Conditional Approval Research Articles

Chemical Synthesis of β‐(1,4)‐d‐Oligomannurarates with Purported Anti‐Alzheimer Activity

Sodium oligomannate, a sophisticated mixture of acidic linear β‐(1,4)‐d‐oligomannurarate ranging from dimers to decamers with an average molecular weight of 670∼880 Da, has gained conditional approval for the treatment of Alzheimer's disease. Herein, we develop an efficient approach to the chemical synthesis of well‐defined β‐(1,4)‐d‐mannurarate di‐, tetra‐, hexa‐ and octasaccharides (1‐4), utilizing N‐phenyl trifluoroacetimidate donors and thioglycoside acceptors for the stereoselective assembly of the desired β‐(1,4)‐d‐mannuronate linkages. This approach features a straightforward protecting group strategy with only two types of protecting groups: tert‐butyldimethylsilyl (TBS) for the 4‐OH at the non‐reducing end and benzyl (Bn) for free hydroxyl and carboxylic acid moieties, thereby ensuring the stereoselective formation of the β‐mannosyl bonds and facilitating sequential transformation into the target β‐(1,4)‐d‐mannurarate oligosaccharides. The scalability of the present synthesis of these oligosaccharides paves the way for in‐depth structure‐activity relationship studies and pharmacological investigations of sodium oligomannates.

Machine learning Bureau score for Home Lending in an American finance company

Our client is a leading provider of mortgage financing, originating loans and lines of credit to consumers in the US. Currently, they receive applications where applicants provide personal information and a soft pull of their FICO score is requested. That score is used to evaluate the applicant’s credit worthiness and determine conditional approval and the type of product available for the customer, including conventional, FHA or other mortgage loans. After conditional approval, a formal application is initiated, and underwriters review the information to determine the final application decision. When evaluating applications below regulatory and business thresholds, the company has the intention to approve more applications and increase loan volume, and there is an expectation that through the enhanced credit assessment, our client will improve the percentage of Low to Moderate Income (LMI) population able to obtain mortgage loans. Both aspects have a direct impact on the reputation and economic profits of the firm, so they are of pressing importance to the company. This project aims to build an applicant-level bureau-only score based on upgraded bureau internal attributes. This score will eventually serve as the basis for evaluating a customer’s credit risk before any loan structure or collateral information is considered. It will be used as a standalone score that can be used in the initial customer evaluation to identify better leads (mortgage inquiries for preapproval) and as input to a future application-level model.

Post-marketing surveillance framework of cell and gene therapy products in the European Union, the United States, Japan, South Korea and China: a comparative study

BackgroundCell and gene therapy products (CGTPs) often receive accelerated approvals, lacking comprehensive long-term safety and efficacy data, which can raise significant safety concerns. This research aims to study the post-marketing surveillance (PMS) of CGTPs in the European Union (EU), the United States (US), Japan, South Korea, and China, to offer insights for the development of a secure and standardized post-marketing regulatory framework for CGTPs.MethodsRelated regulations and the implementation effect of PMS for approved CGTPs were studied searching PubMed, CNKI, and the official websites of the European Medicines Agency, the US Food and Drug Administration, Japan’s Pharmaceuticals and Medical Device Agency, South Korea’s Ministry of Food and Drug Safety, and the National Medical Products Administration of China.ResultsCompared to those in China, the guidelines of PMS for CGTPs in the EU, the US, Japan, and South Korea was more comprehensive. Notably, the EU had dedicated regulations and supporting guidelines of PMS. Of the 26 CGTPs approved in the EU, 88% were under additional monitoring, 38% received conditional marketing authorization, and 12% were authorized under exceptional circumstances, with 77% designated as orphan drugs. The US had released 34 guidelines specifically for CGTPs which, forming the foundation of post-marketing risk management. Among the 27 CGTPs approved in the US, 22% were required to perform risk evaluation and mitigation strategies, 37% added black box warnings in the package inserts, 63% mandated to post-marketing requirements, and 15% subject to post-marketing commitments. In Japan, stringent supervision measures encompassing all-case surveillance (79%) and re-examination (53%) were applied to the 19 approved CGTPs, with 21% approved through conditional and time-limited approval. The PMS for CGTPs in South Korea, mainly included PSUR, re-examination, and re-evaluation. China had introduced several relevant regulations, which consisted of general statements and lacked detailed guidance.ConclusionsThis study demonstrates that the regulatory policies of PMS for CGTPs in the EU, the US, Japan, and South Korea were comprehensive. The implementation of PMS for CGTPs in the EU, the US, and Japan was well developed. This knowledge holds valuable insights for China’s future learning and development in this field.

Expedited program and utilization for anticancer drug approval in China and the United States

Objective: To systematically summarize and comparatively analyze the development, establishment and usage of oncology drugs speedy review approaches in China and in the United States between 2012 and 2021. Methods: Based on National Medical Products Administration (NMPA) and Food and Drug Administration (FDA) websites, the development and current status of the speedy review approaches were consulted and summarized. Approved oncology drugs in China and in the United States (87 in China, 118 in the United States) over the past decade were analyzed using chi-square test for group comparison. Results: Five speedy approaches have been established in China and in the United States, three of which are the same, priority review, conditional approval or accelerated approval and breakthrough therapy. The rest two are special review and approval, special examination and approval in China, and fast track and real-time oncology review in the United States. Compared to the United States, speedy review approaches in China set up late (1992 vs. 2005). The overall utilization rates of the oncology drugs speedy review approaches were similar between the China and United States (90.8% vs. 92.4%, P=0.800) in the previous 10 years, and priority review have highest utilization rates in both China and the United States without significant group difference (77.0% vs. 82.2%, P=0.381); relatively low utilization rates of conditional approval (31.0% vs. 44.9%, P=0.041) and breakthrough therapy (2.3% vs. 50.0%, P＜0.001) were seen in China. 52.9% of new drugs applied for special examination and approval in China and 40.7% of new drugs applied for fast track in the United States. Overall, the priority review both in China and the United States are stable, with a similar average annual utilization rate (84.8% vs. 83.7%); accelerated approval and breakthrough therapies in the United States fluctuate wildly, but the situation is tending towards stability in the last 3 years. Conclusions: Both China and the United States have established a relatively complete accelerated review system, with an overall utilization rate over 90%; China's accelerated review started late, although the overall utilization rate is close to that of the United States. The utilization rates of conditional approval and breakthrough therapy are still relatively low. Flexible usage of speedy review approaches, gaining regulatory recognition to use alternative endpoints, achieving real-time review and guidance are keys to accelerate new drug development in China.

Golidocitinib: First Approval.

Golidocitinib (®) is an oral, potent, selective Janus kinase 1 (JAK1) inhibitor being developed by Dizal (Jiangsu) Pharmaceutical Co., Ltd for the treatment of cancer, including peripheral T cell lymphoma (PTCL). In June 2024, golidocitinib received conditional approval in China for the treatment of adult patients with relapsed or refractory (r/r) PTCL who have received at least one line of systemic treatment. This article summarizes the milestones in the development of golidocitinib leading to this first approval for the treatment of adults with PTCL.

Is Canada Moving towards a More Agile Regulatory Approval and Reimbursement Process with a Shifting Role for Real-World Evidence (RWE) for Oncology Drugs?

Canada is known to have a complex pathway for new drug approval and reimbursement, resulting in delayed access for patients with serious and life-threatening diseases, such as cancer. Several recent publications from key stakeholders, including patients, physicians and policymakers, highlight patient helplessness, physician frustrations and policymakers entangled in a massive network of bureaucracy unable to make headway. Several quantitative and qualitative assessments using time from regulatory approvals to successful reimbursements confirm long review times and high rejection rates for oncology drugs, especially those receiving conditional approvals. A consensus forum of 18 Canadian oncology clinicians recently voiced frustration with the process and inability to deliver guideline-supported efficacious therapies to their patients. This manuscript compares data extracted from publicly available data sources from 2019 to June 2024 to previous publications. Methods: Public databases from Health Canada, the Canadian Agency for Drugs and Technologies in Health (CADTH), which is in the process of changing to Canada's Drug Agency, and the pan-Canadian Pharmaceutical Alliance (pCPA) were reviewed and the data collected were analyzed with descriptive statistics. Results: From the data, three trends emerge, (i) an increasing number of oncology drugs are receiving conditional approvals from Health Canada, (ii) the percentage of conditionally approved oncology drugs receiving positive reimbursement recommendations from CADTH is still low but appears to be improving, but delays in access are now contingent upon pCPA deciding whether to negotiate price and then the duration of any negotiation, and (iii) real-world evidence is no longer part of the decision-making for conditional approvals. A slight increase in the positive endorsement of RWE used to support CADTH recommendations was observed. Conclusions: The lack of timely access to oncology drugs hurts Canadian patients. While a small trend of improvement appears to be emerging, longer-term data collection is required to ensure sustained patient benefits.

Evidence Following Conditional NICE Technology Appraisal Recommendations: A Critical Analysis of Methods, Quality and Risk of Bias.

The National Institute for Health and Care Excellence (NICE) may approve health technologies on condition of more evidence generated only in research (OiR) or only with research (OwR). NICE specifies the information needed to comply with its request, although it may not necessarily guarantee good quality and timely evidence for re-appraisal, before reaching a final decision. This study aimed to critically appraise the methods, quality and risk of bias of evidence generated in response to NICE OiR and OwR technology appraisal (TA) and highly specialised technologies (HSTs) recommendations. NICE TAs (between March 2000 and September 2020) and HST evaluations (to October 2023) of medicines were reviewed. Conditional recommendations were analysed to identify the evidence requested by NICE for re-appraisal. The new evidence was analysed for compliance with NICE's request and assessed using the Cochrane Collaboration's tools for risk of bias in randomised trials and the ROBINS-I tool for non-randomised evidence. NICE made 54 conditional recommendations from TAs (13 OiR and 41 OwR) and five conditional recommendations for HSTs (all OwR). Of these, 16 TAs presented additional evidence for re-appraisal (9 OiR [69%] and 7 OwR [17%]) and three HSTs (3 OwR [60%]). Two of the nine re-appraised TAs with OiR recommendation and four of the seven OwR complied fully with NICE's request for further evidence, while all three from the HSTs complied. The majority of re-appraised TAs and HSTs included evidence that was deemed to be at serious, high, moderate or unclear risk of bias. Among the 26 randomised controlled trials from TAs assessed, eight were categorised as having low risk of bias in all domains and ten had at least one domain as a high risk of bias. Reporting was unclear for the remainder. Twenty-two non-randomised studies, primarily single-arm studies, were susceptible to biases mostly due to the selection of participants and to confounding. Two HSTs provided evidence from randomised controlled trials which were classified as unclear or high risk of bias. All non-randomised evidence from HSTs were categorised as moderate or serious risk of bias. There is widespread non-compliance with agreed data requests and important variation in the quality of evidence submitted in response to NICE conditional approval recommendations. Quality standards ought to be stipulated in respect to evidence contributing to re-appraisals following NICE conditional approval recommendations.

Management of acute-onset pancreatitis in dogs: a Narrative Review.

Acute-onset pancreatitis (AP) is common in dogs and presents diagnostic as well as management challenges. Until recently, the management of AP in dogs was based mainly on supportive and symptomatic care. Identification and management of a possible cause of the disease is important, but the majority of cases are considered to be idiopathic. Fluid therapy that is tailored to the patient's needs is crucial to provide adequate hydration while preventing overhydration. Antiemetics are required to control vomiting and fluid loss and aid in early nutritional support. Recognition and management of complications is also crucial. Furthermore, analgesics for abdominal pain are very important. More recently, pharmaceutical modification of the inflammatory cascade has gained interest and the first specific therapeutic agent for the treatment of AP, fuzapladib sodium, has been shown to have a reasonable expectation of effectiveness in a pilot study. This drug has been licensed for the treatment of clinical signs of AP in dogs in Japan and also has achieved FDA conditional approval in the US. Antibiotics should not be used indiscriminately but are indicated for patients with aspiration pneumonia, gastrointestinal bacterial translocation, or evidence of another bacterial infection. Proton pump inhibitors and plasma are not routinely prescribed in pancreatitis unless specifically indicated. Nonsteroidal anti-inflammatory drugs should be avoided. Corticosteroid therapy, once thought to be contraindicated, may have some beneficial effects, as shown in a single retrospective study. However, further studies are required before their routine use can be recommended. Finally, a surgical approach is rarely indicated.

Lost at SCLC: a review of potential platinum sensitizers.

The expression "lost at sea" means to be confused or perplexed. By extension, lost at SCLC references the current confusion about how to circumvent the chemoresistance, particularly platinum resistance, which so plagues the treatment of extensive-stage small cell lung cancer (ES-SCLC) that in 2012 the US National Cancer Institute (NCI) designated it a "recalcitrant cancer." Over a decade later, despite the approval of immune checkpoint inhibitors and the conditional approval of lurbinectedin, the prognosis for ES-SCLC, and especially platinum-resistant ES-SCLC, has scarcely improved. The focus of this review, which briefly summarizes current treatment options for ES-SCLC, is on five clinical-stage therapies with the potential to successfully reverse the platinum resistance that is perhaps the biggest obstacle to better clinical outcomes.

Resmetirom and Metabolic Dysfunction-Associated Steatohepatitis: Perspectives on Multidisciplinary Management from Global Healthcare Professionals.

The approval of resmetirom brings great hope to patients with metabolic dysfunction-associated steatohepatitis (MASH). The purpose of this review is to explore its impact on the global health environment. The implementation of multidisciplinary management MASH is proposed. Resmetirom has benefits in the treatment of MASH, and its safety and effectiveness have been studied. The adverse events (AEs) need to be noticed. To improve patient outcomes, a multimodal approach with medication such as resmetirom, combined with metabolic and bariatric surgery (MBS) and lifestyle interventions can be conducted. MASH, a liver disease linked with obesity, is a challenging global healthcare burden compounded by the absence of any approved pharmacotherapy. The recent conditional approval by the Food and Drug Administration(FDA) in the United States of resmetirom, an oral, liver-directed, thyroid hormone receptor beta-selective agonist, marks a significant milestone, offering a treatment option for adults with non-cirrhotic MASH and who have moderate to advanced liver fibrosis. This narrative review discusses the efficacy and safety of resmetirom and its role in the therapeutic landscape of MASH treatment. Despite the promising hepatoprotective effect of resmetirom on histological liver endpoints, its use need further research, particularly regarding ethnic differences, effectiveness and cost-effectiveness, production scalability, social acceptance and accessibility. In addition, integrating resmetirom with other multidisciplinary therapeutic approaches, including lifestyle changes and MBS, might further improve clinical liver-related and cardiometabolic outcomes of individuals with MASH. This review highlights the importance of a comprehensive treatment strategy, supporting continued innovation and collaborative research to refine treatment guidelines and consensus for managing MASH, thereby improving clinical patient outcomes in the growing global epidemic of MASH. Studies done to date have been relatively short and ongoing, the course of the disease is highly variable, the conditions of various patients vary, and given this complex clinical phenotype, it may take many years of clinical trials to show long-term benefits.

Analysis of post-marketing requirements for oncology drug conditional approvals in the United States and China

BackgroundConditional approvals, also known as accelerated approvals, have been introduced by many pharmaceutical regulators around the world, allowing innovative drugs to enter the market earlier on the basis of limited evidence. This research aims to systematically analyze and compare the post-marketing requirements for conditional approvals of oncology drugs in China and the United States. By collecting and categorizing different types of post-marketing requirements, this study seeks to elucidate how these requirements are proposed and discern the underlying logic and patterns. MethodsThis study delved into oncology drug approvals, encompassing FDA accelerated approvals (up to December 31, 2022) and NMPA conditional approvals (from 2017 to December 31, 2022). Leveraging review documents from FDA and NMPA, comprehensive data on product characteristics, all post-marketing commitments and requirements, and especially those related to confirmatory requirements were extracted. The analysis incorporated descriptive statistics, visualizations such as Upset plots, and thorough examination of confirmatory requirement timeframes. FindingsThis study examined 168 FDA accelerated approvals and 41 NMPA conditional approvals for oncology indications. Post-marketing requirements displayed diversity: FDA emphasized confirmatory studies, clinical pharmacology studies, and more, while NMPA predominantly focused on confirmatory studies. Confirmatory requirement timeframes indicated higher FDA-required completion times for new confirmatory trials compared to continued completion of original pivotal trials. In contrast, NMPA's requirement patterns were comparatively singular, with relatively fixed timeframes. FDA's evolving trend showed decreasing timeframes over time, suggesting an increasing demand for timely confirmatory data. InterpretationConditional approvals offer a unique approach to bring potentially life-saving drugs to the market faster, despite limited supporting evidence. Our analysis of oncology drug conditional approvals in the U.S. and China reveals diverse post-marketing requirement patterns. This study provides valuable insights for regulatory decision-making in a dynamic pharmaceutical landscape. Balancing the risks and rewards of conditional approvals is crucial in ensuring both patient safety and timely access to innovative treatments.

Characteristics of Clinical Trials for the US Food and Drug Administration Accelerated Approval and Subsequent Confirmatory Trials: Implications for Drug Approval in Japan.

The Accelerated Approval (AA) Program of the United States (US) Food and Drug Administration (FDA) was established to facilitate and expedite access to new drugs for serious or life-threatening conditions. Although many drugs have granted AAs in the US, the number of approvals under the conditional approval system in Japan remains limited. This study aimed to examine whether confirmatory trials after the US AA are conducted in accordance with the design of postmarketing requirements and assess the timing of regular approval (RA) in Japan for drugs that have been granted US AA. Utilizing FDA databases and Japanese regulatory data from 1992 to 2023, we analyzed indications, postmarketing requirements, and clinical trial designs. Our findings indicate that the AA program in the US is well-managed as most AAs were converted to RAs based on confirmatory study data that met the designations. From the Japanese perspective, our findings show that the over half of Japanese RAs can be obtained without waiting for confirmatory trial results. By granting RA, instead of conditional approval, based on exploratory trial data in the US AA, the opportunity to evaluate postmarketing confirmatory trial results might be lost in Japan. Therefore, further improvements are needed to actively utilize the conditional approval system, which could allow for the rapid introduction of innovative drugs and also the verification of their efficacy and safety at an appropriate time.

Tunlametinib: First Approval.

Tunlametinib (®) is an oral, selective, mitogen-activated protein kinase kinase 1 and 2 (MEK 1/2) inhibitor being developed by Shanghai KeChow Pharma, Inc. for the treatment of solid tumours with RAS and RAF mutations, including melanoma, non-small cell cancer (NSCLC), colorectal cancer (CRC) and neurofibromatosis type 1 (NF1) plexiform neurofibromas. In March 2024, tunlametinib was granted conditional approval in China (based on surrogate endpoints) for use in patients with NRAS-mutated advanced melanoma who have failed anti-PD-1/PD-L1 treatment. This article summarizes the milestones in the development of tunlametinib leading to this first approval for the treatment of solid tumours with RAS and RAF mutations.

Sodium glucose transporter 2 inhibitors: Will these drugs benefit non-diabetic veterinary patients with cardiac and kidney diseases?

Sodium glucose transporter type 2 (SGLT2) inhibitors have been introduced into human medicine where their beneficial effects go beyond the expected improvement in blood glucose control. These drugs appear to prevent progression of both cardiovascular and kidney diseases, not only in diabetic but also in non-diabetic human patients. As these drugs have received conditional approval for use in diabetic cats and are being used in other veterinary species, the intriguing question as to whether they will have similar cardioprotective and nephroprotective effects in dogs and cats is being asked. The primary mechanism(s) by which SGLT2 inhibitors are cardio- and nephroprotective remain to be fully characterized. This paper reviews these suggested mechanisms in the context of the pathophysiology of progressive cardiovascular and kidney diseases in dogs and cats with the goal of predicting which categories of non-diabetic veterinary patients these drugs might be of most benefit.

HTA65 How Does Conditional Regulatory Approval Affect the Reimbursement of Drugs in Canada?

HTA65 How Does Conditional Regulatory Approval Affect the Reimbursement of Drugs in Canada?

Plasma ctDNA biomarker study in patients with non-small cell lung cancer with EGFR exon 20 insertion mutation treated with sunvozertinib.

8563 Background: There are limited reports on biomarker studies of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (exon20ins). Sunvozertinib (DZD9008), an oral, potent, irreversible and selective EGFR tyrosine kinase inhibitor (TKI), has been granted conditional approval in China for the treatment of NSCLC with EGFR exon20ins in the ≥ second-line setting. Here we report biomarker analysis of EGFR exon20ins in large sample size, by pooling data from WU-KONG series of studies. Methods: Serial plasma ctDNA samples were collected from baseline until progressive disease (PD). Next generation sequencing was used to assess EGFR exon20ins in baseline plasma ctDNA, and to analyze genetic alterations in baseline and PD plasma ctDNA to identify potential resistance mechanisms to sunvozertinib. Droplet digital PCR was used to dynamically monitor the quantity of EGFR exon20ins during treatment. In addition, association between baseline EGFR exon20ins and disease characteristics as well as antitumor activity of sunvozertinib was analyzed. Furthermore, in vitro and in vivo experiments were performed to explore potential approach which may overcome the resistance to sunvozertinib. Results: A total of 121 patients were included in this biomarker analysis, among them 81 out of 121 (66.9%) had detectable EGFR exon20ins in baseline plasma ctDNA. There was a positive correlation between detectable EGFR exon20ins and higher number of metastasis sites. In addition, higher EGFR exon20ins abundance was positively correlated with more metastasis sites and brain metastasis. Patients with EGFR exon20ins negative in plasma ctDNA achieved a higher objective response rate (ORR) (68.0% vs. 45.8%) and longer median progression free survival (PFS) (7.4 months vs. 5.5 months) with sunvozertinib treatment. In patients with baseline detectable EGFR exon20ins, the mutant allele decreased over time with treatment in majority of patients (12/14, 85.7%), and the earliest clearance of EGFR exon20ins occurred after one week of treatment. In patients who developed disease progression, 12 of 18 (66.7%) maintained EGFR exon20ins at PD, and among them, 3 concurrently acquired EGFR C797S, all in cis with exon20ins. In addition, EGFR G724S and other genetic aberrations in EGFR downstream signaling pathway, were also detected. Exploratory work on overcoming resistance to sunvozertinib suggests that combination of golidocitinib, a selective JAK1 inhibitor, with chemotherapy could be a potential approach. Conclusions: This study showed that positive EGFR exon20ins in plasma ctDNA is associated with advanced disease characteristics. Sunvozertinib can effectively clear EGFR exon20ins in plasma ctDNA, confirming its direct effect on EGFR pathway. The resistance to sunvozertinib can be through EGFR-dependent and EGFR-independent mechanisms.

Bloodborne pathogens in beef herds – a Kansas practitioner’s perspective

Management options for bloodborne diseases depend on preva­lence (herd level and geographic), disease stage and production class. Opportunities to manage disease can be classified ac­cording to disease stage. Newer studies show that, in contrast to older studies, there is not currently a known legal way to clear animals of anaplasmosis. The only currently labeled products for treatment of acute clinical anaplasmosis are injectable oxy­tetracyclines. For a time, an enrofloxacin product (Baytril-CA) was marketed with a label for treatment of anaplasmosis, but the conditional approval application has been withdrawn. Op­portunities for leukosis management are limited to exposure control as there are no effective treatments for animals in the clinical stage and no effective methods to clear infected non-clinical animals. Due to the relatively high prevalence in beef herds, a strict test-and-cull strategy is not practical. Instead identifying animals with high pre-viral load who are most infectious provides an option to decrease disease levels with reasonable economics at the farm level. More research is neces­sary to fully quantify production effects for carrier animals of both bovine leukosis and anaplasmosis.

Cold-stored platelets do not potentiate detrimental monocyte and neutrophil proinflammatory responses in vitro

Abstract Cold-stored platelets (CSP) have increased hemostatic function compared to room temperature-stored platelets (RTP), leading to recent FDA conditional approval for CSP transfusion in bleeding patients. However, the immune consequences of CSP transfusion are not well defined. CD62P and CD40L expression is increased in CSP, potentially enhancing interaction with neutrophils (PMN, CD62P:PSGL-1) and monocytes (Mo, CD40L:CD40). We hypothesized CSP would form aggregates with leukocytes more readily than RTP, thereby increasing tissue factor/CD142 expression, inflammasome assembly, and neutrophil extracellular trap (NET) formation – functions potentiated by native platelets. We stored apheresis platelets in plasma (PLT) for 7 days at 22oC (RT) or 4oC (CS), and incubated PLT with freshly isolated PBMC or PMN at a 1:14 ratio. We measured CD142 and Apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC) expression by flow cytometry in Mo, and ASC specks and NET formation in PMN using fluorescent microscopy. We found no difference in CD142 or ASC GMFI expression in monocytes incubated with RT or CS PLT, and no difference in ASC specks or NET formation between neutrophils incubated with RT and CS PLT. Therefore, our in vitro study shows CSP do not potentiate detrimental acute proinflammatory responses by monocytes or neutrophils, further supporting CSP use in actively bleeding patients and paving the way for precision transfusion medicine.

Factors associated with hematological adverse reactions of drugs authorized via the centralized procedure

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.

Provision of gender affirming care among medical and allied health practitioners: The influence of transnormative beliefs in working with gender diverse patients

Gender diverse patients (including gender diverse, transgender, and non-binary people) deserve quality health care, which has been referred to as gender affirming care. Given that practitioners' attitudes and competence can influence their provision of gender affirming care, this study used a lens of transnormativity (Bradford & Syed, 2019; Johnson, 2016) to develop a measure of practitioners' transnormative beliefs. The aim of the study was to determine if these beliefs were related to practitioners' gender affirming attitudes and perceptions of competence in gender affirming practice. Survey data were collected from Australian medical and allied health practitioners (N = 95). Exploratory factor analysis was applied to items measuring transnormative beliefs, with the results supporting three higher order factors; conditional approval, narrative, and gender role beliefs. Conditional approval reflected belief in gender diverse identity as authentic and worthy of intervention. Narrative beliefs reflected understanding of common developmental experiences among gender diverse populations, specifically experiences of victimisation and nascence. Gender role beliefs reflected belief in the existence of gender roles. In models that regressed gender affirming attitudes and self-perceived competency on all transnormative beliefs, controlling for demographics and work history, practitioners higher in conditional approval were lower in gender affirming attitudes and practitioners higher in narrative beliefs were higher in gender affirming attitudes and competency. Conditional approval was not significantly associated with competency, and gender role beliefs were not significantly associated with attitudes or competency. Results indicate that practitioners' transnormative beliefs are related to their gender affirming attitudes and suggest that targeting these beliefs through training opportunities could bridge the gap between gender diverse people's healthcare needs and the ability of healthcare practitioners to provide high quality care.