Review of Dose Justifications for Antibody-Drug Conjugate Approvals from Clinical Pharmacology Perspective: a Focus on Exposure-Response Analyses.

Antibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs.

Incorporating new approach methods (NAMs) data in dose-response assessments: The future is now!

Regulatory dose-response assessments traditionally rely on in vivo data and default assumptions. New Approach Methods (NAMs) present considerable opportunities to both augment traditional dose-response assessments and accelerate the evaluation of new/data-poor chemicals. This review aimed to determine the potential utilization of NAMs through a unified conceptual framework that compartmentalizes derivation of toxicity values into five sequential Key Dose-response Modules (KDMs): (1) point-of-departure (POD) determination, (2) test system-to-human (e.g. inter-species) toxicokinetics and (3) toxicodynamics, (4) human population (intra-species) variability in toxicodynamics, and (5) toxicokinetics. After using several "traditional" dose-response assessments to illustrate this framework, a review is presented where existing NAMs, including in silico, in vitro, and in vivo approaches, might be applied across KDMs. Further, the false dichotomy between "traditional" and NAMs-derived data sources is broken down by organizing dose-response assessments into a matrix where each KDM has Tiers of increasing precision and confidence: Tier 0: Default/generic values, Tier 1: Computational predictions, Tier 2: Surrogate measurements, and Tier 3: Direct measurements. These findings demonstrated that although many publications promote the use of NAMs in KDMs (1) for POD determination and (5) for human population toxicokinetics, the proposed matrix of KDMs and Tiers reveals additional immediate opportunities for NAMs to be integrated across other KDMs. Further, critical needs were identified for developing NAMs to improve in vitro dosimetry and quantify test system and human population toxicodynamics. Overall, broadening the integration of NAMs across the steps of dose-response assessment promises to yield higher throughput, less animal-dependent, and more science-based toxicity values for protecting human health.

Examining longitudinal associations between initial perceptions and experiences with electronic nicotine delivery system (ENDS) use and use patterns among adults who smoke and recently initiated ENDS.

INTRODUCTION: Limited data exist on factors associated with concurrent use patterns of electronic nicotine delivery systems (ENDS) and cigarettes. We examined longitudinally perceptions and experiences with ENDS in relationship to concurrent use patterns among established, recent smokers who recently initiated ENDS. METHODS: Participant recruitment took place using paid digital advertisements on social media. Between December 2020 and October 2021, 303 adults aged ≥21 years from across the US who currently or recently smoked and had initiated ENDS use within the past 30 days or reinitiated ENDS use after more than one year of non-use were surveyed. Multinomial logistic regressions were conducted to analyze association between the outcome of current use pattern at follow-up at 1 month [rejectors (discontinued ENDS, continued smoking), primary smokers (concurrent users, mostly smoke), dual user (similar smoking and ENDS use), primary vapers (concurrent users, mostly vape), and switchers (discontinued smoking, continued using ENDS) or quitters (discontinued both smoking and ENDS] and perceptions of and experiences with ENDS predictors at baseline. RESULTS: At follow-up at 1 to 2 months after initiating ENDS, 20% were rejectors, 31% were primary smokers, 13% were dual users, 19% were primary vapers, and 17% were switchers/quitters. Perceiving ENDS as less harmful than smoking or being uncertain and as equally or more enjoyable smoking, experiencing a lot or complete reduction in cravings to smoking and in irritability with ENDS use, liking the taste of ENDS, and being satisfied with vaping were associated with higher odds of quitting smoking compared to rejecting ENDS or mostly smoking at follow-up at 1 month. CONCLUSIONS: Findings highlight the importance of initial ENDS perceptions and experiences when examining tobacco outcomes and potentially for developing policies and interventions targeting smoking cessation. ENDS initiators are differentiating into distinct use patterns based on these factors within a short period of time.

Early clinical drug product shelf-life setting using accelerated predictive stability and metabolite data for impurity qualification: A case study.

This case study demonstrates how knowledge of degradation products together with predictions can establish a lean stability strategy using the accelerated predictive stability (APS) principles. Applying all available data for AZD4831, (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one, a reliable predictive model was developed despite minor differences in technical batch tablet compositions. Early forced degradation studies were performed to map potential degradation pathways. The insights from these studies guided the design of an APS study, which in turn inform on a suitable clinical stability program, initial specification and shelf-life. The use of APS predictions of degradants as well as total impurities highlighted at an early stage, when designing the clinical stability program, the opportunity to identify which degradation product that would be shelf-life limiting. Hence, it was possible to guide the development stability activities and set an initial shelf-life of a tablet formulation. The presented study displays the importance of combining several sources of information in drug development, e.g., potential degradation pathways, accelerated stability, stability program design, metabolite data, and specification limits.

Regulatory readiness to facilitate the appropriate use of innovation in clinical trials: The case of decentralized clinical trial approaches.

Methodological and operational clinical trial innovation is needed to address key challenges associated with clinical trials, including limited generalizability and (s)low recruitment rates. In this article, we discuss how appropriate implementation of innovative clinical trial approaches can be facilitated by a timely identification of, and response to, emerging situations and innovation by regulators (i.e. regulatory readiness) using decentralized clinical trial (DCT) approaches - in which trial activities are moved closer to participants and away from the investigative sites - as a case study example. Specifically, we discuss how explorative research (e.g. using regulatory sandboxes) can enable the collection of data on the usefulness of DCT approaches. Additionally, we argue that DCT approaches should be evaluated similarly to conventional clinical trials.

Regulatory science promotes the translation of transcatheter tricuspid valve repair/replacement devices.

For patients with symptomatic and severe tricuspid regurgitation but inoperable with open surgery, transcatheter tricuspid valve intervention (TTVI) is a procedure of great clinical value. TTVI products include repair and replacement devices. TTVI products are one of the hotspots of investigation now, with different innovative biomaterials and structural designs in trials to satisfy divergent indications and reduce complications. With the emerging biomaterials, the technical difficulty of structural design will be greatly reduced, spurring further product innovation and development. The innovativeness and complexity of TTVI products have brought challenges to academia, industry, and regulatory agencies. Regulatory science provides a bridge to address these difficulties and challenges. This perspective article introduces the latest development of the TTVI products. With traditional methods, regulatory agencies face challenges in evaluating the safety and efficacy of TTVr/TTVR devices given the uncertainty of clinical use and the diversity of innovative structural design. This perspective article analyzes the regulatory challenges and discusses regulatory science that can be developed to assess the safety, efficacy, quality and performance of such products: including new approaches for innovative devices, pre-review path, computer modeling and simulation, accelerated wear testing methods for transcatheter heart valves and evidence-based research. This article reveals for the first time how to apply regulatory science systematically to TTVI products, which is of great relevance to their development and translation.

Restrictions of cigarette and e-cigarette flavor and filter ventilation on demand and substitution in the Experimental Tobacco Marketplace.

SIGNIFICANCE: Tobacco product design features, including flavors and cigarette filter ventilation, are subject to regulation. This study examined the effects of cigarette and e-cigarette flavors on demand and substitution by preferred cigarette flavor and ventilation in the Experimental Tobacco Marketplace (ETM). METHODS: In a mixed between-group (usual cigarette flavor and ventilation)/within-subject design (policy conditions), individuals who use tobacco (n=176 cigarette (60.5 % female); n=91 multiple products (26.7 % female)) were recruited using Ipsos and InnovateMR, completed purchasing trials with increasing cigarette prices in the ETM. Participants were exposed to four conditions in a 2×2 factorial design with cigarette flavors restricted or unrestricted and e-cigarette flavors restricted or unrestricted. RESULTS: In individuals who exclusively smoke cigarettes: 1) Cigarette menthol restrictions decreased willingness to purchase cigarettes (OR: 0.001; 95 % CI: 0.00002, 0.015) for individuals that prefer menthol cigarettes and increased willingness to purchase NRT (OR: 4.02; 95 % CI: 1.47, 11.0), 2) cigarette menthol restrictions reduced demand for cigarettes in individuals who smoke menthol cigarettes (p<0.001), 3) e-cigarette flavor restrictions reduced the degree of e-cigarette substitution in individuals who smoke menthol cigarettes (p=0.028), and 4) preference for higher cigarette filter ventilation was associated with higher demand for cigarettes (p=0.003) and lowered substitution of smokeless tobacco products (p=0.028). In individuals who use multiple tobacco products, restrictions did not impact product purchasing. CONCLUSION: Strategies to reduce flavored product sales and increase cessation resource accessibility may improve population health by reducing smoking and increasing NRT use in individuals who use menthol cigarettes.

Effects of Very Low Nicotine Content Cigarettes and Nicotine Vaping Device Characteristics on Choices to Smoke, Vape, or Abstain in Early Young Adults.

INTRODUCTION: A national nicotine reduction policy could reduce the public health toll of smoking. However, reducing nicotine in cigarettes may lead to changes in the use of other tobacco products such as nicotine vaping devices, particularly among young people. Product use outcomes may depend on characteristics of available nicotine vaping devices. We aimed to determine the impact of cigarette nicotine content, vaping device nicotine concentration, and vaping device flavors on choices to smoke, vape, or abstain. METHODS: Early young adults (ages 18-20 inclusive, N=80) who reported smoking daily and vaping nicotine at least twice in their lifetime participated in a laboratory study. Participants received either Very Low Nicotine Content (VLNC; 0.4 mg nicotine/g of tobacco) or Normal Nicotine Content (NNC; 15.8 mg/g) cigarettes. First, participants chose between their assigned cigarette or abstaining. Subsequently, participants chose between 2 cigarette puffs, 2 vape puffs, or abstaining. Vaping device nicotine concentration (3mg vs. 18mg/ml) and flavor (tobacco vs. non-tobacco) were manipulated within-subjects. RESULTS: When only cigarettes were available, there were no differences between the VLNC and NNC groups on cigarette choices. When the nicotine vaping device was concurrently available, the VLNC group made fewer choices to smoke than the NNC group. Non-tobacco flavors and lower vaping device nicotine concentration were associated with fewer choices to smoke. CONCLUSIONS: Nicotine vaping device availability reduced choices to smoke VLNC cigarettes, and vaping devices with lower nicotine and non-tobacco flavors led to the fewest choices to smoke. Regulators should consider that the availability and characteristics of alternative tobacco products can moderate the product standard's impact. IMPLICATIONS: The U.S. Food and Drug Administration may enact a reduced nicotine product standard that would affect all commercially-available cigarettes. One important population affected by this policy would be early young adults who smoke. We aimed to determine the impact of cigarette nicotine content, vaping device nicotine concentration, and vaping device flavors on choices to smoke, vape, or abstain. Lower nicotine in cigarettes, along with non-tobacco flavors and lower nicotine concentration in the vaping device, were associated with the fewest choices to smoke. Regulators should consider that the availability and characteristics of alternative tobacco products can moderate the product standard's impact.

Bayesian network analysis of risk classification strategies in the regulation of cellular products.

Cell therapy, a burgeoning therapeutic strategy, necessitates a scientific regulatory framework but faces challenges in risk-based regulation due to the lack of a global consensus on risk classification. This study applies Bayesian network analysis to compare and evaluate the risk classification strategies for cellular products proposed by the Food and Drug Administration (FDA), Ministry of Health, Labour and Welfare (MHLW), and World Health Organization (WHO), using real-world data to validate the models. The appropriateness of key risk factors is assessed within the three regulatory frameworks, along with their implications for clinical safety. The results indicate several directions for refining risk classification approaches. Additionally, a substudy focuses on a specific type of cell and gene therapy (CGT), chimeric antigen receptor (CAR) T cell therapy. It underscores the importance of considering CAR targets, tumor types, and costimulatory domains when assessing the safety risks of CAR T cell products. Overall, there is currently a lack of a regulatory framework based on real-world data for cellular products and a lack of risk-based classification review methods. This study aims to improve the regulatory system for cellular products, emphasizing risk-based classification. Furthermore, the study advocates for leveraging machine learning in regulatory science to enhance the assessment of cellular product safety, illustrating the role of Bayesian networks in aiding regulatory decision-making for the risk classification of cellular products.

Artificial intelligence integration in the drug lifecycle and in regulatory science: policy implications, challenges and opportunities.

Artificial intelligence tools promise transformative impacts in drug development. Regulatory agencies face challenges in integrating AI while ensuring reliability and safety in clinical trial approvals, drug marketing authorizations, and post-market surveillance. Incorporating these technologies into the existing regulatory framework and agency practices poses notable challenges, particularly in evaluating the data and models employed for these purposes. Rapid adaptation of regulations and internal processes is essential for agencies to keep pace with innovation, though achieving this requires collective stakeholder collaboration. This article thus delves into the need for adaptations of regulations throughout the drug development lifecycle, as well as the utilization of AI within internal processes of medicine agencies.

Development of a Maturity Model for Medical Patient Registries - A Community Approach.

OBJECTIVE: Development of a generic model to visualize the potential for use and further development of registries to assess the suitability of the registry for a specific purpose. METHODS: Multi-stage community approach. RESULTS: The maturity model has 9 categories with 105 items. The purpose of the registry is mapped via potential usage dimensions. CONCLUSION: Important for acceptance is the appropriateness of the requirements in relation to the purposes.

AI as a Medical Device Adverse Event Reporting in Regulatory Databases: Protocol for a Systematic Review.

BACKGROUND: The reporting of adverse events (AEs) relating to medical devices is a long-standing area of concern, with suboptimal reporting due to a range of factors including a failure to recognize the association of AEs with medical devices, lack of knowledge of how to report AEs, and a general culture of nonreporting. The introduction of artificial intelligence as a medical device (AIaMD) requires a robust safety monitoring environment that recognizes both generic risks of a medical device and some of the increasingly recognized risks of AIaMD (such as algorithmic bias). There is an urgent need to understand the limitations of current AE reporting systems and explore potential mechanisms for how AEs could be detected, attributed, and reported with a view to improving the early detection of safety signals. OBJECTIVE: The systematic review outlined in this protocol aims to yield insights into the frequency and severity of AEs while characterizing the events using existing regulatory guidance. METHODS: Publicly accessible AE databases will be searched to identify AE reports for AIaMD. Scoping searches have identified 3 regulatory territories for which public access to AE reports is provided: the United States, the United Kingdom, and Australia. AEs will be included for analysis if an artificial intelligence (AI) medical device is involved. Software as a medical device without AI is not within the scope of this review. Data extraction will be conducted using a data extraction tool designed for this review and will be done independently by AUK and a second reviewer. Descriptive analysis will be conducted to identify the types of AEs being reported, and their frequency, for different types of AIaMD. AEs will be analyzed and characterized according to existing regulatory guidance. RESULTS: Scoping searches are being conducted with screening to begin in April 2024. Data extraction and synthesis will commence in May 2024, with planned completion by August 2024. The review will highlight the types of AEs being reported for different types of AI medical devices and where the gaps are. It is anticipated that there will be particularly low rates of reporting for indirect harms associated with AIaMD. CONCLUSIONS: To our knowledge, this will be the first systematic review of 3 different regulatory sources reporting AEs associated with AIaMD. The review will focus on real-world evidence, which brings certain limitations, compounded by the opacity of regulatory databases generally. The review will outline the characteristics and frequency of AEs reported for AIaMD and help regulators and policy makers to continue developing robust safety monitoring processes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/48156.

Basic regulatory science behind drug substance and drug product specifications of monoclonal antibodies and other protein therapeutics.

In this review, we focus on providing basics and examples for each component of the protein therapeutic specifications to interested pharmacists and biopharmaceutical scientists with a goal to strengthen understanding in regulatory science and compliance. Pharmaceutical specifications comprise a list of important quality attributes for testing, references to use for test procedures, and appropriate acceptance criteria for the tests, and they are set up to ensure that when a drug product is administered to a patient, its intended therapeutic benefits and safety can be rendered appropriately. Conformance of drug substance or drug product to the specifications is achieved by testing an article according to the listed tests and analytical methods and obtaining test results that meet the acceptance criteria. Quality attributes are chosen to be tested based on their quality risk, and consideration should be given to the merit of the analytical methods which are associated with the acceptance criteria of the specifications. Acceptance criteria are set forth primarily based on efficacy and safety profiles, with an increasing attention noted for patient-centric specifications. Discussed in this work are related guidelines that support the biopharmaceutical specification setting, how to set the acceptance criteria, and examples of the quality attributes and the analytical methods from 60 articles and 23 pharmacopeial monographs. Outlooks are also explored on process analytical technologies and other orthogonal tools which are on-trend in biopharmaceutical characterization and quality control.

The Cannabis Gray Market: A Case for Cannabis Regulatory Science Research.

The cannabis gray market poses significant public health concerns and remains a major threat to consumer and/or potential consumer uptake of regulated cannabis markets in jurisdictions with legal state-sponsored cannabis programs. In this perspective, we provide an overview of the cannabis gray market, and describe an integrated epidemiological and regulatory science framework to study the gray market. Using tobacco regulatory science as a guide, we introduce example cannabis regulatory science research activities as a means to improve the field's understanding of the cannabis gray market. Cannabis regulatory science is a developing field that can improve our understanding of the cannabis regulatory ecosystem and provide regulatory officials and policymakers alike with much needed data to inform regulatory decision-making and improve the success and uptake of state-sponsored cannabis programs.

[Discussion on reference sample research of traditional Chinese medicine compound preparations developed from catalogued ancient classical prescriptions].

The concept of reference sample was put forward in the Guidance on CMC of Traditional Chinese Medicine Compound Preparations Developed from Catalogued Ancient Classical Prescriptions(Interim). The research on reference sample is a key link in the research and development of traditional Chinese medicine(TCM) compound prescriptions from catalogued ancient classical prescriptions(known as Category 3.1 TCM). This paper discusses the content of research on reference sample by analyzing the characteristics of Category 3.1 TCM and the purpose of research on reference sample. Furthermore, suggestions on the research of reference sample are proposed according to the development and evaluation practice of Category 3.1 TCM and research achievements of TCM regulatory science, aiming to provide reference for colleagues in this industry.

Toward an international standardisation roadmap for nanomedicine.

The French National Metrology Institute (LNE) initiated a series of events to identify priorities for test methods and their harmonisation that directly address regulatory needs in Nanomedicine. One of these workshops entitled "The International Standardisation Roadmap for Nanomedicine" held in October 2023 (Paris, France) brought together key experts in the characterisation of nanomedicines and medical products containing nanomaterials, including the Joint Research Centre of the European Commission, SINTEF Industry and the metrology institutes of France, the UK, the USA and Canada, two flagship initiatives of the European Commission (PHOENIX and SAFE-n-MEDTECH Open Innovation Test Beds), representatives of a working party on mRNA vaccines at the European Directorate for the Quality of Medicines (EDQM) and members of international standardisation and pre-normative organisations (including CEN, ISO, ASTM, VAMAS). Two take-home message came out from the discussion. First, developing standard test methods and Reference Materials (RMs) for nanomedicines is a key priority for the European Commission and various stakeholders. Furthermore, there was a unanimous recognition of the need for a unified approach between standardisation committees, regulators and the nanomedicine community. At the USA, Canadian and European level, examples of success stories and of future initiative have been discussed. Future perspectives include the creation of a dedicated Working Group under CEN/TC 352 to consolidate efforts and develop a nanomedicine standardisation roadmap.

[Considering the Professionalism of Pharmacists from a Viewpoint of "Regulatory Science"].

Regulatory science underpins scientific regulations, including reflection papers, guidelines, and administrative notices, and is closely related to the quality assurance (QA) of pharmaceuticals, foods, and chemicals in our living environment. Historically, QA has been considered the basis of pharmaceutical science. Therefore, the Pharmaceutical and Medical Device Law specifies that pharmacists, as marketing directors of pharmaceutical products, are responsible for their QA. Furthermore, a pharmacist is responsible for the QA of foods and environmental chemicals by several laws; for example, as a food sanitation supervisor or an environmental sanitation training officer. This suggests that the professional expertise of pharmacists is expected in medical care where pharmaceuticals are used and in other fields associated with QA. Thus, I consider that the professionalism of a pharmacist is guided by spiritual concepts with a pragmatic attitude and conformance to these expectations.

International regulatory and publicly-funded initiatives to advance drug repurposing.

Introduction: Although drug repurposing holds great potential in addressing unmet needs, successful practical implementation is challenging and has been less widespread than anticipated. Regulators may play a critical role in addressing this, and recent years have seen the conception of regulator-initiated and publicly-funded repurposing initiatives, with significant regulator involvement. Methods: International regulators and public funders (n = 8) were interviewed to obtain insight in how repurposing can be advanced from a regulatory perspective. Transcripts were thematically analyzed. Results: Most initiatives employed a broad concept of repurposing. While patient access was the main focus, label extension remained the gold standard. Commonly perceived barriers were a lack of regulatory expertise, limited downstream drug development, insufficient financial incentives, inadequate awareness of challenges, and poor collaboration. Ways for regulators to facilitate repurposing include early and accessible involvement fostering education, collaboration, and awareness. Increased stakeholder engagement, including internationally, was recommended. Legislative changes may enable the current repurposing ecosystem to evolve. Discussion: Regulators may play a central role in advancing repurposing by reconsidering their responsibilities within the current regulatory framework, both in mitigating repurposing pitfalls and actively encouraging repurposing initiatives by industry and non-traditional drug developers.

Importance of Various E-Cigarette Device and E-Liquid Characteristics by Smoking Status among Young Adults Who Vape.

BACKGROUND: E-cigarette product characteristics are known to influence appeal among young adults. Understanding which characteristics appeal to individuals with (vs. without) a history of combusted tobacco use is essential for developing effective tobacco control policies. METHODS: Anonymous, self-report data were collected from young adults (18-30 years) who had used e-cigarettes in the past 30 days (n = 295) online via Prolific from September-October 2019. Using a visual analogue scale (range: 0-100), participants rated the importance of ten e-cigarette device and nine e-liquid characteristics. Adjusted linear regression models were used to evaluate the association of combusted tobacco use status (never, former, current) with mean rating scores for each of the nineteen characteristics. RESULTS: The most important e-cigarette device characteristics were price (Mean = 81.1; [SD = 17.9]), size (Mean = 75.5 [SD = 20.9]), and hit strength (Mean = 73.8 [SD = 20.4]) while the most important e-liquid characteristics were flavor (M = 85.1 [SD = 16.3]), price (M = 80.9 [SD = 18.4]), and nicotine level (M = 77.8 [18.9]). Differences by combusted tobacco use status were observed for device brand, temperature/voltage, customizability, color, and popularity, with the highest ratings generally observed among those concurrently using combustible tobacco products. For e-liquids, differences by use status were observed for flavor, price, and bottle type. Notably, those concurrently using combusted products rated flavor as less important than those with no history of combustible tobacco use (B=-5.01[95%CI=-9.97, -0.05]). CONCLUSIONS: The self-rated importance of e-cigarette device and e-liquid attributes varies by combustible tobacco use status among young adults which may be used to inform regulatory decisions regarding e-cigarette product characteristics.