Postmarket safety communications on drugs approved in Japan: A 25-year analysis.

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information to healthcare professionals and patients. Previous studies characterized DSCs issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, knowledge about the activities of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) is limited. This study characterized DSCs by the PMDA/MHLW in comparison with previously reported DSCs by the FDA and the EMA. We retrospectively analyzed 37 DSCs of 41 adverse drug reactions (ADRs) for 33 drugs in Japan from 1997 to 2022. Most DSCs were related to non-oncology drugs (30/37, 81.1%), and the median (interquartile range) time from approval to DSC issuance was 19 (10-51) months. Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) of the ADRs related to DSCs, respectively. Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn. Some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues addressed by DSCs differ among the three jurisdictions. Our study emphasized the importance of continuous efforts to gather postmarket drug safety information because substantial ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals. Future studies are required to address global challenges for regulatory harmonization of safety-related regulatory actions.

A framework enabling LLMs into regulatory environment for transparency and trustworthiness and its application to drug labeling document.

Regulatory agencies consistently deal with extensive document reviews, ranging from product submissions to both internal and external communications. Large Language Models (LLMs) like ChatGPT can be invaluable tools for these tasks, however present several challenges, particularly the proprietary information, combining customized function with specific review needs, and transparency and explainability of the model's output. Hence, a localized and customized solution is imperative. To tackle these challenges, we formulated a framework named askFDALabel on FDA drug labeling documents that is a crucial resource in the FDA drug review process. AskFDALabel operates within a secure IT environment and comprises two key modules: a semantic search and a Q&A/text-generation module. The Module S built on word embeddings to enable comprehensive semantic queries within labeling documents. The Module T utilizes a tuned LLM to generate responses based on references from Module S. As the result, our framework enabled small LLMs to perform comparably to ChatGPT with as a computationally inexpensive solution for regulatory application. To conclude, through AskFDALabel, we have showcased a pathway that harnesses LLMs to support agency operations within a secure environment, offering tailored functions for the needs of regulatory research.

Review of the standards of proof (of safety) for FDA regulated consumer products and how the generally recognized as safe criteria could be applied to cosmetics.

The Modernization of Cosmetics Regulation Act of 2022 (MoCRA) amends the Food, Drug and Cosmetic Act (FDCA), elevating the standard of proof of safety (better known as a "safety standard") for cosmetics to the standard of a "reasonable certainty … [of] … safe."a standard equal to that of food ingredients. The standards of the proof of safety differ for various classes of FDA-regulated product categories e.g., cosmetics, dietary supplements, food ingredients and food itself. This manuscript describes the various standards of proof, the essential differences between the standards, key elements required to achieve a particular standard and, compares the standards to more familiar legal terms such as "a preponderance of the evidence" or "beyond reasonable doubt." The standards of proof for these product categories are also ranked according to increasing threshold for achievement of "safe" status. Lastly, this manuscript suggests how the requirements for the high standard of a "reasonable certainty of safe" (or "reasonable certainty of no harm") might be met.

Ensuring Clarity and Understandability of the FDA's Breast Density Notifications.

This Viewpoint discusses the use of breast density notifications to inform women with dense breast tissue of the potential need for supplemental cancer screening, as well as the need to ensure that such notifications are clear and understandable to women of all language backgrounds, literacy levels, educational levels, and socioeconomic backgrounds.

De-risking in Tier I CNS safety assessments is the primary function of study design and technical training of laboratory staff observers.

Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.S. Regulatory Agencies and the International Commission on Harmonization. The validity and reliability of the Functional Observational Batter (FOB) is critically dependent on consistency and technical quality in each risk assessment plan. US Federal and International drug approval organizations have universally adopted the concept of principles of test construction rather than delineating specific behavioral assay endpoints for inclusion of the FOB in nonclinical safety protocols. The validity and reliability of behavioral observations in standardized neurotoxicity screening is critically dependent on the FOB developed by the Study Director with the Sponsor throughout all stages of testing.. The individual risk factors selected for observation to be included in the early Tier 1 safety program should be determined by the mechanism and mode of action of the test article. The results of Tier I testing are the basis for Tier II testing designs. Critical to the compliance with Good Laboratory Practices is the documentation of training of the operational staff scheduled to conduct all aspects of the established protocol.

Assessment of black cumin (Nigella sativa L.) as a food ingredient and putative therapeutic agent.

The whole or ground seeds of the food ingredient Nigella sativa L., known in Western culture as "black cumin" or "black caraway", has a three-millennial history of use in Middle- and Far-Eastern cultures as a food ingredient. The seed and its extracts have also been increasingly reported as a successful therapeutic agent with efficacy often attributed to the presence of the powerful antioxidant, thymoquinone. However, quantitative analysis of the seed (especially the volatile fraction) yields widely variable results, which may be due to one or a combination of different crop origins or possible varietal differences, contamination/adulteration, method of extraction, stage of maturation of the extracted seed and other factors. Nonetheless, despite the reported wide variability in bioactive constituents, many publications cite quantifiable outcomes in in vitro and in vivo toxicity testing and in clinical trials. There are a few reports describing allergic reactions in humans when N. sativa extracts are applied to the skin. Notwithstanding the foregoing, N. sativa seeds, used as a food ingredient at historical levels of consumption and as traditionally practiced are safe and Generally Recognized As Safe.

Challenges in Formulating Sunscreen Products.

Developing efficient sunscreen products with an acceptable sensory feel after application on skin, that meet current regulatory market and consumer requirements, is a major challenge, exacerbated by new restrictions limiting the use of certain ingredients previously considered crucial. This paper outlines a development strategy for -formulating sunscreens along a generic professional development pathway. Each galenic system will be different and must be customized. Development starts with benchmarking, followed by UVA/UVB filter platform selection and in silico calculation/optimization of photoprotection performance for the desired SPF, UVA-PF, and other requested endpoints. Next comes the selection of the emulsifier system and other key formulation ingredients, such as oil components, triplet quenchers, and antioxidants, with sensory, rheological, and film formation functions. Preliminary cost estimation is then performed to -complete the conceptual process before the start of the practical galenic development. The successful development of modern sunscreen products is based on -comprehensive expertise in chemistry, galenic methodology, regulation, and patenting, as well as specific -market and consumer requirements. The selection of the UV filters is the first key decision and constrains later choices. Other properties, such as water resistance and preservation or active ingredients, may need to be considered. The 4 basic requirements of efficacy, safety, registration, and patent freedom become checklist items to ensure that after development, a sunscreen product has a chance of success.

The FDA Revokes Authorizations for Certain Respirators and Decontamination Systems.

Changes reflect replenished stockpiles of approved equipment.

Controversial Approval of New Drug to Treat Alzheimer's Disease.

Aducanumab (Aduhelm), the first new drug to treat Alzheimer's disease since 2003, has received accelerated approval from the Food and Drug Administration (FDA).This drug's approval has been highly contentious in the medical and scientific community owing to contradictory study findings and the FDA's advisory panel not recommending its approval.

Sunscreens and Photoaging: A Review of Current Literature.

Sunscreens have been on the market for many decades as a means of protection against ultraviolet-induced erythema. Over the years, evidence has also shown their efficacy in the prevention of photoaging, dyspigmentation, DNA damage, and photocarcinogenesis. In the USA, most broad-spectrum sunscreens provide protection against ultraviolet B (UVB) radiation and short-wavelength ultraviolet A (UVA) radiation. Evidence suggests that visible light and infrared light may play a role in photoaging and should be considered when choosing a sunscreen. Currently, there is a paucity of US FDA-approved filters that provide protection against long UVA (> 370 nm) and none against visible light. Additionally, various sunscreen additives such as antioxidants and photolyases have also been reported to protect against and possibly reverse signs of photoaging. This literature review evaluates the utility of sunscreen in protecting against photoaging and further explores the requirements for an ideal sunscreen.

A critical appraisal of Japan's new drug approval process: a case study of FLT3-ITD inhibitor quizartinib.

In the last two decades, simultaneous global development of novel drugs become more common by conducting multiregional clinical trials. However, regulatory authorities of different regions often make different decisions on the approvals of the same new drugs. We would like to discuss the appropriateness of Japanese regulatory approach through a case study of quizartinib, a novel anti-leukemia drug developed in Japan. The pivotal clinical trial "QuANTUM-R" conducted in 19 countries showed a modest increase in median overall survival with quizartinib than the conventional chemotherapy. However, because several critical defects in this trial were pointed out by the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA), quizartinib has not been approved in the US and Europe to date. On the contrary, the regulatory authority of Japan gave a notice of approval to quizartinib as a "standard of care", and the country becomes the sole country that granted market authorization. In our paper, we provide more detailed discussion about the methodology for scientific evaluation of the new drug.

Meeting Report: N-Nitrosamine Impurity Control Strategies in the Pharmaceutical and Biotechnology Industries.

The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Control (CMC) Community hosted a virtual panel discussion on December 9, 2020, to provide a forum to discuss N-nitrosamine control strategies in the pharmaceutical and biotechnology industries. The panel included staff from the US Food and Drug Administration (FDA) and industry subject matter experts. Meeting topics included acceptable intake levels for nitrosamine impurities, definitions of "acceptable level of risk," water as a contributor in nitrosamine risk assessments, nitrosamine impurity control strategies based upon fate/purge data, early vs. late development assessment expectations, application to oncology programs developed under ICH S9, and Drug Master File (DMF) regulatory expectations. During the meeting, divergence in global health authority expectations was additionally discussed. One of the most important outputs from this AAPS panel discussion was the criticality of continued dialog between industry and health authorities to help understand actual versus perceived risks and provide pragmatic, scientifically justified solutions to ensure patients are provided with an uninterrupted supply of safe medicines based on globally harmonized requirements.

Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations.

BACKGROUND: It has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice. METHODS: We searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time-to-event. We compared FI and trial and approval characteristics using Mann-Whitney U and Kruskal-Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow-up (WCLFU) exceeding the calculated FI. RESULTS: The median FI among 125 included studies was 23 (range 1-322). The FI was ≤10 in 35 studies (28%), 11-20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1-51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p < 0.001). In a sensitivity analysis including only studies with 1:1 randomization, 51% of studies had WCLFU >FI. CONCLUSION: The median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm.