalances inherent in EU risk regulation. We end by sketching out a normative and doctrinally sound vision of how CJEU review could contribute to EU expert accountability in a more publicly oriented way.

Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting).

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.

Recommendations related to the analytical equivalence assessment of gene panel testing.

Advances in cancer genome care over the past few years have included the development of gene panel testing for various biomarkers. This article summarizes issues and provides recommendations related to analytical performance evaluations for new oncology gene panels. The scope of these recommendations includes comprehensive genomic profiling assays related to gene panel testing that uses histological or serum specimens to detect gene mutations. As a research project of the Japan Agency for Medical Research and Development Research on Regulatory Science of Pharmaceuticals and Medical Devices, we convened the working group committee that consisted of more than 30 experts from academia, industry, and government. We have discussed the points that should be considered to allow maximal simplification of assessments using clinical specimens in evaluating accuracy and limit of detection in equivalence and analytical performance for 3 years. We provide recommendations specific to each type of gene mutation as well as to reference standards or specimens used for evaluations. In addition, in order to facilitate the discussion on the analytical performance of gene panel tests by multidisciplinary tumor boards of hospitals, the present recommendations also describe the items that companies are expected to provide information on in their packaging inserts and reports, and the items that are expected to be discussed by multidisciplinary tumor boards. Our working group document will be important for participants in multidisciplinary tumor boards, including medical oncologists and genome scientists, and developers of gene panels not only in Japan but also in other countries.

Can Observational Analyses of Routinely Collected Data Emulate Randomized Trials? Design and Feasibility of the Observational Patient Evidence for Regulatory Approval Science and Understanding Disease Project

ObjectivesThe Observational Patient Evidence for Regulatory Approval Science and Understanding Disease (OPERAND) project examines whether real-world data (RWD) can be used to inform regulatory decision making. MethodsOPERAND evaluates whether observational analyses using RWD to emulate index trials can produce effect estimates similar to those of the trials and examines the impact of relaxing the eligibility criteria of the observational analyses to obtain samples that more closely match the real-world populations receiving the treatments. In OPERAND, 2 research teams independently attempt to emulate the ROCKET Atrial Fibrillation and LEAD-2 trials using OptumLabs data. This article describes the design of the project, summarizes the approaches of the 2 research teams, and presents feasibility results for 2 emulations using new-user designs. ResultsThere were differences in the teams’ conceptualizations of the emulation, design decisions for cohort identification, and resulting RWD cohorts. These differences occurred even though both teams were guided by the same index trials and had access to the same source of RWD. ConclusionsReasonable alternative design and analysis approaches may be taken to answer the same research question, even when attempting to emulate the same index trial. Researcher decision making is an understudied and potentially important source of variability across RWD analyses.

Strategic science translation in emerging science: genetically modified crops and Bisphenol A in two cases of contested animal toxicity studies

ABSTRACT When controversies develop around scientific facts or technologies, the potential of science to become a tool in plays of interests and power between different actors is not well recognized. Cordner’s concept of Strategic Science Translation (SST) shows that such actions are enabled by the uncertainty and the complexity of the scientific processes that allow the use of science in support of various, often contradictory interests and goals. Two high-profile controversies around animal toxicity studies in two different fields of European regulatory science (genetically modified food and food contact materials) were chosen as case studies to explore and expand the SST concept. Both studies involve emerging science issues, emphasizing tensions between regulatory and academic science. Communications from key Civil Society Organizations (CSOs) and industry groups were used for analysis of each controversy. We found that both groups of actors try to present their own interpretation of scientific results, taking advantage of the lack of scientific consensus, of the uncertainties associated with the negotiation in the interpretation of results, and of the wider scientific and political context. In the same time, each actor attempts to challenge the credibility of the other. The lack of formal acknowledgment of the limitations of the emerging scientific fields, as well as of different research approaches between regulatory and academic research contribute to the continuation of controversies in the public domain, as the public cannot easily assess the information presented.

Preparing for future challenges in risk assessment in the European Union

In light of the new EU policy targets (e.g., Farm to Fork strategy) and the revised legal framework (Transparency Regulation), the European Food Safety Authority (EFSA) needs to invest further in preparedness in regulatory and communication science for food safety. To achieve this, EFSA has established a process of advancing selected scientific themes to anticipate future challenges.

Regulatory safety evaluation of nanomedical products: key issues to refine

Nanotechnologies enable great opportunities for the development and use of innovative (nano)medicines. As is common for scientific and technical developments, recognized safety evaluation methods for regulatory purposes are lagging behind. The specific properties responsible for the desired functioning also hamper the safety evaluation of such products. Pharmacokinetics determination of the active pharmaceutical ingredient as well as the nanomaterial component is crucial. Due to their particulate nature, nanomedicines, similar to all nanomaterials, are primarily removed from the circulation by phagocytizing cells that are part of the immune system. Therefore, the immune system can be potentially a specific target for adverse effects of nanomedicines, and thus needs special attention during the safety evaluation. This DDTR special issue on the results of the REFINE project on a regulatory science framework for nanomedical products presents a highly valuable body of knowledge needed to address regulatory challenges and gaps in currently available testing methods for the safety evaluation of nanomedicines.

The Use of Machine Learning in Regulatory Drug Safety Evaluation

ABSTRACT There has been growing interest of using machine learning (ML) methods with real-world data (RWD) to generate real-world evidence (RWE) to support regulatory decisions. In the U.S. Food and Drug Administration (FDA), ML has been applied in both prediction and causal inference problems for drug safety evaluation. The ML applications include health outcome identification, missing data imputation, risk factor identification, drug utilization discovery and causal inference study. We demonstrate the present utility and future potential of ML for regulatory science. We then discuss the challenges and considerations when using ML methods with RWD to generate RWE. Specifically, we focus on the transparency and reproducibility issue of using ML, the potential of ML and natural language processing (NLP) for missing data in RWD, training data issue for rare events, and interpretability of studies using ML.

Common Measures to Evaluate Flavored Tobacco Products: Recommendations From the Tobacco Centers for Regulatory Science (TCORS) Flavored Tobacco Products Measurement Subcommittee.

Flavored electronic nicotine delivery systems (ENDS) and tobacco products are associated with the initiation and progression of tobacco use. With recent restrictions around flavored products, it is critical to measure both the product and the flavor being used. The Tobacco Centers of Regulatory Science (TCORS) Flavored Tobacco Products Measurement Subcommittee (FTPMS) was established to develop core measures to assess flavored tobacco and ENDS product usage, facilitate data harmonization, replicability, and comparisons across studies. The FTPMS used a mixed-method approach to inform the development of recommended measures (first use, current use, reasons for use) to assess tobacco and ENDS product flavors. This included reviewing existing surveys, identifying priority areas, developing new measures, cognitive testing, and finalization of recommended measures. Recommended measures were selected from national surveys (e.g. PATH study) and survey items used in TCORS studies to evaluate first use, current use, and reasons for use of tobacco and ENDS products. Response options were expanded for questions about specific flavors and adapted to allow for assessments relevant to recent federal policies. Supplemental measures were developed for researchers conducting more in-depth research around flavored products. Using an expert consensus process supplemented with cognitive testing, the FTPMS developed recommendations for core and supplemental measures for flavored tobacco and ENDS products. Harmonizing data on these factors for flavored tobacco and ENDS products are critical for researchers and may provide actionable evidence to federal, state, and local regulators and policymakers, as well as support evaluations of policies restricting flavors in these products. The development of core measures to assess first use, current use, and reasons for use of flavored tobacco and ENDS products will facilitate data harmonization, replicability, and comparisons across studies conducted in different samples or across communities with varying levels of regulation for these products. Use of these standardized measures will allow for a greater understanding of the role of flavors and helps to build a more robust evidence base to inform regulatory decisions to reduce tobacco and ENDS use at the population level.

Packaging research artefacts with RO-Crate

An increasing number of researchers support reproducibility by including pointers to and descriptions of datasets, software and methods in their publications. However, scientific articles may be ambiguous, incomplete and difficult to process by automated systems. In this paper we introduce RO-Crate, an open, community-driven, and lightweight approach to packaging research artefacts along with their metadata in a machine readable manner. RO-Crate is based on Schema.org annotations in JSON-LD, aiming to establish best practices to formally describe metadata in an accessible and practical way for their use in a wide variety of situations. An RO-Crate is a structured archive of all the items that contributed to a research outcome, including their identifiers, provenance, relations and annotations. As a general purpose packaging approach for data and their metadata, RO-Crate is used across multiple areas, including bioinformatics, digital humanities and regulatory sciences. By applying “just enough” Linked Data standards, RO-Crate simplifies the process of making research outputs FAIR while also enhancing research reproducibility. An RO-Crate for this article11 https://w3id.org/ro/doi/10.5281/zenodo.5146227 is archived at https://doi.org/10.5281/zenodo.5146227.

A Comparative Analysis of Physiologically Based Pharmacokinetic Models for Human Immunodeficiency Virus and Tuberculosis Infections.

Physiologically based pharmacokinetic (PBPK) models have gained in popularity in the last decade in both drug development and regulatory science. PBPK models differ from classical pharmacokinetic models in that they include specific compartments for tissues involved in exposure, toxicity, biotransformation, and clearance processes connected by blood flow. This study aimed to address the gaps between the mathematics and pharmacology framework observed in the literature. These gaps included nonconserved systems of equations and compartment concentration that were not biologically relatable to the tissues of interest. The resulting system of nonlinear differential equations is solved numerically with various methods for benchmarking and comparison. Furthermore, a sensitivity analysis of all parameters were conducted to elucidate the critical parameters of the model. The resulting model was fit to clinical data as a performance benchmark. The clinical data captured the second line of antiretroviral treatment, lopinavir and ritonavir. The model and clinical data correlate well for coadministration of lopinavir/ritonavir with rifampin. Drug-drug interaction was captured between lopinavir and rifampin. This article provides conclusions about the suitability of physiologically based pharmacokinetic models for the prediction of drug-drug interaction and antiretroviral and anti-TB pharmacokinetics.

A worldwide survey on the use of animal-derived materials and reagents in scientific experimentation.

The use of cell and tissue‐based methods in basic, applied and regulatory science has been increasing exponentially. Animal‐derived components, including serum, coating materials, growth factors and antibodies are routinely used in cell/tissue cultures and in general laboratory practices. In addition to ethical issues, the use and production of animal‐derived materials and reagents raises many scientific concerns, generally associated with presence of undefined components and batch‐to‐batch variability, which may compromise experimental reproducibility. On the other hand, non‐animal materials and reagents, such as human cells, alternatives to animal sera or non‐animal recombinant antibodies, are becoming increasingly available, and their use is encouraged by the EU Directive 2010/63 and the Guidance Document on Good In vitro Method Practices (GIVIMP), published by the Organization for Economic Cooperation and Development (OECD). In an effort to map the current state of use of animal‐derived reagents across different sectors and to identify the obstacles possibly hampering the implementation of non‐animal derived alternatives, a global online survey addressed to scientists working on in vivo, in vitro, in silico methods, in academia as well as pharmaceutical or cosmetic companies, was conducted with the goal to understand: 1) the most commonly used animal‐derived materials and reagents, 2) the main issues associated with the production and use of animal‐derived materials and reagents, 3) the current level of knowledge on available non‐animal alternative materials and reagents, and 4) what educational and information sources could be most useful or impactful to disseminate knowledge on non‐animal alternatives. This paper provides an overview of the survey replies and discusses possible proposals to increase awareness, acceptance and use of non‐animal ingredients.

Development of a panel of U.S. adult tobacco users to inform tobacco regulatory science

The National Panel of Tobacco Consumer Studies (TCS Panel) is a probability-based panel of about 4,000 U.S. adult cigarette, cigar, and smokeless tobacco users developed by the U.S. Food and Drug Administration’s Center for Tobacco Products to conduct observational and experimental studies to inform tobacco regulatory activities. This paper describes the methods and characteristics of the current panel. The TCS Panel employed a stratified 4-stage sample design and in-person screening of U.S. sampled households. Selected eligible adults participated in an enrollment interview and completed a baseline survey assessing tobacco use behaviors to enroll in the Panel; 3,893 individuals were enrolled from September 2016–August 2017. Replenishment occurred from July 2019–December 2019 with 2,260 new members, for a current panel of 3,929 members. Demographic and tobacco use characteristics of the current panel were analyzed in 2020. Most demographic characteristics of the TCS Panel are similar to those of U.S. tobacco users in the 2018 National Health Interview Survey, suggesting a lack of systematic bias in the Panel. Small, but statistically significant, differences were observed in the proportion of 18- to 25-year-olds; high school diploma and bachelor’s degree/higher; never married and married (p < 0.05 for all). The TCS Panel appears to be representative of U.S. cigarette, cigar, and smokeless tobacco users; such panels can be a feasible method for conducting tobacco regulatory science research. The TCS Panel has been used to field studies examining purchasing behaviors, receipt and use of free samples/coupons, and the impact of a hypothetical tobacco product standard.

Standardization of an in vitro assay matrix to assess cytotoxicity of organic nanocarriers: a pilot interlaboratory comparison

Nanotechnologies such as nanoparticles are established components of new medical devices and pharmaceuticals. The use and distribution of these materials increases the requirement for standardized evaluation of possible adverse effects, starting with a general cytotoxicity screening. The Horizon 2020 project “Regulatory Science Framework for Nano(bio)material-based Medical Products and Devices (REFINE)” identified in vitro cytotoxicity quantification as a central task and first step for risk assessment and development for medical nanocarriers. We have performed an interlaboratory comparison on a cell-assay matrix including a kinetic lactate dehydrogenase (LDH) release cell death and WST-8 cell viability assay adapted for testing organic nanocarriers in four well-characterized cell lines of different organ origins. Identical experiments were performed by three laboratories, namely the Biomedical Technology Center (BMTZ) of the University of Münster, SINTEF Materials and Chemistry (SINTEF), and the National Institute for Public Health and the Environment (RIVM) of the Netherlands according to new standard operating procedures (SOPs). The experiments confirmed that LipImage™ 815 lipidots® are non-cytotoxic up to a concentration of 128 µg/mL and poly(alkyl cyanoacrylate) (PACA) nanoparticles for drug delivery of cytostatic agents caused dose-dependent cytotoxic effects on the cell lines starting from 8 µg/mL. PACA nanoparticles loaded with the active pharmaceutical ingredient (API) cabazitaxel showed a less pronounced dose-dependent effect with the lowest concentration of 2 µg/mL causing cytotoxic effects. The mean within laboratory standard deviation was 4.9% for the WST-8 cell viability assay and 4.0% for the LDH release cell death assay, while the between laboratory standard deviation was 7.3% and 7.8% for the two assays, respectively. Here, we demonstrated the suitability and reproducibility of a cytotoxicity matrix consisting of two endpoints performed with four cell lines across three partner laboratories. The experimental procedures described here can facilitate a robust cytotoxicity screening for the development of organic nanomaterials used in medicine.Graphical abstract