Spectrum of psychiatric adverse reactions to cyclin-dependent kinases 4/6 inhibitors: A pharmacovigilance analysis of the FDA adverse event reporting system.

BACKGROUND: The emergence of cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) represented a major breakthrough in the treatment of breast cancer over the past decade. In both clinical trials and real-world settings, it was observed that patients using CDK4/6i might experience psychiatric adverse events (PAEs). Herein, we conducted a pharmacovigilance study to comprehensively assess the correlation between CDK4/6i and PAEs. METHOD: We obtained individual case safety reports submitted to the FDA Adverse Events Reporting System (FAERS) during the period from January 2015 to December 2023. In disproportionality analysis, the reporting odds ratio (ROR) and information component (IC) values were calculated for each adverse event-drug combination. Univariate logistic regression analysis was utilized to explore factors associated with PAEs following CDK4/6i treatment. RESULTS: A total of 95,591 reports related to CDK4/6i were identified, with 6.72% reporting PAEs, and this proportion exhibited an annual upward trend. Based on the ROR and IC values, 17 categories of PAEs were defined as CDK4/6i-related PAEs. Among these PAEs, insomnia, stress, eating disorder, depressed mood, and sleep disorder were very common, each accounting for over 10% of CDK4/6i reports. Ribociclib showed the highest risk signal of CDK4/6i-related PAEs (ROR = 1.89[1.75-2.04], IC025 = 0.79), followed by palbociclib (ROR = 1.47[1.41-1.53], IC025 = 0.49), while abemaciclib did not exhibit a significant signal (ROR = 0.52[0.44-0.62], IC025 = -1.13). Female sex, younger age and weight exceeding 80 kg were significant risk factors for the incidence of CDK4/6i-related PAEs. CONCLUSIONS: Using data from a real-world, large-scale spontaneous reporting system for adverse drug reactions, our study delineated the spectrum of PAEs to CDK4/6i. This potentially offered valuable insights for healthcare professionals to manage the risk of PAEs in patients receiving CDK4/6i treatment, particularly those with psychiatric disorders.

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.

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.

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.

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.

Potential Mandated Lowering of Nicotine Levels in Cigarettes: A Plant Perspective.

The Food and Drug Administration has announced the potential for mandated lowering of nicotine levels in combustible cigarettes. The World Health Organization has recommended a lowering of cigarette filler nicotine levels to below 0.4 mg/g. To devise appropriate nicotine control strategies, regulators must consider technical feasibility, timelines for compliance, and potential impediments to implementation. Outlined here is previously unsummarized information on genetic approaches that might be used to reduce nicotine levels in cured tobacco leaves. For the benefit of regulators, altered alkaloid or toxicant profiles that might result by implementation of some of these methodologies are discussed. Also mentioned are potential licensing or regulatory impediments to use of some of the technologies per se. Implications: An understanding of technical feasibility of plant-based nicotine reduction technologies, along with the potential for corresponding alterations in alkaloid or toxicant profiles, is needed by regulators to develop effective nicotine control strategies with minimal impediments or undesirable consequences.

Reduced-Risk Warnings Versus the US FDA-Mandated Addiction Warning: The Effects of E-Cigarette Warning Variations on Health Risk Perceptions.

INTRODUCTION: Research on electronic cigarette (e-cigarette) warnings has primarily focused on addiction warnings, such as the one soon to be required by the Food and Drug Administration (FDA) in the United States. However, reduced-risk warnings, similar to the warnings recently proposed for smokeless tobacco products, remain a future possibility for e-cigarettes. Thus, this brief report compares e-cigarette health risk perceptions based on reduced-risk warnings and the FDA addiction risk warning, and considers whether these warnings differ in believability, ease of comprehension, and perceptions about the clarity of risk communication. METHODS: A quota sample of 672 smokers, e-cigarette users, dual users, and nonusers participated in this between-subjects experiment. Study participants were randomly assigned to one of three warning conditions, including the FDA-mandated addiction warning and two reduced-risk warnings. After exposure to the warning statement, participants responded to measures of health risk perceptions, believability, ease of comprehension, and perception about the clarity of risk communication. RESULTS: Results reveal that the addiction warning is perceived as more believable, easier to comprehend, and more clearly communicating the health risks of e-cigarettes use compared with the reduced-risk warnings. In addition, overall health risk perceptions and addiction risk perceptions based on the addiction warning are greater than health risk perceptions based on the reduced-risk warnings. In contrast, specific disease-related risk perceptions such as cancer, heart disease, lung disease, and harm to an unborn baby are greater for the reduced-risk warnings. CONCLUSIONS: This study provides a comparison of the forthcoming FDA-mandated e-cigarette addiction warning and reduced-risk warnings that have begun to be considered in the literature on a number of critical outcomes. IMPLICATIONS: This research provides a greater understanding of how variations of e-cigarette warnings, including addiction and reduced-risk warnings, are perceived by smokers, e-cigarette users, dual users, and nonusers. Specifically, findings show that overall health risk perceptions and addiction risk perceptions based on the addiction warning are greater than risk perceptions based on the reduced-risk warnings. In contrast, specific disease-related risk perceptions, such as cancer and heart disease, are greater for the reduced-risk warnings.

E-cigarette Use Among US Adults: Population Assessment of Tobacco and Health (PATH) Study.

Introduction: In 2011 the US Food and Drug Administration launched the Population Assessment of Tobacco and Health (PATH) Study to gather information for regulatory activities authorized by the Family Smoking Prevention and Tobacco Control Act (TCA). Methods: Data were drawn from the first wave of the PATH survey, involving interviews of 32 320 civilian and non-institutionalized adults. In addition to conventional classifications for current, former and never smoking and e-cigarette use, we used PATH questions to classify former and current triers of these products. Descriptive statistics were used to describe the prevalence, patterns of, and reasons for e-cigarette use, and the perceptions of nicotine and e-cigarettes among user groups, according to smoking status. Results: The prevalence of current smoking was 18%; an additional 3.1% of participants were current triers. The prevalence of current e-cigarette use was 2.4% (1.0% every day, 1.4% some days), with another 3.2% as current triers. The majority of nonsmokers who were current e-cigarette users were already current (56%) or former (34%) cigarette triers. Reasons for e-cigarette use were similar across subgroups, but patterns of use were different. Majorities of participants believed that nicotine is the main substance driving tobacco use, that nicotine causes most cancers, and that e-cigarettes were less harmful than cigarettes. Conclusions: E-cigarettes were used primarily by current smokers and recent former smokers. The main reasons for use center around perceptions that e-cigarettes are less harmful than cigarettes to users and others. Implications: This study reports detailed information about the prevalence, patterns of, and reasons for e-cigarette use in the first (baseline) wave of the PATH Study in 2014. In addition to conventional categories for current, former and never smoking and e-cigarette use, the PATH questionnaire facilitated classification of new usage groups consisting of current and former triers of these products, which may impact prevalence estimates.

FDA's regulatory shift on tobacco control.

In July 2017, the Food and Drug Administration (FDA) announced that it wants to reduce the nicotine in cigarettes to make them less addictive. Also, it is delaying for several years a key regulation affecting cigars and e-cigarettes, including flavored vaping products that tend to appeal to younger consumers. Specifically, it postponed the requirement that such products be approved by the agency. Both actions are part of a comprehensive plan to eventually wean smokers off conventional cigarettes and steer them toward less harmful alternative forms of nicotine. With its new approach to the fight against smoking, the FDA has unquestionably made great strides toward more effectively addressing the prevalence of related deaths and diseases in the U.S. However, much important work must be undertaken before this ultimate goal can be accomplished. For instance, further research into long-term effects of e-cigarettes must be conducted before these products can truly be seen as safer alternatives to combustible cigarettes. Additionally, public education is necessary to inform smokers about the range of tobacco products available and the actual harms associated with their use. Finally, the agency might have to work alongside the powerful tobacco industry to minimize potential legal challenges and to convince businesses that a shift to low-nicotine products and e-cigarettes is best for their future success and for the health of the American citizenry.

Serious Adverse Drug Events Reported to the FDA: Analysis of the FDA Adverse Event Reporting System 2006-2014 Database.

BACKGROUND: Data on adverse drug events (ADEs) observed at the population level provide important evidence regarding the safety of a pharmaceutical product in real-world settings. Recent patterns in serious and fatal ADE reporting have not been documented. OBJECTIVE: To assess recent patterns in serious and fatal ADE reports in the United States. METHODS: We conducted a retrospective analysis of the publicly available 2006-2014 FDA Adverse Event Reporting System database. Non-U.S. reports, reports from clinical trials, and reports with missing outcome data were excluded. The annual numbers of ADEs with reported outcome of death, disability, and other serious outcomes were determined. Types (direct, manufacturer expedited, or manufacturer periodic) and sources (consumer, health professional, or other) of these serious ADE reports were also identified. The distribution of serious ADE reports by patient age groups (< 18, 18-44, 45-64, and ≥ 65 years) was determined. Drugs listed as primary suspects in serious ADEs (death, disability, and other serious outcomes) were identified and ranked. Descriptive statistics were used to characterize the patterns in serious or fatal ADE reporting. RESULTS: From 2006 to 2014, the number of serious ADEs reported to the FDA increased 2-fold. A total of 902,323 serious outcomes were reported over the 9-year study period: 244,408 deaths, 72,141 disabilities, and 585,774 other serious outcomes. The relative percentage of reports of deaths was highest during 2012 (32.4%). The percentage of reports of disability was highest during 2006 (12.1%). Overall, the "other serious outcomes" category accounted for almost 65% of serious ADEs reports. Expedited reports from drug manufacturers were most common (about 72%) of the serious ADEs with available data on report type. Health professionals (47.3%) were the most common source of report followed by consumers (36.1%) and other sources (16.6%). A disproportionately high number of reported ADEs was among patients aged 45-64 years (40%) and ≥ 65 years (32.6%). Antineoplastic drugs were more frequently reported with deaths. Three antidepressant drugs were among the top 10 drugs reported with disability. During 2006-2014, there were 38 drugs with more than 1,000 reports of serious ADEs in a given year: 2 drugs currently withdrawn from the market (rofecoxib and parecoxib), 10 drugs with an FDA risk evaluation and mitigation strategies (REMS) program, 13 biologic or specialty drugs, and 14 others. CONCLUSIONS: An overall increase in the trend of the number of serious ADE reports was observed from 2006 to 2014. Drugs with a REMS program and biologic and specialty drugs were involved in a significant number of reported serious ADEs. Data on reporting patterns can guide surveillance and pharmacoepidemiological studies to understand the public health burden of serious ADEs. DISCLOSURES: No outside funding supported this study. Hansen has received consulting fees from and has provided expert testimony for Daichii Sankyo and Takeda. The other authors have nothing to disclose.

2017 in review: FDA approvals of new molecular entities.

An overview of drugs approved by the FDA in 2017 reflected a reversion to the mean after a low number of NME approvals in 2016. This reversal was largely driven by the largest number of biologics-based NMEs recorded to date, which offset an average number of small-molecule approvals. Oncology indications continued to dominate followed by novel treatments for infectious, immunologic and neurologic diseases. From a mechanistic standpoint, the industry has continued a trend of target diversification, reflecting advances in scientific understanding of disease processes. Finally, 2017 continued a period of relatively few mergers and acquisitions, which broke a more-than-a-decade-long decline in the number of organizations contributing to research and development.

US Adult Cigar Smoking Patterns, Purchasing Behaviors, and Reasons for Use According to Cigar Type: Findings From the Population Assessment of Tobacco and Health (PATH) Study, 2013-2014.

Introduction: The US cigar market is diverse, yet until recently most research studies and tobacco surveillance systems have not reported behavioral and related outcomes by cigar type. Methods: The 2013-2014 Population Assessment of Tobacco and Health Study collected data separately for filtered cigars (FCs), cigarillos, and traditional cigars, which were further distinguished as premium or nonpremium. Descriptive statistics for adult established current smokers of each cigar type and cigarettes were calculated for demographic characteristics, tobacco use patterns, purchasing behaviors and reasons for use. Adjusted prevalence ratios (APRs) using a marginal predictions approach with logistic regression assessed correlates of dual cigar and cigarette smoking. Results: Age, sex, race/ethnicity, education level, and poverty status of smokers varied according to cigar type. Daily cigar smoking prevalence and number of cigars smoked per day were higher for FCs (37.3%; median: 1.6 cigars/day, respectively), than all other cigar types (6.7%-25.3%, all p < .01; 0.1-0.4 cigars/day, all p < .01, respectively); daily smoking and cigars per day were similar for nonpremium cigars and cigarillos (p = .11; p = .33, respectively). Cigarette smoking was twice as common among smokers of nonpremium cigars, cigarillos, and FCs (58.0%-66.0%) than among premium cigars (29.9%). Among current cigar smokers, FC smokers (APR = 1.23, 95% confidence interval [CI] = 1.09-1.39), other tobacco product users (APR = 1.27, 95% CI = 1.15-1.41), and those with a GED/high school diploma or less (APR = 1.20, 95% CI = 1.09-1.33) were more likely to also smoke cigarettes. Conclusion: User characteristics, cigar smoking patterns, and dual smoking with cigarettes varied by cigar type highlighting the importance of adequately describing the cigar type studied and, where appropriate, differentiating results by cigar type. Implications: Despite the diversity of the cigar market place, historically many research studies and tobacco surveillance systems have treated cigars as a single product type. This study describes similarities and differences in the user characteristics, tobacco use patterns, and purchasing behaviors of premium, nonpremium, cigarillo, and filtered cigar smokers. To enhance tobacco regulatory science, sufficient descriptions of the cigar type(s) studied and, where appropriate, differentiation of the particular cigar type(s) studied should be undertaken to improve the interpretation of study findings, understanding of cigar use patterns and related behaviors and future approaches to reducing cigar-attributable morbidity and mortality.

Strategies to Maximize Patient Participation in Clinical Trials.

Despite considerable interest and success in oncology drug development, the minority of patients with cancer diagnoses enroll in clinical trials. Multiple obstacles account for this low enrollment rate. An improvement in patient participation in clinical trials could increase patient access to novel and potentially promising agents, provide faster trial results, and, with implementation of rational eligibility criteria, allow for a better understanding of the drug's safety and efficacy in a heterogeneous population. We present barriers and potential solutions to maximize patient participation, including a review of the ASCO and Friends of Cancer Research (FoCR) Modernizing Eligibility Criteria Project, U.S. Food and Drug Administration (FDA) regulatory considerations, an industry perspective, and a patient perspective.

Commentary on R&D Trends Away from General Medicine/Cardiovascular Drugs: Can the FDA Help Reverse the Trend?

In the latter part of the 20th century, drug development in cardiovascular diseases (CVDs) was a paragon of "modern" therapeutics, bringing about a substantial number of effective, well-tolerated agents targeting some of the most prevalent diseases of the Western world. These drugs were often examples of rational drug development targeting specific pathophysiologic pathways previously elucidated through basic research (e.g., targeting of the renin-angiotensin system or the cholesterol synthesis pathway). The widespread adoption of these ground-breaking medications in practice and into medical guidelines undoubtedly played a role in the fall of morbidity and mortality from CVD in the United States in recent decades. For instance, the combined, age-adjusted rates of death due to heart disease and CVD fell in the United States from an aggregate of 329.6 per 100,000 in 1999 to 203.5 in 2014. Although lifestyle trends (e.g., decreased smoking prevalence) contributed to this decline, the impact of safe and effective medications for common CVD conditions cannot be dismissed. Yet, despite the drop in CVD morbidity and mortality, CVDs remain a leading cause of morbidity and mortality in the United States and, therefore, a large area of unmet medical need.

Trends in utilization of smoking cessation agents before and after the passage of FDA boxed warning in the United States.

BACKGROUND: In 2009, the FDA required a black box warning (BBW) on bupropion and varenicline, the two commonly prescribed smoking cessation agents due to reports of adverse neuropsychiatric events. We investigated if there was a decline in use of bupropion and varenicline after the BBW by comparing the percent using these medications before and after BBW. METHODS: We conducted a retrospective observational study using data from the Medical Expenditure Panel Survey from 2007 to 2014. The study sample consisted of adult smokers, who were advised by their physicians to quit smoking. We divided the time period into "pre-warning", "post-warning: immediate", and "post-warning: late." Unadjusted analysis using chi-square tests and adjusted analyses using logistic regressions were conducted to evaluate the change in bupropion and varenicline use before and after the BBW. Secondary analyses using piecewise regression were also conducted. RESULTS: On an average, 49.04% of smokers were advised by their physicians to quit smoking. We observed a statistically significant decline in varenicline use from 22.1% in year 2007 to 9.23% in 2014 (p value<0.001). In the logistic (Adjusted Odds Ratio=0.36, 95% CI=0.22-0.58) and piecewise regressions (Odds Ratio=0.64, 95% CI=0.41-0.99) smokers who were advised to quit smoking by their physicians were less likely to use varenicline in the immediate post-BBW period as compared to pre-BBW period. While the use of varenicline continued to be significantly low in the late post-BBW period (AOR=0.45, 95% CI=0.31-0.64) as compared to the pre-BBW period, the trend in use as seen in piecewise regression remained stable (OR=0.90, 95% CI=0.75-1.06). We did not observe significant differences in bupropion use between the pre- and post-BBW periods. CONCLUSION: The passage of the FDA boxed warning was associated with a significant decline in the use of varenicline, but not in the use of bupropion.