Regulatory Science Perspective Research Articles

Regulatory Science Perspective on the Analysis of Microplastics and Nanoplastics in Human Food.

Microplastics are increasingly reported, not only in the environment but also in a wide range of food commodities. While studies on microplastics in food abound, the current state of science is limited in its application to regulatory risk assessment by a continued lack of standardized definitions, reference materials, sample collection and preparation procedures, fit-for purpose analytical methods for real-world and environmentally relevant plastic mixtures, and appropriate quality controls. This is particularly the case for nanoplastics. These methodological challenges hinder robust, quantitative exposure assessments of microplastic and nanoplastic mixtures from food consumption. Furthermore, limited toxicological studies on whether microplastics and nanoplastics adversely impact human health are also impeded by methodology challenges. Food safety regulatory agencies must consider both the exposure and the risk of contaminants of emerging concern to ascertain potential harm. Foundational to this effort is access to and application of analytical methods with the capability to quantify and characterize micro- and nanoscale sized polymers in complex food matrices. However, the early stages of method development and application of early stage methods to study the distribution and potential health effects of microplastics and nanoplastics in food have largely been done without consideration of the stringent requirements of methods to inform regulatory activities. We provide regulatory science perspectives on the state of knowledge regarding the occurrence of microplastics and nanoplastics in food and present our general approach for developing, validating, and implementing analytical methods for regulatory purposes.

Artificial intelligence and real-world data for drug and food safety – A regulatory science perspective

In 2013, the Global Coalition for Regulatory Science Research (GCRSR) was established with members from over ten countries (www.gcrsr.net). One of the main objectives of GCRSR is to facilitate communication among global regulators on the rise of new technologies with regulatory applications through the annual conference Global Summit on Regulatory Science (GSRS). The 11th annual GSRS conference (GSRS21) focused on “Regulatory Sciences for Food/Drug Safety with Real-World Data (RWD) and Artificial Intelligence (AI).” The conference discussed current advancements in both AI and RWD approaches with a specific emphasis on how they impact regulatory sciences and how regulatory agencies across the globe are pursuing the adaptation and oversight of these technologies. There were presentations from Brazil, Canada, India, Italy, Japan, Germany, Switzerland, Singapore, the United Kingdom, and the United States. These presentations highlighted how various agencies are moving forward with these technologies by either improving the agencies’ operation and/or preparing regulatory mechanisms to approve the products containing these innovations. To increase the content and discussion, the GSRS21 hosted two debate sessions on the question of “Is Regulatory Science Ready for AI?” and a workshop to showcase the analytical data tools that global regulatory agencies have been using and/or plan to apply to regulatory science. Several key topics were highlighted and discussed during the conference, such as the capabilities of AI and RWD to assist regulatory science policies for drug and food safety, the readiness of AI and data science to provide solutions for regulatory science. Discussions highlighted the need for a constant effort to evaluate emerging technologies for fit-for-purpose regulatory applications. The annual GSRS conferences offer a unique platform to facilitate discussion and collaboration across regulatory agencies, modernizing regulatory approaches, and harmonizing efforts.

Regulatory Approval With Real-World Data From Regulatory Science Perspective in Japan

Recently, there has been a growing trend in clinical development to utilize real-world data (RWD) to improve the efficiency of drug/medical device development. Especially, the use of RWD to generate real-world evidence (RWE) in regulatory approval is currently undergoing a period of great change with an increasing degree of active discussion. In Japan, RWE has been used in the control arms of clinical trials, observational studies, post-marketing surveillance, and public knowledge-based applications for regulatory approval. However, the exclusive use of RWE applications has still not been applied. In this paper, we summarize the history and the current situation of RWE and focus on the utilization for the purpose of regulatory approval. In addition, we will discuss the issues and perspectives for registry research in the utilization for regulatory approval in Japan.

(Bio)manufactured Solutions for Treatment of Bone Defects with an Emphasis on US‐FDA Regulatory Science Perspective

Biomanufacturing In article number 2100073, Mehdi Kazemzadeh-Narbat, Ali Tamayol, and co-workers emphasize on the fabrication strategies for bone tissue engineering and their United States Food and Drug Administration regulatory perspective. Bone biology and materials for engineering bone grafts are discussed. (Bio)manufacturing approaches are critically reviewed. Subsequently, a road map for United States Food and Drug Administration conformance is provided.

(Bio)manufactured Solutions for Treatment of Bone Defects with Emphasis on US-FDA Regulatory Science Perspective.

Bone defects, with second highest demand for surgeries around the globe, may lead to serious health issues and negatively influence patient lives. The advances in biomedical engineering and sciences have led to the development of several creative solutions for bone defect treatment. This review provides a brief summary of bone graft materials, an organized overview of top-down and bottom-up (bio)manufacturing approaches, plus a critical comparison between advantages and limitations of each method. We specifically discuss additive manufacturing techniques and their operation mechanisms in detail. Next, we review the hybrid methods and promising future directions for bone grafting, while giving a comprehensive US-FDA regulatory science perspective, biocompatibility concepts and assessments, and clinical considerations to translate a technology from a research laboratory to the market. The topics covered in this review could potentially fuel future research efforts in bone tissue engineering, and perhaps could also provide novel insights for other tissue engineering applications.

PMD7 Analysis of Medical Device Recall Reports in China from a Regulatory Science Perspective: Implications for Post-Marketing Surveillance

In China, medical device is an essential part of healthcare service and represents a fasting growing healthcare market. To safeguard patient safety and improve regulatory decision-making, the National Medical Products Administration (NMPA) has set to advance the post-marketing surveillance system and adopt regulatory science (RS) for capacity enhancement. However, little is known about the most recent concerns of medical devices in the sizeable marketplace. This research aimed to analyze the official medical device recall reports and to explore priority actions for advancing RS in medical device.

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum.

Identifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH. Past work of The Liver Forum has focused on recommendations for disease definitions and baseline parameters to be implemented in clinical trials that are designed to assess disease status and prevent progression to cirrhosis, liver transplantation, hepatocellular carcinoma, and death. The purpose of this summary is to review currently available clinical data to identify parameters that change in parallel with liver histology and are likely to reflect clinically meaningful reductions in the risk of developing cirrhosis and its complications. We review available data on exploratory histological, blood-based, and imaging pharmacodynamic biomarkers that may reflect meaningful treatment responses and provide recommendations regarding measurements to be considered in phase 2 and 3 trials as well as during postmarketing monitoring trials.

Characterization of nanomedicine in terms of regulatory science perspective

Characterization of nanomedicine in terms of regulatory science perspective

Real-World Data and Clinical Pharmacology: A Regulatory Science Perspective.

Real-World Data and Clinical Pharmacology: A Regulatory Science Perspective.

3523 Innovative Approaches to Clinical Research on Placebo Effects: A Regulatory Science Perspective

OBJECTIVES/SPECIFIC AIMS: To analyze contemporary study design methods and clinical trial approaches in placebo research. METHODS/STUDY POPULATION: An analysis was conducted on the following studies: I. “Managing” the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models by RN Haden, et al. The objective of the study was to consider elements of the placebo response in the context of two pain models using a “single-blind placebo lead-in” design (SBPLI) by engaging the “placebo response” prior to randomization to active drug and placebo-controlled conditions. The methods of the study included two pilot drug trials using knee osteoarthritis (KOA) and non-radicular low back pain (LBP) subjects, SBPLI protocols were conducted. In the first study, 36 subjects with non-radicular CLBP were enrolled in a double-blind, randomized, placebo-controlled trial of hydromorphone ER. In the second study, a total of 42 subjects with chronic KOA pain were enrolled in a double-blind, randomized, placebo-controlled study of milnacipran. Gender and/or diagnosis affected placebo responses as observed in changes in patient self-reported pain, depressive and pain anxiety symptoms were examined. Additionally, the placebo response on performance-based tests (stair climbing, range of motion (ROM), sit to stand repetitions, and 6-minute treadmill distance) was evaluated. II. Randomized Placebo-Controlled Placebo Trial to Determine the Placebo Effect Size by L. Gerdesmeyer, et al. The objective of the study was to analyze the pure placebo effect on clinical, chronic pain through a blinded RCT. The methods of the study included 182 patients suffering from chronic plantar heel pain for over 6 months, who failed to respond to conservative treatments, were screened and 106 of these patients were enrolled into this study. The patients were randomly assigned to receive either a blinded placebo shockwave treatment or an unblinded placebo shockwave treatment. The primary outcome measure was the differences in percentage change of visual analogue scale (VAS) scores 6 weeks after the intervention. The secondary outcome measure was the differences in Roles and Maudsley pain score (RMS) 6 weeks after intervention. III. Open-label placebo treatment in chronic low back pain: a randomized controlled trial by C. Carvalho, et al. The objective of the study was to investigate whether placebo effects in chronic low back pain could be harnessed ethically by adding open-label placebo (OLP) treatment to treatment as usual (TAU) for 3 weeks. The methods of the study included 97 randomized participants in a 3-week randomized control trial comparing current treatment plus OLP to current treatment alone (TAU). RESULTS/ANTICIPATED RESULTS: N/a DISCUSSION/SIGNIFICANCE OF IMPACT: The aforementioned studies provide placebo researchers with contemporary and reliable methodologies to examine placebo effects on participants. These methodologies provide scientists with clinical translational research methodology styles based on the foundation of regulatory science.

Preclinical Development of Cell-Based Products: a European Regulatory Science Perspective

PurposeThis article describes preclinical development of cell-based medicinal products for European markets and discusses European regulatory mechanisms open to developers to aid successful product development. Cell-based medicinal products are diverse, including cells that are autologous or allogeneic, have been genetically modified, or not, or expanded ex vivo, and applied systemically or to an anatomical site different to that of their origin; comments applicable to one product may not be applicable to others, so bespoke development is needed, for all elements - quality, preclinical and clinical.MethodsAfter establishing how the product is produced, proof of potential for therapeutic efficacy, and then safety, of the product need to be determined. This includes understanding biodistribution, persistence and toxicity, including potential for malignant transformation. These elements need to be considered in the context of the intended clinical development.ResultsThis article describes regulatory mechanisms available to developers to support product development that aim to resolve scientific issues prior to marketing authorization application, to enable patients to have faster access to the product than would otherwise be the case.ConclusionsDevelopers are encouraged to be aware of both the scientific issues and regulatory mechanisms to ensure patients can be supplied with these products.

Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.

Nonalcoholic steatohepatitis (NASH) is an important cause of liver‐related morbidity and mortality. There are no approved therapies, and the results of clinical trials have been difficult to compare due to inconsistent definitions of relevant disease parameters in patients with NASH. The natural course of the disease has not been rigorously characterized, particularly with respect to the contributions of underlying obesity, type 2 diabetes, and other comorbidities and the treatments provided for these comorbidities. Efforts to perform analyses of pooled data are limited by heterogeneous case definitions used across studies to define disease states. There remains a major unmet need in the field to develop standardized definitions for populations for interventional trials. Such definitions are expected to impact how endpoints for clinical trials are constructed. The Liver Forum is a multistakeholder effort including US and European regulatory agencies, academic investigators, professional and patient representative organizations, and industry to catalyze therapeutic development for NASH by developing potential solutions to barriers to development. The Case Definitions Working Group was established by The Liver Forum to evaluate the validity of case definitions for populations to be included in clinical trials for NASH from a regulatory science perspective. Based on such analyses, specific recommendations are provided noting the strengths and weaknesses of the case definitions along with knowledge gaps that require additional study. (Hepatology 2018;67:2001‐2012)

Integration of Near-Infrared Spectroscopy and Mechanistic Modeling for Predicting Film-Coating and Dissolution of Modified Release Tablets

This study demonstrates the feasibility of predicting polymeric film coating and dissolution of theophylline (active pharmateutical ingredients, API) tablets based on integration of multivariate data analysis of near-infrared (NIR) spectra and first-principal modeling. Tablets of various API strengths were manufactured and were spray-coated in a fluid bed using a mixture of ethyl cellulose and hydroxypropyl methylcellulose. Tablets were subjected in NIR spectroscopy and in vitro USP dissolution testing. The characteristic peaks of coating materials were identified via Norris Gap second derivative preprocessing of the NIR spectra of coated tablets. Principal component analysis revealed a linear relationship between PC1 score and tablet coating level. Principal component regression and partial least squares calibration models were developed to correlate the NIR spectra with the dissolution data within the time window of 10–120 min. A linear relationship between tablet initial dissolution rate and tablet coating level was found with a slope of S. On the basis of a Fickian diffusion model, a mathematical equation was derived to relate S to the diffusion coefficient (D) of the drug across the polymeric film. The mechanistic modeling of the film-coated theophylline tablet dissolution profiles suggested that the film-coated tablet dissolution process might be governed by Fick diffusion control for the initial and early release, and governed by the Hixson and Crowell first order kinetics for the late release stage. Finally, some of the current challenges and future outlook on development of such a hybrid modeling approach for characterizing and understanding film-coated tablet manufacturing and dissolution via process analytical technology implementation was discussed from both a technical and a regulatory science perspective.

In response: Assessing the effects of chemicals in freshwaters under multiple stress: A regulatory science perspective.

In response: Assessing the effects of chemicals in freshwaters under multiple stress: A regulatory science perspective.

Assessment of Recent Process Analytical Technology (PAT) Trends: A Multiauthor Review

This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratories and in manufacture e.g. at GSK, AstraZeneca and Roche. Furthermore, the paper discusses the PAT paradigm from the regulatory science perspective. Given the multidisciplinary nature of PAT, such an endeavour would be almost impossible for a single author, so the concept of a multiauthor review was born. Each section of the multiauthor review has been written by a single expert or group of experts with the aim to report on its own research results. This paper also serves as a comprehensive source of information on PAT topics for the novice reader.

Clinical implementation of genetic testing in medicine: a US regulatory science perspective

Heterogeneity of treatment effects in unselected patient populations has stimulated various strategic approaches to reduce variability and uncertainty and improve individualization of drug selection and dosing. The rapid growth of DNA sequencing and related technologies has ramped up progress in interpreting germline and somatic mutations and has begun to reshape medicine, especially in oncology. Over the past decade, regulatory agencies realized that they needed to be proactive and not reactive if personalized medicine was to become a reality. The US Food and Drug Administration, in particular, took steps to nurture the field through peer-reviewed publications, co-sponsoring public workshops and issuing guidance for industry. The following two major approaches to personalized medicine were taken: (i) encouragement of de novo co-development of drug-genetic test combinations by industry; and (ii) retrospective assessment of legacy genetic data for the purpose of updating drug labels. The former strategy has been more successful in getting new targeted therapies to the marketplace with successful adoption, while the latter, as evidenced by the low adoption rate of pharmacogenetic testing, has been less successful. This reflection piece makes clear that several important things need to happen to make personalized medicine diffuse in more geographical areas and among more therapeutic specialties. The debate over clinical utility of genetic tests needs to be resolved with consensus on evidentiary standards. Physicians, as gatekeepers of prescription medicines, need to increase their knowledge of genetics and the application of the information to patient care. An infrastructure needs to be developed to make access to genetic tests and decision-support tools available to primary practitioners and specialists outside major medical centres and metropolitan areas.

Built-in quality systems in regulated contract research organizations (CRO) conducting bioequivalence studies: a regulatory science perspective

As contract research organizations are now familiar with GXPs and have become more popular for conducting bioequivalence studies, it is very important that the sponsor has the assurance that the study has been conducted not only to the highest standard of science but also in compliance with regulatory requirements. The dynamic role of quality personnel requires alert knowledgeable people to recognise all the issues which arise and take the proper actions—experienced persons can detect and rectify these. On the basis of equality, for quality system personnel and scientists a firm grasp of regulatory science is needed to succeed. It must be remembered that compliance is monitored by adherence to regulatory standards, whereas the regulatory bodies review the appropriately implemented regulatory science principles.

Medical applications of microarray technologies: a regulatory science perspective.

The potential medical applications of microarrays have generated much excitement, and some skepticism, within the biomedical community. Some researchers have suggested that within the decade microarrays will be routinely used in the selection, assessment, and quality control of the best drugs for pharmaceutical development, as well as for disease diagnosis and for monitoring desired and adverse outcomes of therapeutic interventions. Realizing this potential will be a challenge for the whole scientific community, as breakthroughs that show great promise at the bench often fail to meet the requirements of clinicians and regulatory scientists. The development of a cooperative framework among regulators, product sponsors, and technology experts will be essential for realizing the revolutionary promise that microarrays hold for drug development, regulatory science, medical practice and public health.