US Food Research Articles

Ranolazine New Potential Therapeutic Aspects

Since Ranolazine approval as an antianginal medication by the US Food and Drug Administration in 2006, it has been administered to specific patient populations with stable angina. Originally, it was thought that ranolazine's therapeutic actions were due to its inhibition of the metabolism of fatty acids. However, as research progressed, it became clear that ranolazine's primary advantageous benefits come from its influence on the heart's late sodium current. Numerous experimental and clinical studies have tested ranolazine either directly or indirectly on heart failure since late-sodium currents have been found to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure. The inhibition of the underlying mechanisms of cardiac remodeling, such as ion disruptions, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal dysfunction, by ranolazine is reviewed after any kind of severe injury, along with open questions. Ranolazine additional metabolic properties contribute to its efficacy in treating conditions other than coronary artery disease. Our publication will focus on potential therapeutic applications of ranolazine, extending beyond cardiology.

Non/Low-Caloric Artificial Sweeteners and Gut Microbiome: From Perturbed Species to Mechanisms.

Non/low-caloric artificial sweeteners (NAS) are recognized as chemical additives substituting sugars to avoid caloric intake and subsequent sugar-derived diseases such as diabetes and hyperglycemia. Six NAS have been claimed safe and are authorized by the US Food and Drug Administration (FDA) for public use, with acceptable daily intake information available: aspartame, acesulfame-K, saccharin, sucralose, neotame, and advantame. However, the impacts of NAS on the gut microbiome have raised potential concerns, since sporadic research revealed NAS-induced microbial changes in the gastrointestinal tracts and alterations in the microbiome-host interactive metabolism. Given the fact that the gut microbiome influences kaleidoscopic physiological functions in host health, this review aimed to decipher the impacts of NAS on the gut microbiome by implementing a comprehensive two-stage literature analysis based on each NAS. This review documented disturbed microbiomes due to NAS exposure to a maximal resolution of species level using taxonomic clustering analysis, and recorded metabolism alterations involved in gut microbiome-host interactions. The results elucidated that specific NAS exhibited discrepant impacts on the gut microbiome, even though overlapping on the genera and species were identified. Some NAS caused glucose tolerance impairment in the host, but the key metabolites and their underlying mechanisms were different. Furthermore, this review embodied the challenges and future directions of current NAS-gut microbiome research to inspire advanced examination of the NAS exposure-gut microbiome-host metabolism axis.

Cost-effectiveness of iptacopan for paroxysmal nocturnal hemoglobinuria

AbstractIptacopan, a novel oral factor B inhibitor, recently obtained US Food and Drug Administration approval for treating paroxysmal nocturnal hemoglobinuria, a rare blood disorder characterized by persistent complement-mediated hemolytic anemia. The standard-of-care (SOC) has traditionally relied on complement C5 inhibitors eculizumab and ravulizumab, which are limited by persistent anemia from extravascular hemolysis and requirement for intravenous infusion. Recent publication of phase 3 studies in this arena reinforces iptacopan as an effective anticomplement monotherapy compared with SOC. Given ongoing price negotiations and limited literature showing its cost-ineffectiveness in the anti-C5–treated population, we conducted a comprehensive cost-effectiveness analysis of iptacopan monotherapy in anti-C5–treated patients from the societal perspective, as compared with C5 inhibition. The primary outcomes were the incremental net monetary benefit across a lifetime horizon and the cost-effective maximum monthly threshold price of iptacopan monotherapy compared with the SOC. The secondary outcome was time saved for patients and nurses with the use of oral iptacopan therapy. Iptacopan monotherapy and SOC accrued 12.6 and 10.8 quality-adjusted life-years at costs of $9.52 million and $13.5 million, respectively. Iptacopan remained cost saving across extensive sensitivity and all scenario analyses, including alternative parameterization for anemia resolution and aggregated individual-level utilities and transition probability matrix. Across all probabilistic sensitivity analyses, iptacopan therapy was favored over SOC in 100% of 10 000 Monte Carlo iterations. Cost-saving thresholds for iptacopan vs anti-C5 in are ∼1.1, 1.4, and 1.4 in Brazil, Japan, and the United States, respectively. Iptacopan monotherapy can improve quality-adjusted life expectancy for patients while saving health care costs across jurisdictions.

Novel Therapeutics and Upcoming Clinical Trials Targeting Inflammation in Cardiovascular Diseases.

Cardiovascular disease (CVD) remains a major health burden despite significant therapeutic advances accomplished over the last decades. It is widely and increasingly recognized that systemic inflammation not only represents a major cardiovascular risk and prognostic factor but also plays pivotal roles in CVD development and progression. Despite compelling preclinical evidence suggesting large potential of anti-inflammatory pharmacological interventions across numerous CVDs, clinical translation remains incomplete, mainly due to (1) yet undefined molecular signaling; (2) challenges of safety and efficacy profile of anti-inflammatory drugs; and (3) difficulties in identifying optimal patient candidates and responders to anti-inflammatory therapeutics, as well as optimal therapeutic windows. Randomized controlled trials demonstrated the safety/efficacy of canakinumab and colchicine in secondary cardiovascular prevention, providing confirmation for the involvement of a specific inflammatory pathway (NLRP3 [NACHT, LRR, and PYD domain-containing protein 3] inflammasome/IL [interleukin]-1β) in atherosclerotic CVD. Colchicine was recently approved by the US Food and Drug Administration for this indication. Diverse anti-inflammatory drugs targeting distinct inflammatory pathways are widely used for the management of other CVDs including myocarditis and pericarditis. Ongoing research efforts are directed to implementing anti-inflammatory therapeutics across a growing number of CVDs, through repurposing of available anti-inflammatory drugs and development of novel anti-inflammatory compounds, which are herein concisely discussed. This review also summarizes the main characteristics and findings of completed and upcoming randomized controlled trials directly targeting inflammation in CVDs and discusses the major challenges and future perspectives in the exciting and constantly expanding landscape of cardioimmunology.

US FDA Advisory Panel Members’ Assessment of Premarket Approval Process and Suggestions for Improvement

The manufacturing and marketing of medical devices is regulated by the US Food and Drug Administration (FDA), and the FDA premarket approval (PMA) process evaluates the safety and effectiveness of medical devices. The PMA process includes a detailed scientific, regulatory and quality system review and is critical to ensure that novel devices are safe, effective, and meet the needs of patients. To survey current voting members serving on panels of the FDA's Medical Devices Advisory Committee to better characterize panel decision-making and identify steps for improvement. This qualitative survey study included 36 questions that were mailed to FDA device panelists regarding their opinions on the influence of sources of information, pivotal trial design, quality of evidence, panel composition and internal deliberative process, time allocation, and impartiality of the FDA. The survey was mailed to the members of all 18 FDA device panels in January and February 2017. Data were collected from January to May 2017 and analyzed from 2018 to 2019. Respondents read and returned the aforementioned paper survey, while nonrespondents did not. The main outcomes included panel members' perceptions, and their implications for process improvement. χ2 or Fisher exact tests were used to test differences between subgroups. Of 64 of 92 panel members who responded (69.6%), 38 of 64 (59.4%) were male, 3 of 63 (4.8%) were Black respondents, 46 of 63 (73.0%) were White respondents, and 36 of 60 (60.0%) were in academic practice. The mean (range) panel service was 6.8 (1-22) years with 3.9 (1-19) meetings attended. Overall, respondents considered information presented by the FDA unbiased, and 28 of 61 (45.9%) believed that pivotal trials were frequently well-designed, 55 of 62 respondents (88.7%) suggested FDA consult panel members preemptively regarding trial design and 54 of 64 (84.4%) regarding the device label. Most indicated that prior FDA approval of another device serving the same medical purpose (43 of 62 [69.4%]) or approval in other countries with comparable regulatory regimes, such as Canada and Europe (39 of 62 [62.9%]), would make them more likely to recommend approval. Respondents rated written information (50 of 60 [83.3%]), live presentations (43 of 58 [74.1%]), and prior professional knowledge (41 of 60 [68.3%]) as the most important sources of information in deciding whether to recommend approval. Additionally, 52 of 58 respondents (89.7%) recommended that a panel member-only executive session would allow more clarity and honesty in deliberations, and 33 of 59 (55.9%) believed a three-fourths majority appropriate for recommending approval, which would be a deviation from the current system in which an overall vote is reported without designation of a vote threshold. In this survey study of FDA device panel members, respondents wanted improved study designs, more relevant clinical data, including from other countries, involvement of panelists in study design and device label development, and inclusion of an executive session. Demographically, panels could be made more diverse.

Accelerated approvals: Early-phase success or premature authorization?

We compare the clinical trial success rates of products receiving US Food and Drug Administration (FDA) accelerated approval (AA) to those approved without using this pathway. Our findings raise important questions about how the AA pathway can best optimize early access to therapeutics that are ultimately proven safe and effective.

Drug Development Considerations for Additives to Organ Preservation Solutions.

The addition of a novel therapeutic agent to an organ preservation solution has the potential to address unmet needs in organ transplantation and enhance outcomes for transplant recipients. However, the development expectations for novel therapeutic agents in this context are unclear because of limited precedence and published regulatory guidance documents. To address these gaps, we have articulated a drug development strategy that leverages expectations for parenteral drug products administered via more conventional routes (eg, intravenous) and provided considerations for when deviations may be justified. We have supplemented this strategy with a comparison to available regulatory guidance from the US Food and Drug Administration to highlight potential areas for further clarification. The strategy articulated here is based on Genentech's internal experience for a program intended for use in kidney transplantation.

A maturity assessment methodology for ISO 13485 implementation in the medical devices industry

PurposeThis study aims to develop a novel diagnostic methodology for implementing ISO13485:2016 and test its applicability to improve quality management systems (QMS) in the medical devices industry context.Design/methodology/approachFirst, a literature review on the topic was conducted. Second, insights gained from the literature and expert interviews were employed to develop the new maturity assessment methodology. Subsequently, the methodology was tested on a medical device manufacturer. Next, based on the evaluation of the intervention, actions were recommended to improve the QMS.FindingsResearch findings have developed a maturity assessment methodology comprising 52 certifiable requirements structured into four macro-requirements derived from ISO 13485:2016. Findings show that the methodology is valuable for aiding QMS implementation, and the diagnosed maturity levels corresponded with the company’s empirical perceptions of the requirement’s maturity.Practical implicationsEmpirical evidence validates the significance and practical utility of the proposed methodology, as evidenced by the company’s attainment of FDA (US Food and Drug Administration) approval after the intervention. Findings suggest that the methodology could be replicated within the medical products industry or adapted to assess other QMS, leveraging the organizational alignment with the international regulations of the sector and the ISO 9000 requirements.Originality/valueThe developed methodology fills existing gaps in both literature and practice within the medical devices industry, providing a valuable contribution by addressing the limited research on diagnostic methodologies designed for ISO 13485:2016 implementation. The article assists medical device enterprises in addressing QMS maturity levels as a metric for evaluating QMS requirements, which is an underexplored avenue in existing QMS evaluation approaches.

Innovations through crop switching happen on the diverse margins of US agriculture

Crop switching, in which farmers grow a crop that is novel to a given field, can help agricultural systems adapt to changing environmental, cultural, and market forces. Yet while regional crop production trends receive significant attention, relatively little is known about the local-scale crop switching that underlies these macrotrends. We characterized local crop-switching patterns across the United States using the US Department of Agriculture (USDA) Cropland Data Layer, an annual time series of high resolution (30 m pixel size) remote-sensed cropland data from 2008 to 2022. We found that at multiple spatial scales, crop switching was most common in sparsely cultivated landscapes and in landscapes with high crop diversity, whereas it was low in homogeneous, highly agricultural areas such as the Midwestern corn belt, suggesting a number of potential social and economic mechanisms influencing farmers' crop choices. Crop-switching rates were high overall, occurring on more than 6% of all US cropland in the average year. Applying a framework that classified crop switches based on their temporal novelty (crop introduction versus discontinuation), spatial novelty (locally divergent versus convergent switching), and categorical novelty (transformative versus incremental switching), we found distinct spatial patterns for these three novelty dimensions, indicating a dynamic and multifaceted set of cropping changes across US farms. Collectively, these results suggest that innovation through crop switching is playing out very differently in various parts of the country, with potentially significant implications for the resilience of agricultural systems to changes in climate and other systemic trends.

Changes in Internet Search Behavior After a Direct-to-Consumer Advertising Campaign for Faricimab-svoa

Purpose: To analyze changes in Google search volume after US Food and Drug Administration (FDA) approval and initiation of a direct-to-consumer marketing campaign for faricimab-svoa. Methods: Google Trends data between December 26, 2021, and June 17, 2023, were downloaded and searched for terms prominently featured in the marketing campaign, including “wet AMD”, “diabetic macular edema”, “Vabysmo”, and “faricimab-svoa”. Data were standardized to the week and the term with the highest search volume, resulting in weekly relative search volumes for each term. The mean relative search volume and percentage change in relative search volume were calculated for the time periods of interest. Results: The direct-to-consumer campaign was associated with an increase in relative search volume in the first month for the terms “Vabysmo” (2.5% to 18.0%) and “wet AMD” (3.0% to 77.3%) and was sustained in the second month ( P < .01). No significant changes in relative search volume were seen for the terms “diabetic macular edema” or “faricimab-svoa”. After FDA approval, “Vabysmo” had the only significant increase in relative search volume (0.3% to 2.8%; P = .02). Conclusions: A direct-to-consumer advertising campaign for faricimab-svoa was associated with a surge in Google search volume of 620% and 2475% for “Vabysmo” and “wet AMD,” respectively ( P < .01), without a corresponding increase for “diabetic macular edema”. Although FDA approval was associated with an increase in search volume for “Vabysmo” ( P = .02), the marketing campaign was more influential at driving internet search behavior.

Radioligand therapy in sympathetic-adrenal-medullary axis tumors: state of art and perspectives.

The approval in 2017 by the European Medicines Agency (EMA) and in 2018 by the US Food and Drug Administration (FDA) of radioligand therapy (RLT) led to its wide application in therapeutic management of neuroendocrine neoplasms (NENs). However, the indications are currently limited to certain specific histotypes belonging to the broader NEN's family, mainly advanced well-differentiated gastro-entero-pancreatic NENs. As a consequence, several other tumors of the NEN spectrum that can potentially benefit, due to their biological characteristics, from RLT are still ineligible and can be considered "RLT-orphans". Among those, the subgroup of NENs originating from the sympathetic-adrenal-medullary (SAM) axis can be listed. This paper discusses the state of art and perspectives of the theragnostic applications in pheochromocytomas and paragangliomas, considering both the traditional theragnostic model - with radiolabelled metaiodobenzylguanidine (MIBG) - and the innovative one with radiolabeled somatostatin analogs (SSAs), that will hopefully become available for these patients in the near future.

Bioactives from marine resources as natural health products: A review.

The oceans are a rich source of a myriad of structurally different and unique natural products that are mainly found in invertebrates with potential applications in different disciplines. Microbial infection and cancer are the leading causes of death worldwide. Discovery of new sources of therapy for microbial infections is an urgent requirement due to the emergence of pathogenic microorganisms that are resistant to existing therapies. Marine bioactives have demonstrated to be promising sources for the discovery and development of novel antimicrobial and anticancer compounds. Several marine compounds are confirmed to have antibacterial effects and most marine-based antifungal compounds are cytotoxic. Numerous antitumor marine natural products, derived mainly from sponges or molluscs, and also bryozoans and cyanobacteria, exhibit potent antimitotic activity. In addition, marine biodiversity offers some possible leads or new drugs to treat human immunodeficiency virus (HIV). A majority of marine derived drugs are currently in clinical trials or under preclinical evaluation. Furthermore, marine-based drugs, approved by the US Food and Drug Administration (FDA) are available in the market. This review summarizes the sources, mechanisms of action and potential utilization of marine natural products such as peptides, alkaloids, polyketides, polyphenols, terpenoids and sterols as antifungal, antibacterial, antiviral, and anticancer compounds. Significance Statement Utilization of marine bioactives as natural health products leads to crucial advancement in providing dietary supplements, nutraceuticals, functional foods and pharmaceuticals. Their myriad of application promotes health and plays a role in disease risk reduction. Therapeutic potential of potent compounds from marine organisms and use of their bioactives have promising medicinal value for preventing ailments and advancing pharmaceutical and nutraceutical industries. Their utilization benefits human health globally and contributes to the conservation of marine ecosystem in a transformative / sustainable approach.

Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases.

Ryanodine receptor type 2 (RyR2) is the principal intracellular calcium release channel in the cardiac sarcoplasmic reticulum (SR). Pathological RyR2 hyperactivity generates arrhythmia risk in genetic and structural heart diseases. RYR2 gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia. In structural heart diseases (i.e., heart failure), posttranslation modifications render RyR2 channels leaky, resulting in pathologic calcium release during diastole, contributing to arrhythmogenesis and contractile dysfunction. Hence, RyR2 represents a therapeutic target in arrhythmogenic heart diseases. We provide an overview of the structure and function of RyR2, and then review US Food and Drug Administration-approved and investigational RyR2 inhibitors. A therapeutic classification of RyR2 inhibitors is proposed based on their mechanism of action. Class I RyR2 inhibitors (e.g., flecainide) do not change SR calcium content and are primarily antiarrhythmic. Class II RyR2 inhibitors (e.g., dantrolene) increase SR calcium content, making them less effective as antiarrhythmics but preferable in conditions with reduced SR calcium content such as heart failure.

Testing of New Drugs Approved From 2015 Through 2021 Under the US Pediatric Research Equity Act

This study uses public US Food and Drug Administration lists to identify new drugs approved from 2015 through 2021 to examine recent estimates of compliance with and timing of pediatric testing requirements after passage of the Pediatric Research Equity Act.

Circulating Tumor Cell Count and Overall Survival in Patients With Metastatic Hormone-Sensitive Prostate Cancer

In metastatic hormone-sensitive prostate cancer (mHSPC), new first-line combination therapies have enhanced overall survival (OS), but clinical outcomes for individual patients vary greatly and are difficult to predict. Peripheral blood circulating tumor cell (CTC) count is the most extensively validated prognostic liquid biomarker in metastatic castration-resistant prostate cancer (mCRPC), and recent studies have suggested that it may also be informative in mHSPC. To examine the prognostic value of CTC count in men with mHSPC. In this prognostic study, peripheral blood was drawn at registration (baseline) and at progression to mCRPC in the S1216 study (March 1, 2013, to July 15, 2017), a phase 3, prospective, randomized clinical trial in men with mHSPC. The CTCs were enumerated using a US Food and Drug Administration-cleared isolation platform. Counts were categorized as 0, 1 to 4, or 5 or more CTCs per 7.5 mL based on the prognostic value of these cut points in prior studies. The data analysis was performed between October 28, 2022, and June 15, 2023. Metastatic hormone-sensitive prostate cancer. Circulating tumor cell count was evaluated for an association with 3 prespecified trial end points: OS, progression-free survival, and 7-month prostate-specific antigen, after adjusting for other baseline covariates using proportional hazards and logistic regression models. Of 1313 S1216 participants (median [IQR] age, 68 [44-92] years), evaluable samples from 503 (median [IQR] age, 69 [46-90] years) with newly diagnosed mHSPC were collected at baseline, and 93 samples were collected at progression. Baseline counts were 5 or more CTCs per 7.5 mL in 60 samples (11.9%), 1 to 4 CTCs per 7.5 mL in 107 samples (21.3%), and 0 CTCs per 7.5 mL in 336 samples (66.8%). Median OS for men with 5 or more CTCs per 7.5 mL was 27.9 months (95% CI, 24.1-31.2 months) compared with 56.2 months (95% CI, 45.7-69.8 months) for men with 1 to 4 CTCs per 7.5 mL and not reached at 78.0 months follow-up for men with 0 CTCs per 7.5 mL. After adjusting for baseline clinical covariates, men with 5 or more CTCs per 7.5 mL at baseline had a significantly higher hazard of death (hazard ratio, 3.22; 95% CI, 2.22-4.68) and disease progression (hazard ratio, 2.46; 95% CI, 1.76-3.43) and a lower likelihood of prostate-specific antigen complete response (odds ratio, 0.26; 95% CI, 0.12-0.54) compared with men with 0 CTCs per 7.5 mL at baseline. Adding baseline CTC count to other known prognostic factors (covariates only: area under the curve, 0.73; 95% CI, 0.67-0.79) resulted in an increased prognostic value for 3-year survival (area under the curve, 0.79; 95% CI, 0.73-0.84). In this prognostic study, the findings validate CTC count as a prognostic biomarker that improved upon existing prognostic factors and estimated vastly divergent survival outcomes regardless of subsequent lines of therapy. As such, baseline CTC count in mHSPC may serve as a valuable noninvasive biomarker to identify men likely to have poor survival who may benefit from clinical trials of intensified or novel regimens.

12481 Evaluating The Device Handling And Preference Assessment Questionnaire For Growth Hormone Deficiency: Results From Content Validation Interviews

Abstract Disclosure: J. Neergaard: Employee; Self; Novo Nordisk. S. Akhtar: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. B. Berg: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. S. Hamilton: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. E. Hildebrand: Consulting Fee; Self; Novo Nordisk. J. Medina: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. G. Ter-Borch: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. N. Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. Background: Patient experiences with injection devices may affect treatment adherence, and hence it is important to ensure patient-reported outcomes (PRO) instruments used to assess experience are supported by evidence of validity. As part of a study that compared patient preference and ease of use between the devices used to administer Somapacitan (Sogroya®, Novo Nordisk A/S) and Somatrogon (Ngenla®, Pfizer), we assessed relevance, comprehensiveness and comprehension of a PRO instrument, the Device Handling and Preference Assessment Questionnaire (DHPAQ), in adolescent patients with growth hormone deficiency (GHD) and their caregivers. Methods: We recruited 33 adolescent patients with GHD and 37 caregivers across five sites in the US for an open label, randomized, crossover study in which participants simulated an injection with each device using an injection pad or mannequin. The DHPAQ was used to assess patients’ device preference. Two-sided statistical tests with 5% significance levels were performed using DHPAQ responses. After completing the DHPAQ, a random subgroup of 10 adolescents and 10 caregivers were offered additional compensation to participate in a cognitive interview (CI). The CIs were conducted in accordance with the US Food and Drug Administration 2022 Principles for PRO Instruments and 2009 PRO Guidance for Industry. Trained interviewers used a structured guide to evaluate questions, statements, tasks and response options in the DHPAQ. Participants’ interview responses for each question were coded and added to summary tables. These summary tables were evaluated by the study team to determine the relevance, comprehensiveness and participant comprehension of instructions, item stems and response options. Results: When asked if any questions in the DHPAQ did not seem relevant to their device experience, all 20 CI participants answered “no”. Questions on “learning how to use the device”, “selecting the correct dose” and “injecting the dose” were ranked as most relevant. Participants responses from the CIs supported perceived comprehensiveness of all DHPAQ items. All CI participants reported comprehension of all test items in the DHPAQ, and only three items did not receive a “no difficulty” response from all 20 participants. In the main study, the number of participants who preferred the somapacitan device was significantly greater than those who preferred the somatrogon device (84.3% vs 12.9%, p<0.0001). More participants found the somapacitan device easy or very easy to use compared with the somatrogon device (98.6% vs 74.3%). Conclusions: The results from the CIs indicated that the instructions, item stems and response options of the DHPAQ were relevant, comprehensive and fully comprehended by all participants. In the main study, patients with GHD and their caregivers were found to prefer the somapacitan device to the somatrogon device. Presentation: 6/2/2024

Strategic Expansion into Emerging Markets: Risk Management and Market Entry Strategies for US Food and Beverage Companies

Strategic Expansion into Emerging Markets: Risk Management and Market Entry Strategies for US Food and Beverage Companies

Les cellules CAR-T anti-CD19 : prototypes du médicament vivant

Chimeric antigen receptors (CARs) are synthetic receptors that determine the specificity and functions of transduced T cells. They bind cell surface antigens through their extracellular domain and initiate via their intracellular domain cytolytic functions, cytokine secretion and proliferation. The CAR thus specifies the properties of a living drug that is programmed to exert anti-tumor and immunoregulatory effects.After establishing a method to stably integrate foreign genes in primary T lymphocytes in the early 1990s, we identified combinatorial signaling modules that could sustain a prolonged T cell function [17], which underpins an essential feature of a living drug. We further identified CD19 as a promising molecular target, which, based on encouraging preclinical results in mice [30], paved the way for clinical trials.The first clinical studies in patients with relapsed, refractory leukemias and lymphomas, which all made use of CAR T cells produced in the academic setting, yielded remarkable clinical response that were soon confirmed at several centers [2]. CAR T cells targeting CD19 were the first living drugs to be approved by the US Food and Drug Administration in 2017 and the European Medicines Agency in 2018.CD19 CARs have thus spawned a new class of drugs and inspired new applications to treat cancer and autoimmune diseases with engineered immune cells, warranting sustained efforts to lower their cost and increase their availability in equitable fashion.

Adverse Event Profile of First-line Drugs for Treating Patent Ductus Arteriosus in Neonates: A Disproportionality Analysis Study of USFDA Adverse Event Reporting System.

Acetaminophen, ibuprofen, and indomethacin are widely used as first-line drugs for patent ductus arteriosus (PDA) closure in preterm neonates. However, their relative safety profiles remain unclear. Adverse event reports related to the first-line drugs used in PDA and neonates in general were retrieved from the US Food and Drug Authority (FDA) Adverse Event Reporting System. Deduplicated reports were analyzed using proportional reporting ratios and reporting odds ratios to identify disproportionality safety signals between drugs. A total of 969 unique reports related to the first-line drugs used in PDA and 499 reports in the neonatal period were included. Acetaminophen signals primarily involved the liver, while ibuprofen and indomethacin signals pertained to gastrointestinal, renal, vascular, and mortality outcomes. Higher occurrences of death were reported with indomethacin and ibuprofen compared with acetaminophen. This first comparison of PDA drug safety profiles from spontaneous reports highlights some differences, with acetaminophen potentially conferring a safer adverse effect profile overall. While limitations include missing data and reporting biases, the signals warrant further validation. Given its comparable efficacy to ibuprofen, as demonstrated in other studies, acetaminophen has the potential to be preferred as an initial medical therapy for PDA.

Addressing Drug-Drug Interaction Knowledge Gaps at the Time of Approval: An Analysis of FDA Postmarketing Requirements and Commitments from 2009 to 2023.

It has become increasingly common for patients to rely on the use of multiple prescription medications. The management of polypharmacy requires careful consideration for how drugs are metabolized and their potential for interaction with other drugs. Drug-drug interaction (DDI) assessments are typically performed in a stepwise manner during drug development, though knowledge gaps can exist at the time of approval. The US Food and Drug Administration can establish postmarketing requirements (PMRs) or postmarketing commitments (PMCs) to address these knowledge gaps. In this study, we systematically evaluated PMRs and PMCs established to new molecular entities (NMEs) at the time of initial approval between 2009 and 2023, for the assessment of pharmacokinetics-based DDIs (i.e., drug metabolizing enzyme- and transporter-related DDIs). We found that 22% of NMEs had at least one DDI-related PMR or PMC, with a total of 263 that were pharmacokinetic based. Of these, 67% were for the assessment of drug metabolizing enzymes, which were established most frequently for their evaluation as a substrate, and 28% for transporters, which were established most frequently for their evaluation as an inhibitor. The 89% of PMRs and PMCs that were considered fulfilled had a revision to the United States prescribing information, the majority of which resulted in updated new instructions for use. This study highlights the value in conducting PMRs and PMCs early in the drug development process allowing broad patient inclusion at the time of initial drug approval.