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ABSTRACT Objective To assess the incidence of febrile neutropenia without primary granulocyte colony-stimulating factor prophylaxis in patients undergoing chemotherapy with adjuvant docetaxel and cyclophosphamide, and to evaluate the toxicity profile of brand-name docetaxel (Taxotere ® ) and the generic formulation. Methods This retrospective study was conducted using data obtained from electronic medical records of patients treated at a Brazilian cancer center. Patients with breast cancer who underwent adjuvant treatment between January 2016 and June 2019 were selected. Data were analyzed using chi-square and Fisher correlation of variables, and multivariate analyses were adjusted for propensity score. Results A total of 231 patients with a mean age of 55.9 years at the time of treatment were included in the study. The majority (93.9%) had luminal histology, 84.8% were at clinical stage I, and 98.2% had a good performance status. The overall incidence of febrile neutropenia in the study population was 13.4% (31 cases). The use of brand-name docetaxel (Taxotere ® ) was the only factor associated with febrile neutropenia occurrence (OR= 3.55, 95%CI= 1.58-7.94, p=0.002). Conclusion In patients with breast cancer who require treatment with adjuvant docetaxel and cyclophosphamide regimen, the toxicity profile differs between brand-name and generic docetaxel. Regardless of the formulation used, the incidence of febrile neutropenia was less than 20%, which may allow for the omission of primary prophylactic granulocyte colony-stimulating factor use in this setting.

ABSTRACT Purpose: To explore effect and mechanism of olsalazine of Chinese generic drugs on ulcerative colitis induced by dextran sulfate sodium salt (DSS) in BALB/c mice. Methods: The mouse model of ulcerative colitis was induced by free drinking of 3% (w/v) DSS aqueous solution for seven days. The mice were treated with olsalazine (0.6 g·kg-1) of Chinese generic drugs. The therapeutic effect of olsalazine on ulcerative colitis mice was evaluated by measuring disease activity index (DAI), colonic mucosal injury index (CMDI), histopathological score (HS), and detected the expression levels of interleukin (IL)-2, IL-10, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-1β in serum and IL-7, IL-17, IL-22, epidermal growth factor (EGF), transforming growth factor β1 (TGF-β1) in colonic homogenate of mice. Results: Olsalazine significantly increased the contents of IL-2, IL-10, IL-22, TGF and EGF in ulcerative colitis rats, and significantly decreased the scores of DAI, CMDI, HS and the contents in IL-7, IL-17, TNF-α, IL-1β and IFN-γ when compared with the model group. It improved the degree of colonic lesion in ulcerative colitis mice. Conclusions: It was suggested that olsalazine has a therapeutic effect on ulcerative colitis induced by DSS in mice, and the mechanism may be related to the increase of IL-2, IL-10, IL-22, TGF, and EGF and the decrease of the expression of IL-7, IL-17, TNF-α, IL-1β, and IFN-γ.

Background/Aim. The treatment of chronic myeloid leukemia (CML) has changed dramatically with the advent of targeted therapies. This study aimed to assess the efficacy of generic imatinib in CML patients treated in our center. Methods. The study was retrospective. It included 101 patients diagnosed with CML – chronic phase (CP). The patients were divided into two groups. Group 1 included 55 patients initially treated with branded imatinib and then switched to generic imatinib. Group 2 consisted of 46 newly diagnosed patients who received only generic imatinib from the beginning of therapy. Results. The patients were treated with branded imatinib for the mean of 42 months (range 6–132 months) before switching to generic imatinib. Treatment with generic imatinib lasted for 25 months on average (range 3–66 months). A quarter of the patients from the group 1 lost their cytogenetic reponse after being switched to generic imatinib, but with-out signs of transformation to acute leukemia. The patients treated with branded imatinib had a significantly longer event-free survival (EFS) and failure-free survival (FFS) (log-rank p = 0.01 and p = 0.03, respectively). These results could have been influenced by frequent changes of the brand and dosage formulation of generic imatinib. Conclusions. Our study showed a significantly longer EFS and FFS in the patients who were initially treated with branded imatinib, compared to those treated with generic imatinib only. These results provide useful information, but have to be interpreted within the context of the crossover study.

Disruptions to the pharmaceutical supply chain (PSC) have negative implications for patients, motivating their prediction to improve risk mitigation. Although data analytics and machine learning methods have been proposed to support the characterization of probabilities to inform decisions and risk mitigation strategies, their application in the PSC has not been previously described. Further, it is unclear how well these models perform in the presence of emergent events representing deep uncertainty such as the COVID-19 pandemic. This article examines the use of data-driven models to predict PSC disruptions before and during the COVID-19 pandemic. Using data on generic drugs from the pharmacy supply chain division of a Fortune 500 pharmacy benefit management firm, we have developed predictive models based on the naïve Bayes algorithm, where the models predict whether a specific supplier or whether a specific product will experience a supply disruption in the next time period. We find statistically significant changes in the relationships of nearly all variables associated with product supply disruptions during the pandemic, despite pre-pandemic stability. We present results showing how the sensitivity, specificity, and false positive rate of predictive models changed with the onset of the COVID-19 pandemic and show the beneficial effects of regular model updating. The results show that maintaining model sensitivity is more challenging than maintaining specificity and false positive rates. The results provide unique insight into the pandemic's effect on risk prediction within the PSC and provide insight for risk analysts to better understand how surprise events and deep uncertainty affect predictive models., (© 2024 Society for Risk Analysis.)

Objective: To analyse the rational prescription of medicines by village clinics following China's implementation of the New Healthcare System Reform (NHCSR)., Design: Retrospective study., Setting: Village clinics in a province in eastern China., Primary and Secondary Outcome Measures: Our evaluation was based on the core drug use indicators reported in the study ' How to Investigate Drug Use in Health Facilities: Selected Drug Use Indicators '., Results: The level of rational use of medicines (RUMs) in village clinics improved in 2018 compared with 2009; the average number of drugs per prescription decreased from 3.66 to 2.77, the percentage of prescriptions including antibiotics decreased from 65.40% to 46.00%, and the percentage of prescriptions including injections decreased from 55.75% to 37.48% (all p<0.01), whereas the percentage of drugs prescribed from the list of essential medicines increased from 66.50% to 80.34%, and the percentage of drugs prescribed by generic names increased from 61.29% to 70.65% (all p<0.01)., Conclusion: The level of RUMs improved after the implementation of the NHCSR, however, it was found that there was still a gap between the level of RUMs in 2018 and the international reference value. Financial investments, electronic prescription systems, improved supervision and regular training are essential actions that must be implemented., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The perception of taking a generic, relative to brand, medication has been demonstrated to exacerbate the nocebo effect. Conversely, positive attribute framing has been shown to attenuate the nocebo effect. However, little is known about the longevity of positive attribute framing nor how it interacts with generic versus brand treatment cues. Healthy participants (N = 205) were randomised to receive either sham-modafinil capsules with a brand or generic appearance, in conjunction with standard negative side effect framing (brand-negative: N = 42; generic-negative: N = 41) or positive side effect framing (brand-positive: N = 40; generic-positive: N = 40). The remainder were randomised to a no-treatment control (N = 42). Participants were informed that modafinil could enhance alertness and cognitive performance and reduce fatigue. Critically, modafinil was described as having several potential side effects. Treatment-related side effects, alertness, fatigue and cognitive performance were measured at baseline, 30-min post-treatment and 24 h later. Nocebo and placebo effects were observed across modafinil-treated participants relative to control. Positive framing significantly reduced warned side effects for 24 h. Perceived side effect likelihood, severity, and worry mediated the nocebo, but not framing, effect. Results have important implications for the presentation of side effect information, providing a potential route to reduce unwanted negative effects of generic medication., (© 2024 The Author(s). Applied Psychology: Health and Well‐Being published by John Wiley & Sons Ltd on behalf of International Association of Applied Psychology.)

Background: Antihypertensive medication use patterns have likely been influenced by changing costs and accessibility over the past 3 decades. This study examines the relationships between patent exclusivity loss, medication costs, and national health policies on antihypertensive medication use., Methods: Using 1996 to 2021 Medical Expenditure Panel Survey data of US adults with hypertension taking at least 1 antihypertensive medication, we conducted a cross-sectional analysis. We explored the associations between patent exclusivity loss, per-pill costs, and Medicare Part D enactment on medication use over time, focusing on the most commonly used medications (lisinopril, amlodipine, losartan, hydrochlorothiazide, and metoprolol)., Results: The unweighted sample comprised 50 095 US adults (mean age, 62 years; 53% female). The survey-weighted number of adults taking antihypertensive medications increased from 22 million (95% CIs, 20-23 million) to 55 million (95% CI, 51-60 million) between 1996 and 2021. Loss of patent exclusivity led to increased medication fills, notably for lisinopril, amlodipine, and losartan, which all exhibited within-class dominance. However, per-pill cost decreases coinciding with Medicare Part D did not increase the number of individuals treated or the use of specific antihypertensive medications or classes., Conclusions: The increase in antihypertensive medication use over the past decades highlights the significant impact of loss of patent exclusivity on the uptake in the use of specific medications. These findings underscore the complexity of factors influencing medication use, beyond cost reductions alone, and suggest that policies need to consider multiple facets to effectively improve antihypertensive medication accessibility and utilization., Competing Interests: B.K Bellows was supported by K01HL140170 from the National Heart, Lung, and Blood Institute (Bethesda, MD). I. Hernandez discloses consulting fees from BMS and Pfizer, outside of the submitted work. A.P Bress is supported by R01AG74989, K24AG080168, and R01AG065805 from the National Institute on Aging (Bethesda, MD) and R01HL139837 from the National Heart, Lung, and Blood Institute (Bethesda, MD). W.C. Cushman has received institutional grants from George Medicines and ReCor Medical. Dr Whelton is an associated editor at Hypertension. George Institute Ventures, the social enterprise arm of The George Institute for Global Health, has received investment to develop fixed-dose combination products containing aspirin, statin, and blood pressure–lowering drugs. George Institute Ventures has submitted patents for low-dose blood pressure combinations, on which Professor Rodgers is listed as one of the inventors. A. Rodgers has served on a Data and Safety Monitoring Board for a trial sponsored by Idorsia. George Institute Ventures Pty Ltd, the social enterprise arm of The George Institute for Global Health (TGIGH), has received investment to develop fixed-dose combination products containing aspirin, statin, and blood pressure–lowering drugs. TGIGH holds and have filed applications for combination products for the treatment of hypertension and diabetes, and Professor Rodgers is listed as one of the inventors (granted: US 10,369,15; US 10,799,487; US 10,322,117; US 11,033,544; US 11,478,462; Pending: US 17/932,982; US 18/446,268; US 17/598,122; US 17/317,614). A. Rodgers is seconded part-time to George Medicines Pty Ltd (GM), a subsidiary of George Institute Ventures. Professor Rodgers does not have a personal financial interest in these patents or products. The other authors report no conflicts.

The Abbreviated New Drug Application (ANDA) is used for the regulatory submission of generic drugs, which are pharmaceutical equivalents to brand-name drugs and distributed without patent protection. Different countries have their own regulatory requirements for the approval of generic drugs, enforced by authorities such as the CDSCO in India, EDQM in Europe, and USFDA in the United States. This review aims to compare the regulatory processes and requirements for generic drug approval in India, Europe, and the US, highlighting key differences and challenges. The involvement of regulatory authorities in the drug development process is crucial for expediting approval and addressing queries, helping to minimize delays. The Common Technical Document (CTD) format is employed across regions to harmonize submission requirements. This study underscores the differences in dossier submission for generics across the three regions, illustrating India's position in the global generic drug approval landscape. By comparing approval requirements, this work provides insight into the hurdles India must overcome to streamline its approval process. The ANDA allows generic manufacturers to submit bioequivalence studies, using the original innovator's safety and efficacy data. However, obtaining approval simultaneously from multiple regulatory authorities remains a challenging task. Careful review of regulatory documents by skilled personnel can reduce regulatory queries, ultimately accelerating the market launch of generic drugs. This review provides a comprehensive overview of the generic drug approval process, emphasizing the need for harmonization and improved efficiency in India's regulatory framework.

Background/Aim. Antimicrobial drug-nutrition interactions can compromise the efficacy and safety of therapeutic regimen, as well as the nutritional status of a patient. In order to prevent them, health professionals consult the reference information sources. Summary of Product Characteristics (SmPC) is the basis for reliable and objective informing, and in the case of generic products, the content of documents should be consistent. The aim of the study was to compare information on antimicrobial drug-nutrition interactions for generic products, and to consider the influence of relevant factors (the time of the first authorization and the number of generic products) on the outcome of evaluation. Methods. SmPCs for all generic antimicrobial products for systemic use were retrieved from the Medicines and Medical Devices Agency of Serbia website, and statements of interest were extracted from different sections and were compared. The comparison was based on classification of statements on interaction into one of five classes: “effect of nutrition status on drug action”, “effect of food in general on drug action”, “effect of specific nutrient on drug action”, “effect of drug on nutrient and metabolic status”, or “effect of drug on nutrition status”. Results. A total of 160 SmPCs were evaluated for 30 antimicrobial drugs corresponding to 46 dosage forms [mean number 3.48, standard deviation (SD) = 1.68; median 3.00, interquartile range (IQR) = 2; range: 2-9]. Nine (30%) antimicrobials (azithromycin, clarithromycin, cefazolin, cefepime, pipemidic acid, ciprofloxacin, levofloxacin, moxifloxacin and gentamicin) had inconsistent information. The inconsistency was related to different classes of interactions, and in some cases it could have clinically important implications (gentamicin, fluoroquinolones). The existence of a larger number of generic products was related to identified differences (p = 0.003). Conclusion. One third of generic antimicrobial products had inconsistent drug-nutrition interaction statements. Given the potential clinical implications, strategies for further harmonization of this information should be considered.

Introduction: The independent French drug bulletin Prescrire International rates the therapeutic innovation of new drug-indications approved for marketing in France using an ordinal scale with the lowest rating being "not acceptable". This study investigates whether these drugs were approved by Health Canada., Methods: A list of "not acceptable" drug-indications was generated by handsearching all issues of Prescrire International between January 2013 and December 2022. The generic names, indications and reasons why Prescrire labeled them not acceptable were recorded. The approval date was determined by consulting the website of the European Medicines Agency (EMA). The status of these drug-indications in Canada was determined by searching multiple Health Canada websites. Therapeutic Evaluations for new drug-indications done by the Patented Medicine Prices Review Board (PMPRB) were recorded., Results: Prescrire rated 57 new drug-indications and 42 new indications for existing drugs as not acceptable. Seventy of these drug-indications were available in Canada- 42 new drug-indications and 28 new indications for existing drugs. Twenty (90.9%) of the 22 new drugs evaluated by the PMPRB were rated as slight/no therapeutic improvement and 2 as moderate therapeutic improvement. The median difference, in days, between approval times by the EMA/ANSM and Health Canada was 129 (interquartile range -102, 341) in favour of the former., Discussion: The majority of the not acceptable drug-indications were approved by Health Canada. The difference between when Prescrire and Health Canada examined the evidence for these drug-indications is unlikely to explain the difference in their evaluations. A change in regulatory standards at Health Canada may be one factor behind the presence of these drugs. To what degree those drugs led to more harms than benefits for patients who are taking them needs to be urgently investigated. Finally, the reasoning behind Health Canada's approval of these drugs should be interrogated., Competing Interests: Between 2020-2024, Joel Lexchin received payments for writing a brief on the role of promotion in generating prescriptions for a legal firm, for being on a panel about pharmacare and for co-writing an article for a peer-reviewed medical journal. He is a member of the Board of Canadian Doctors for Medicare. He receives royalties from University of Toronto Press and James Lorimer & Co. Ltd. for books he has written. He is participating in research funded by the Canadian Institutes of Health Research. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Joel Lexchin. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background/Aim. Under the current financial crisis in Greece, an effort has been made by the Greek health authorities to encourage generic prescribing, in order to lower medicinal cost. The purpose of this work was to study antipsychotics use, and to calculate utilization of generics in antipsychotics sales in a sample from the medicines market of Thessaloniki, the second largest city in Greece. Methods. A sample of antipsychotics registered sales was collected using the new Electronic Health Records that have been applied in pharmacies during the last years in Greece. The sample corresponded to a small amount of sales from the market of Thessaloniki during the period July 2014–June 2015, including only community and no hospital sales. All brand names (prototype and generics) of antipsychotics and their relative ratios in the sales were estimated, and the percentage of generics in the sale of each medicine was calculated. The amount of medicines was estimated in Defined Daily Doses (DDDs) of the reference/prototype drug and its generics. Results. Olanzapine, quetiapine, haloperidol and risperidone sales corresponded to 77% of total antipsychotics sales with percentages of sales 25%, 19%, 19% and 14% respectively. The percentage of sales of other antipsychotics was 7% for amisulpride, 6% for aripiprazole, 4% for ziprasidone and 3% for clozapine. Generic use corresponded to 41% of total sales of antipsychotic drugs (10.884 DDDs out of 26.433 DDDs). Concerning second generation antipsychotics, generic use was high for amisulpride, olanzapine, risperidone and quetiapine. Conclusion. In the study sample, second generation antipsychotics corresponded to 78% of sales in the community of Thessaloniki. Haloperidol utilization was also notable. Considering Greek practices, the percentage of generics in antipsychotics sales was very high even for some of the newest antipsychotics.

Purpose: The generic drug industry currently faces multiple, serious issues that threaten the US drug supply. So-called "skinny labels" are one of the few tools authorized by Congress to expedite entry into the market by generic competitors when the first patent for a brand's drug compound (only) expires. This article reviews the law on this expedited marketing pathway for generic competitors, as well as limitations on its use., Methods: We examined the literature on patent protection of brand drugs, including the timelines for production of generic competitors. We also examined the law concerning skinny labels, including a recent decision of the US Federal Circuit Court that clearly articulates the guidelines concerning entry into the generic market, including labeling, marketing, and promotion., Findings: Skinny labels that follow the regulations set forth in the Hatch-Waxman Act, including the necessary carve-out procedure for "methods of use" still protected by 1 or more active patents, do not infringe a brand drug's label. Furthermore, the skinny label does not induce or contribute to infringement merely because its label contains US Food and Drug Administration-required safety profile data-even when the data cross-reference superiority studies on still-patent protected methods of use elsewhere in the label., Implications: Generic drugs have become essential to the broad, general availability of clinical therapeutic agents. The Hatch-Waxman Act was intended to facilitate entry of generic competitors into the marketplace, and the skinny label is an important tool to accomplish that end. As long as the generic manufacturer follows the essential skinny-label rules, specifically including marketing the compound without promoting or advertising those methods of use still protected by ongoing patents, the law will not find induced or contributory infringement., Competing Interests: Declaration of competing interest Marcia Boumil has no interests to report. Dr. Beninger was employed by Merck from 1995-2006 in Regulatory Affairs, Medical Affairs and Pharmacovigilance, although he never had any responsibility or oversight of Fosamax(Ⓡ) (alendronate sodium)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro "Matrix of Chemistry, Manufacturing and Control" (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations. MoCMC can detect inter and intra batch variabilities, thereby identifying potential generics versus brand product similarities or differences with a single numeric value and a specific & distinctive fingerprint., Methods: The FDA-approved IMM formulation, SPECTRAMAST Ⓡ LC, was selected as the reference product for the MoCMC. Twelve in-house test formulations containing ceftiofur hydrochloride were formulated and characterized. The MoCMC was developed to include six input parameters and three output parameters. The MoCMC system was used to evaluate and compare SPECTRAMAST Ⓡ LC with its in-house formulations., Results: Based on the MoCMC generated parameters, the distinctive fingerprints of MoCMC for each IMM formulations, and the statistical analyses of MCI and PPI values, in-house formulations, F-01 and F-02 showed consistency while the rest of in-house formulations (F-03-F-12) were significantly different as compared to SPECTRAMAST Ⓡ LC., Conclusion: This research showed that the MoCMC approach can be used as a tool for intra batch variabilities, generics versus brand products comparisons, post-approval formulations changes, manufacturing changes, and formulation variabilities., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Serious hematological adverse drug reactions (HADRs) may lead to or prolong hospitalization and even cause death. The aim of this study was to determine the regulatory factors associated with HADRs caused by drugs that were authorized up to July 2023 by the European Medicines Agency (EMA) and to evaluate the frequency of HADRs. Using a cross-sectional approach, the type and frequency of HADRs were collected from the Summaries of Product Characteristics of Drugs Authorized by the EMA and analyzed within proprietary, nonproprietary, and biosimilar/biological frameworks. Multivariate statistical analysis was used to investigate the associations of generic status, biosimilar status, conditional approval, exceptional circumstances, accelerated assessment, orphan drug status, years on the market, administration route, and inclusion on the Essential Medicines List (EML) with HADRs. In total, 54.78% of proprietary drugs were associated with HADRs at any frequency, while anemia, leucopenia, and thrombocytopenia were observed in approximately 36% of the patients. The predictors of any HADR, anemia, and thrombocytopenia of any frequency are generic status, biosimilar status, and inclusion on the EML, while the only protective factor is the administration route. Biosimilars and their originator biologicals have similar frequencies of HADRs; the only exception is somatropin. Knowledge of the regulatory factors associated with HADRs could help clinicians address monitoring issues when new drugs are introduced for the treatment of patients., (© 2024. The Author(s).)

Background: On July 4, 2021, China officially introduced the drug patent linkage system, which has made more localized adjustments than have similar systems in the US and South Korea. This study describes the characteristics and outcomes of China's patent linkage system., Methods: For this study, we used the database of China's patent information registration platform for marketed drugs to capture all listed patents and patent certifications from June 25, 2021, to June 30, 2023. We used descriptive statistics for the above data to assess the impact of patent linkage on branded drug manufacturers, generic drug manufacturers, and the public's access to medicines., Results: During the study period, the patents of 632 branded drugs were listed, and 5058 ANDAs submitted patent certifications to the Registration Platform. Of these 632 branded drugs, 462 (73.1%) drugs were approved before the year of patent registration, and the average number of listed patents per drug was 1.8, with a standard deviation of 1.4. However, of these 5058 ANDAs, P1 certifications accounted for 85.1%, and P3 and P4 certifications accounted for 16% combined. In addition, according to the detailed statistics of P2 certifications, we found that the proportion of patent invalidation cases was 46.4%. The remaining validity of the patents corresponding to P3 certifications was longer, with a median value of 17 months, and the IQR was 10-30.75, ranging from - 2 to 204 months., Conclusions: China's patent linkage aims to promote the balance of multiple interests -innovation, imitation and public health-and has its own system characteristics. Patent listing and patent certification are the key indicators reflecting the implementation effect of the system. From the perspective of system outcomes, ANDAs have been connected to the patent linkage system in an orderly manner, but the growth of patent challenges is not obvious. Moreover, manufacturers of foreign branded drugs that have not yet entered the Chinese market need to pay more attention to the role of patent listing., (© 2024. The Author(s).)

Spiking neural networks are of high current interest, both from the perspective of modelling neural networks of the brain and for porting their fast learning capability and energy efficiency into neuromorphic hardware. But so far we have not been able to reproduce fast learning capabilities of the brain in spiking neural networks. Biological data suggest that a synergy of synaptic plasticity on a slow time scale with network dynamics on a faster time scale is responsible for fast learning capabilities of the brain. We show here that a suitable orchestration of this synergy between synaptic plasticity and network dynamics does in fact reproduce fast learning capabilities of generic recurrent networks of spiking neurons. This points to the important role of recurrent connections in spiking networks, since these are necessary for enabling salient network dynamics. We show more specifically that the proposed synergy enables synaptic weights to encode more general information such as priors and task structures, since moment-to-moment processing of new information can be delegated to the network dynamics., (© 2024. The Author(s).)

In the century of precision medicine and predictive modeling, addressing quality-related issues in the medical supply chain is critical, with 62 % of the disruptions being attributable to quality challenges. This study centers on the development and safety of liposomal doxorubicin, where animal studies alone often do not adequately explain the complex interplay between critical quality attributes and in vivo performances. Anchored in our aim to elucidate this in vitro-in vivo nexus, we compared TLD-1, a novel liposomal doxorubicin delivery system, against the established formulations Doxil® and Lipodox®. Robust in vitro-in vivo correlations (IVIVCs) with excellent coefficients of determination (R 2  > 0.98) were obtained in the presence of serum under dynamic high-shear conditions. They provided the foundation for an advanced characterization and benchmarking strategy. Despite the smaller vesicle size and reduced core crystallinity of TLD-1, its release behavior closely resembled that of Doxil®. Nevertheless, subtle differences between the dosage forms observed in the in vitro setting were reflected in the bioavailabilities observed in vivo. Data from a Phase-I clinical trial facilitated the development of patient-specific IVIVCs using the physiologically-based nanocarrier biopharmaceutics model, enabling a more accurate estimation of doxorubicin exposure. This advancement could impact clinical practice by allowing for more precise dose estimation and aiding in the assessment of the interchangeability of generic liposomal doxorubicin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The 2023 Generic Drug Science and Research Initiative Public Workshop organized by the U.S. Food and Drug Administration (FDA) discussed the research needs to improve and enhance bioequivalence (BE) approaches for generic drug development. FDA takes such research needs and panel discussions into account to develop its Generic Drug User Fee Amendments III (GDUFA III) Science and Research Initiatives specific to generics. During the five workshop sessions, presentations and panel discussions focused on identifying and addressing scientific gaps and research needs related to nitrosamine impurity issues, BE assessment for oral products, innovative BE approaches for long-acting injectable products, alternative BE approaches for orally inhaled products, and advanced BE methods for topical products. Specifically, this report highlights the discussions on how to improve BE assessment for developing generic drug products based on research priorities for leveraging quantitative methods and modeling, as well as artificial intelligence/machine learning (AI/ML)., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Importance: Drug shortages are a chronic and worsening issue that compromises patient safety. Despite the destabilizing impact of the COVID-19 pandemic on pharmaceutical production, it remains unclear whether issues affecting the drug supply chain were more likely to result in meaningful shortages during the pandemic., Objective: To estimate the proportion of supply chain issue reports associated with drug shortages overall and with the COVID-19 pandemic., Design, Setting, and Participants: This longitudinal cross-sectional study used data from the IQVIA Multinational Integrated Data Analysis database, comprising more than 85% of drug purchases by US pharmacies from wholesalers and manufacturers, from 2017 to 2021. Data were analyzed from January to May 2023., Exposure: Presence of a supply chain issue report to the US Food and Drug Administration or the American Society of Health-Systems Pharmacists (ASHP)., Main Outcomes and Measures: The main outcome was drug shortage, defined as at least 33% decrease in units purchased within 6 months of a supply chain issue report. Random-effects logistic regression models compared the marginal odds of shortages for drugs with vs without reports. Interaction terms assessed heterogeneity prior to vs during the COVID-19 pandemic and by drug characteristics (formulation, age, essential medicine status, clinician- vs self-administered, sales volume, and number of manufacturers)., Results: A total of 571 drugs exposed to 731 supply chain issue reports were matched to 7296 comparison medications with no reports. After adjusting for drug characteristics, 13.7% (95% CI, 10.4%-17.8%) of supply chain issue reports were associated with subsequent drug shortages vs 4.1% (95% CI, 3.6%-4.8%) of comparators (marginal odds ratio [mOR], 3.7 [95% CI, 2.6-5.1]). Shortages increased among both drugs with and without reports in February to April 2020 (34.2% of drugs with supply chain issue reports and 9.5% of comparison drugs; mOR, 4.9 [95% CI, 2.1-11.6]), and then decreased after May 2020 (9.8% of drugs with reports and 3.6% of comparison drugs; mOR, 2.9 [95% CI, 1.6-5.3]). Significant associations were identified by formulation (parenteral mOR, 1.9 [95% CI, 1.1-3.2] vs oral mOR, 5.4 [95% CI, 3.3-8.8]; P for interaction = .008), WHO essential medicine status (essential mOR, 2.2 [95% CI, 1.3-5.2] vs nonessential mOR, 4.6 [95% CI, 3.2-6.7]; P = .02), and for brand-name vs generic status (brand-name mOR, 8.1 [95% CI, 4.0-16.0] vs generic mOR, 2.4 [95% CI, 1.7-3.6]; P = .002)., Conclusions and Relevance: In this national cross-sectional study, supply chain issues associated with drug shortages increased at the beginning of the COVID-19 pandemic. Ongoing policy work is needed to protect US drug supplies from future shocks and to prioritize clinically valuable drugs at greatest shortage risk.

Objectives: Generic medications represent 90% of prescriptions in the US market and provide a tremendous financial benefit for patients. Recently, multiple generic drugs have been recalled due to the presence of carcinogens, predominantly N-nitrosodimethylamine (NDMA), including an extensive recall of extended-release (ER) metformin products in 2020., Study Design: Primary pharmaceutical quality testing and database analysis., Methods: We tested marketed metformin immediate-release (IR) and ER tablets from a wide sample of generic manufacturers for the presence of carcinogenic impurities NDMA and N,N-dimethylformamide (DMF). We examined the association of level of impurity with drug price and the impact of the 2020 FDA recalls on unit price and prescription fill rate., Results: Postrecall NDMA levels were significantly lower in metformin ER samples (standardized mean difference = -2.0; P = .01); however, we found continued presence of carcinogens above the FDA threshold in 2 of 30 IR samples (6.67%). Overall, the presence of contaminant levels was not significantly associated with price for either IR (NDMA: R2 = 0.142; P = .981; DMF: R2 = 0.382; P = .436) or ER (NDMA: R2 = 0.124; P = .142; DMF: R2 = 0.199; P = .073) samples. Despite recalls, metformin ER prescription fills increased by 8.9% while unit price decreased by 19.61% (P < .05)., Conclusions: Recalls of metformin ER medications were effective in lowering NDMA levels below the FDA threshold; however, some samples of generic metformin still contained carcinogens even after FDA-announced recalls. The absence of any correlation with price indicates that potentially safer products are available on the market for the same price as poorer-quality products.

Although generic oral contraceptives (OCPs) can improve adherence and reduce health care expenditures, use of generic OCPs remains low, and the factors that affect generic prescribing are not well understood. We aimed to understand the barriers and facilitators of generic OCP prescribing and potential solutions to increase generic OCP prescribing, as well as pilot an educational module to address clinician misconceptions about generic OCPs. We developed focus group scripts using the 4D model of appreciative inquiry. A total of four focus groups occurred, two at the American Association of Nurse Practitioners (AANP) national conference and two at the American College of Physicians (ACP) Internal Medicine meeting. Focus group transcripts were analyzed using a constant comparative method with no a priori hypothesis to generate emerging and reoccurring themes. Findings from these focus groups were used to develop an educational module promoting generic OCP prescribing. Participants were recruited from the AANP Network for Research and the ACP Research Panel. This study demonstrates that health system factors, workflow factors, clinician factors, and patient factors were the main barriers to and facilitators of generic OCP prescribing. Nurse practitioners were responsive to an educational module and reported increased willingness to discuss and prescribe generic OCPs after completing the module. Interventions to increase generic OCP prescribing must address clinician and patient factors within the context of workflow and larger health system factors. [ABSTRACT FROM AUTHOR]