An Insight Into Risk Assessment and Reformulation of Drug Products Manufactured Using Benzene Grade Carbomer: A Regulatory Perspective.

Cancer has been an enormous pain point for patients and regulatory bodies across the globe. In Dec. 2023, the US FDA released guidance on benzene-grade carbomer formulations, which triggered pharmaceutical manufacturers to assess risk, test finished products, and reformulate drug products with benzene-grade carbomer. The immediate implementation of the stoppage of finished products with benzene-grade carbomers has threatened pharmaceutical excipients and finished product manufacturers. The gravity of this situation prompted the US Pharmacopeia to extend the deadline for discontinuation from August 1, 2025, to August 1, 2026, allowing manufacturers ample time for reformulation and regulatory compliance.There is an immediate need to understand the guidance and to learn how manufacturers should do the risk assessment and approach reformulation. This review provides an in-depth analysis of the risk assessment and reformulation processes involved in various dosage forms utilizing benzene-grade carbomer, supported by specific case studies.This review offers insights into navigating the USFDA guidelines to ensure formulation safety and compliance, thus enabling pharmaceutical practitioners to uphold the highest standards of patient care and tackle life cycle management challenges.The decision of the USFDA to restrict the usage of high benzene content of carbomer in the formulation is a welcome move. This article has shown a way for researchers to see opportunities in the path and provide best-in-class medicines to patients with a better formulation safety profile.

Clarifications on the Intended Use of USP <61> Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests.

In the execution of its legislated responsibilities, the United States Food and Drug Administration commonly refers to standard test methods detailed in the United States Pharmacopeia (USP). Microbiological test methods (contained in general chapters) are listed in chapters <51> to <80> with details regarded as enforceable where referenced as a test method. USP <61> "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests" is a globally harmonized chapter that has been successfully employed for the enumeration of microorganisms recoverable from nonsterile finished drug products. The content of USP <61> is not always scientifically principled nor emphatically understood by all pharmaceutical microbiologists. Consequently, misunderstanding and misapplication of USP <61> may result in analyses and assessments of microbiological quality that are flawed or erroneous. In this article, clarification is provided to assist the pharmaceutical microbiologist in the appropriate and intended use of USP <61>, including provision of details not always commonly known or understood.

Fosamax Fractures-Justice Has Not Been Served.

This Viewpoint discusses the ongoing lawsuit between plaintiffs who had been affected by atypical femoral fractures while receiving alendronate and the drug manufacturer.

Transparency, reproducibility, and replicability of pharmacoepidemiology studies in a distributed network environment.

PURPOSE: Our objective is to describe how the U.S. Food and Drug Administration (FDA)'s Sentinel System implements best practices to ensure trust in drug safety studies using real-world data from disparate sources. METHODS: We present a stepwise schematic for Sentinel's data harmonization, data quality check, query design and implementation, and reporting practices, and describe approaches to enhancing the transparency, reproducibility, and replicability of studies at each step. CONCLUSIONS: Each Sentinel data partner converts its source data into the Sentinel Common Data Model. The transformed data undergoes rigorous quality checks before it can be used for Sentinel queries. The Sentinel Common Data Model framework, data transformation codes for several data sources, and data quality assurance packages are publicly available. Designed to run against the Sentinel Common Data Model, Sentinel's querying system comprises a suite of pre-tested, parametrizable computer programs that allow users to perform sophisticated descriptive and inferential analysis without having to exchange individual-level data across sites. Detailed documentation of capabilities of the programs as well as the codes and information required to execute them are publicly available on the Sentinel website. Sentinel also provides public trainings and online resources to facilitate use of its data model and querying system. Its study specifications conform to established reporting frameworks aimed at facilitating reproducibility and replicability of real-world data studies. Reports from Sentinel queries and associated design and analytic specifications are available for download on the Sentinel website. Sentinel is an example of how real-world data can be used to generate regulatory-grade evidence at scale using a transparent, reproducible, and replicable process.

Urgent Need for Regulatory Oversight of Human Cells, Tissues, and Cellular and Tissue-Based Products.

This Viewpoint discusses the death of a patient caused by unregulated biological products and efforts to encourage federal government oversight of such products.

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.

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.

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.

Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma Clinical Trials: An FDA Educational Symposium.

In October 2022, the FDA Oncology Center of Excellence hosted an educational symposium entitled, "Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma (pLGG) Clinical Trials." The symposium brought together patient advocates, regulators from the FDA and the European Medicines Agency (EMA), and an international group of academic thought leaders in the field of pediatric neuro-oncology to discuss the potential role of functional outcomes, including visual acuity, motor function, and neurocognitive performance, as endpoints in clinical trials enrolling patients with pLGG. The panel discussed challenges and opportunities regarding the selection, implementation, and evaluation of clinical outcome assessments in these functional domains and outlined key considerations for their inclusion in future clinical trial design and role in new drug development.

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.