Another Monoclonal Antibody Granted EUA to treat COVID-19.

The Food and Drug Administration has granted emergency use authorization to sotrovimab for the treatment of mild to moderate COVID-19 in patients at increased risk for progression to severe illness.Sotrovimab is a monoclonal antibody that works directly against the spike protein of SARS-CoV-2 to block its attachment and entry into a human cell.

A Decade of FDA-Approved Drugs (2010-2019): Trends and Future Directions.

A total of 378 novel drugs and 27 biosimilars approved by the U.S. Food and Drug Administration (FDA) between 2010 and 2019 were evaluated according to approval numbers by year, therapeutic areas, modalities, route of administration, first-in-class designation, approval times, and expedited review categories. From this review, oncology remains the top therapy area (25%), followed by infection (15%) and central nervous system disorders (11%). Regulatory incentives have been effective as evidenced by an increase in orphan drugs as well as antibacterial drugs approved under the GAIN act. Clinical development times may be increasing, perhaps as a result of the increase in orphan drug indications. Small molecules continue to mostly adhere to "Rule of 5" (Ro5) parameters, but innovation in new modalities is rapidly progressing with approvals for antisense oligonucleotides (ASO), small-interfering RNA (siRNAs), and antibody-directed conjugates (ADCs). Finally, novel targets and scientific breakthroughs that address areas of unmet clinical need are discussed in detail.

The Influence of the Food and Drug Administration Pregnancy and Lactation Labeling Rule on Drug Information Resources.

BACKGROUND: Drug information resources are commonly used by health-care providers answering pregnancy-related medication questions. In 2015, the United States Food and Drug Administration approved a new pregnancy and lactation medication labeling content and format, removing the pregnancy category, and using a narrative. Despite labeling requirements changing, it is unknown if drug information resources updated monographs to reflect these changes. OBJECTIVE: The primary objective was to evaluate if commonly used drug information resources provide pregnancy information listed similar to the requirements of the Pregnancy and Lactation Labeling Rule (PLLR). Secondary analyses included evaluating the references and inclusion of the pregnancy category rating. METHODS: Pregnancy recommendations for 23 medications were evaluated in 9 drug information resources (Clinical Pharmacology, Drugs in Pregnancy and Lactation, Epocrates®, First Databank, LexiComp® Online, LexiComp® Online Pregnancy & Lactation, In-Depth, Medi-Span®, Micromedex®, and Multum®). The number of references per drug monograph and most recent reference publication year was obtained. RESULTS: LexiComp® Online Pregnancy & Lactation, In-Depth mimics the new PLLR structure and consistently had the highest number of and most recent references when the medication was included. Drugs in Pregnancy and Lactation was the next most similar in content with the PLLR and second in most references per monograph; however, the most recent reference was the textbook publication year. CONCLUSION AND RELEVANCE: LexiComp® Online Pregnancy & Lactation, In-Depth and Drugs in Pregnancy and Lactation provided pregnancy information in a format most similar to the PLLR. However, several drug information resources contained pregnancy categories ratings that were to be removed from medication labeling per the PLLR.

Global Regulatory Review Needed for Cochlear Implants: A Call for FDA Leadership.

INTRODUCTION: Using the United States Food and Drug Administration (FDA) as example, we argue that regulatory agencies worldwide should review their guidance on cochlear implants (CIs). METHODS: This is a position paper, thus the methods are strictly argumentation. Here we give the motivation for our recommendation. The FDA's original approval of implantation in prelingually deaf children was granted without full benefit of information on language acquisition, on childcaregiver communication, and on the lived experience of being deaf. The CI clinical trials, accordingly, did not address risks of linguistic deprivation, especially when the caregiver's communication is not fully accessible to the prelingually deaf child. Wide variability in the effectiveness of CIs since initial and updated approval has been indicated but has not led to new guidance. Children need to be exposed frequently and regularly to accessible natural language while their brains are still plastic enough to become fluent in any language. For the youngest infants, who are not yet producing anything that could be called language although they might be producing salient social signals (Goldstein et al. Child Dev 80:636-644, 2009), good comprehension of communication from caregiver to infant is critical to the development of language. Sign languages are accessible natural languages that, because they are visual, allow full immersion for deaf infants, and they supply the necessary support for this comprehension. The main language contributor to health outcomes is this combination of natural visual language and comprehension in communication. Accordingly, in order to prevent possible language deprivation, all prelingually deaf children should be exposed to both sign and spoken languages when their auditory status is detected, with sign language being critical during infancy and early childhood. Additionally, all caregivers should be given support to learn a sign language if it is new to them so that they can comprehend their deaf children's language expressions fully. However, both languages should be made accessible in their own right, not combined in a simultaneous or total communication approach since speaking one language and signing the other at the same time is problematic. RESULTS: Again, because this is a position paper, our results are our recommendations. We call for the FDA (and similar agencies in other countries) to review its approval of cochlear implantation in prelingually deaf children who are within the sensitive period for language acquisition. In the meantime, the FDA should require manufacturers to add a highlighted warning to the effect that results with CI vary widely and CIs should not be relied upon to provide adequate auditory input for complete language development in all deaf children. Recent best information on users' experience with CIs (including abandonment) should be clearly provided so that informed decisions can be made. The FDA should require manufacturers' guidance and information materials to include encouragement to parents of deaf children to offer auditory input of a spoken language and visual input of a sign language and to have their child followed closely from birth by developmental specialists in language and cognition. In this way parents can align with providers to prioritize cognitive development and language access in both audio-vocal and visuo-gestural modalities. DISCUSSION: The arguments and recommendations in this paper are discussed at length as they come up.

A Call to Action to Track Generic Drug Quality Using Real-World Data and the FDA's Sentinel Initiative.

DISCLOSURES: The author reports funding from the U.S. Food and Drug Administration to study real-world data approaches to detect generic drug quality issues. There are no further conflicts or disclosures.

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

PURPOSE: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. METHODS: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. RESULTS: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. CONCLUSION: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.

Ten-Year Trends in Enrollment of Women and Minorities in Pivotal Trials Supporting Recent US Food and Drug Administration Approval of Novel Cardiometabolic Drugs.

Background In 1993, the US Food and Drug Administration established guidelines to increase diversity by sex and race/ethnicity of participants in clinical trials supporting novel drug approvals. In this study we investigated the 10-year trends of participation of women and minorities in pivotal trials supporting approval of new molecular entities in cardiometabolic drugs from January 2008 to December 2017. Methods and Results A list of new molecular entities was abstracted from publicly available data at Drugs@Fda. Sex and race/ethnicity data were collected from trial publications. Linear regression analysis was performed to assess the relation between drug approval year and proportion of women and minorities enrolled. Thirty-five novel cardiovascular (n=24) and diabetes mellitus (n=11) drugs were approved by the US Food and Drug Administration during the study period. The median number of participants supporting each drug was 5930 (interquartile range, 3175-10 942). Women represented 36% (n=108 052) of trial participants (n=296 163). Women were underrepresented compared with their proportion of the disease population in trials of coronary heart disease (participation-to-prevalence ratio, 0.52), heart failure (participation-to-prevalence ratio, 0.58), and acute coronary syndrome (participation-to-prevalence ratio, 0.68). Among trial participants, 81% were white, 4% black, 12% Asian, and 11% Hispanic/Latino. There was no significant association between enrollment of women (P=0.29) or underrepresented minorities (P=0.45) with the drug approval year. Conclusions Over the past decade (2008-2017), women and minorities, particularly blacks, have continued to be inadequately represented in pivotal cardiometabolic clinical trials that support US Food and Drug Administration approval of new molecular entities. This may have major implications in determining efficacy of such therapies in these groups, and may impair generalizability of trial results to routine clinical practice.

Translational Knowledge Discovery Between Drug Interactions and Pharmacogenetics.

Clinical translation of drug-drug interaction (DDI) studies is limited, and knowledge gaps across different types of DDI evidence make it difficult to consolidate and link them to clinical consequences. Consequently, we developed information retrieval (IR) models to retrieve DDI and drug-gene interaction (DGI) evidence from 25 million PubMed abstracts and distinguish DDI evidence into in vitro pharmacokinetic (PK), clinical PK, and clinical pharmacodynamic (PD) studies for US Food and Drug Administration (FDA) approved and withdrawn drugs. Additionally, information extraction models were developed to extract DDI-pairs and DGI-pairs from the IR-retrieved abstracts. An overlapping analysis identified 986 unique DDI-pairs between all 3 types of evidence. Another 2,157 and 13,012 DDI-pairs and 3,173 DGI-pairs were identified from known clinical PK/PD DDI, clinical PD DDI, and DGI evidence, respectively. By integrating DDI and DGI evidence, we discovered 119 and 18 new pharmacogenetic hypotheses associated with CYP3A and CYP2D6, respectively. Some of these DGI evidence can also aid us in understanding DDI mechanisms.

Pharmacogenomic biomarker information differences between drug labels in the United States and Hungary: implementation from medical practitioner view.

Pharmacogenomic biomarker availability of Hungarian Summaries of Product Characteristics (SmPC) was assembled and compared with the information in US Food and Drug Administration (FDA) drug labels of the same active substance (July 2019). The level of action of these biomarkers was assessed from The Pharmacogenomics Knowledgebase database. From the identified 264 FDA approved drugs with pharmacogenomic biomarkers in drug label, 195 are available in Hungary. From them, 165 drugs include pharmacogenomic data disposing 222 biomarkers. Most of them are metabolizing enzymes (46%) and pharmacological targets (41%). The most frequent therapeutic area is oncology (37%), followed by infectious diseases (12%) and psychiatry (9%) (p < 0.00001). Most common biomarkers in Hungarian SmPCs are CYP2D6, CYP2C19, estrogen and progesterone hormone receptor (ESR, PGS). Importantly, US labels present more specific pharmacogenomic subheadings, the level of action has a different prominence, and offer more applicable dose modifications than Hungarians (5% vs 3%). However, Hungarian SmPCs are at 9 oncology drugs stricter than FDA, testing is obligatory before treatment. Out of the biomarkers available in US drug labels, 62 are missing completely from Hungarian SmPCs (p < 0.00001). Most of these belong to oncology (42%) and in case of 11% of missing biomarkers testing is required before treatment. In conclusion, more factual, clear, clinically relevant pharmacogenomic information in Hungarian SmPCs would reinforce implementation of pharmacogenetics. Underpinning future perspective is to support regulatory stakeholders to enhance inclusion of pharmacogenomic biomarkers into Hungarian drug labels and consequently enhance personalized medicine in Hungary.

Workshop Report: FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms.

Given that cardiovascular safety concerns remain the leading cause of drug attrition at the preclinical drug development stage, the National Center for Toxicological Research of the US Food and Drug Administration hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development. The main conclusion is that to reduce cardiovascular safety liabilities of new therapeutic agents, there is an urgent need to integrate human-relevant platforms/approaches into drug development. Potential regulatory applications of human-derived cardiomyocytes and future directions in employing human-relevant platforms to fill the gaps and overcome barriers and challenges in preclinical cardiovascular safety assessment were discussed. This paper is intended to serve as an initial step in a public-private collaborative development program for human-relevant cardiotoxicity tools, particularly for cardiotoxicities characterized by contractile dysfunction or structural injury.

Teaching non-FDA approved nonprescription products: Educating students about potential risks and liability.

INTRODUCTION: University professors who teach self-care and nonprescription products must decide which products and ingredients to recommend to students. The Food and Drug Administration (FDA) has approved many nonprescription ingredients as both safe and effective through the evidence-based FDA Over-the-Counter (OTC) Product Review or New Drug Application (NDA) processes. However, thousands of nonprescription products sold in community pharmacies are of unproven safety and/or efficacy. These include herbs, dietary supplements, homeopathic products, and essential oils. Selling products of unproven safety and/or efficacy can have serious consequences, exposing pharmacists to legal liability due to violations of the principles of implied and/or express warranties, as found in the Uniform Commercial Code. Further, the FDA defines products lacking proven safety and efficacy as health fraud, a crime aggressively pursued by both the FDA and the Federal Trade Commission. COMMENTARY: Faculty members who limit their nonprescription ingredient recommendations to those with FDA approval can justify those recommendations by weight of evidence. If the faculty member recommends ingredients that the FDA has not approved (e.g., kava), students should be taught that those ingredients pose unknown risks and lack proven benefit, and also that their labels virtually always lack doses proven to be safe, precautions, contraindications, and drug interactions. IMPLICATIONS: Selling unproven products can lower trust in pharmacy, cause patient harm, and expose the pharmacist to legal action. These issues should be explained to students whenever unproven products are discussed or recommended.

Endocrine disruptors and the future of toxicology testing - lessons from CLARITY-BPA.

Five years ago, an ambitious collaboration, the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA; henceforth CLARITY), was launched by three US agencies. The goal was to provide a definitive evaluation of bisphenol A (BPA) and explain disparities between traditional regulatory studies and findings from independent investigators. BPA or vehicle-treated rats from an FDA facility were used in a guideline study and animals and/or tissues were provided to academic researchers for analysis. An interim summary released in February 2018 by the FDA concluded that currently authorized uses of BPA continue to be safe. We disagree. In this Perspectives, we summarize the goals, design and problems of CLARITY. We conclude that, despite its flaws, CLARITY provides important insight and, taken together, the data provide compelling evidence that low-dose BPA exposure induces marked adverse effects. Indeed, the greatest number of effects were observed at doses 20,000 times lower than the current 'safe' dose of BPA for humans.