Premarket Evidence and Postmarketing Requirements for Real-Time Oncology Review Indication Approvals.

This cross-sectional study evaluates the use of the US Food and Drug Administration's Real-Time Oncology Review (RTOR) program in confirming the effectiveness of cancer drugs.

A Public Option for Clinical Trials? Lessons from Convalescent Plasma.

The case of clinical trials for convalescent plasma during COVID-19 illustrates important lessons for realizing public sector approaches to biomedical research and development. These lessons, centering on mission, transparency, and spillover effects, can be translated to wider efforts to develop a "public option" for clinical trials.

Trans-Cinnamaldehyde Primes More Robust Channel Catfish Immune Responses to Edwardsiella ictaluri Infection.

Infection with Edwardsiella ictaluri, a causative agent of enteric septicemia of catfish, threatens profitable catfish production through inventory losses. We previously demonstrated that trans-cinnamaldehyde (TC) enhances the survival of catfish following E. ictaluri infection. The present study was conducted to investigate catfish immune responses to TC feeding and E. ictaluri infection. The expression of 13 proinflammatory, innate, and adaptive immune-related genes was evaluated over time in two sets of experiments using real-time polymerase chain reaction (PCR). In the first experiment, catfish were fed a basal diet with or without TC supplementation, while in the second they were fed a TC-supplemented or normal diet followed by infection with E. ictaluri. The catfish group infected with E. ictaluri and fed a TC-diet showed significant changes in the expression of innate and adaptive immune-related genes compared to control group. At 21 and 28 days post-infection, recovered fish showed significant increases in the expression of IgM in the anterior kidney and spleen. These results suggest that the supplemental dietary intake of TC can improve the immune status of catfish via engaging innate and adaptive immune responses and the production of memory cells in immunocompetent tissues. Together, this study provides an important foundation for the potential application of TC as an antimicrobial alternative in aquaculture.

Characterization of accelerated approval status, trial endpoints and results, and recommendations in guidelines for oncology drug treatments from the National Comprehensive Cancer Network: cross sectional study.

Objectives: To evaluate National Comprehensive Cancer Network (NCCN) guideline recommendations for oncology drug treatments that have been granted accelerated approval, and to determine whether recommendations are updated based on the results of confirmatory trials after approval and based on status updates from the US Food and Drug Administration (FDA). Design: Cross sectional study. Setting: US FDA and NCCN guidelines. Population: Oncology therapeutic indications (ie, specific oncological conditions for which the drug is recommended) that have been granted accelerated approval in 2009-18. Main outcome measures: NCCN guideline reporting of accelerated approval status and postapproval confirmatory trials, and guideline recommendation alignment with postapproval confirmatory trial results and FDA status updates. Results: 39 oncology drug treatments were granted accelerated approval for 62 oncological indications. Although all indications were recommended in NCCN guidelines, accelerated approval status was reported for 10 (16%) indications. At least one postapproval confirmatory trial was identified for all 62 indications, 33 (53%) of which confirmed benefit; among these indications, NCCN guidelines maintained the previous recommendation or strengthened the category of evidence for 27 (82%). Postapproval confirmatory trials failed to confirm benefit for 12 (19%) indications; among these indications, NCCN guidelines removed the previous recommendation or weakened the category of evidence for five (42%). NCCN guidelines reflected the FDA's decision to convert 30 (83%) of 36 indications from accelerated to traditional approval, of which 20 (67%) had guideline updates before the FDA's conversion decision. NCCN guidelines reflected the FDA's decision to withdraw seven (58%) of 12 indications from the market, of which four (57%) had guidelines updates before the FDA's withdrawal decision. Conclusions: NCCN guidelines always recommend drug treatments that have been granted accelerated approval for oncological indications, but do not provide information about their accelerated approval status, including surrogate endpoint use and status of postapproval confirmatory trials. NCCN guidelines consistently provide information on postapproval trial results confirming clinical benefit, but not on postapproval trials failing to confirm clinical benefit. NCCN guidelines more frequently update recommendation for indications converted to traditional approval than for those approvals that were withdrawn.

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments.

Importance: Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals. Objective: To systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases. Data sources: The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023. Study Selection: Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded. Data Extraction and Synthesis: Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes. Main Outcomes and Measures: Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized. Results: Thirty-seven surrogate markers listed in FDA's table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result. Conclusions and Relevance: Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

Increase in temperature facilitates Campylobacter jejuni biofilm formation under both aerobic and microaerobic incubation.

The formation of Campylobacter jeuni biofilms on processing surfaces is a significant concern in poultry processing, contributing to food safety risks. This study focused on assessing the biofilm forming capabilities of 12 field isolates of C. jejuni of different aerotolerance categories on stainless steel surfaces, a prevalent material in poultry processing environments. Working cultures of each isolate were prepared to approximately 6 log CFU/mL and incubated on stainless steel coupons under microaerobic or aerobic conditions at room temperature or 42°C for 72 h. Biofilm attached cells were enumerated using direct plating and biofilm density was measured using a crystal violet assay by measuring the optical density (OD600) a. Data analysis was conducted using the PROC GLIMMIX procedure in SAS 9.4 with a significance level of 0.05. The study revealed a notable interaction between aerotolerance categories and temperature (P < 0.039) impacting the number of biofilms attached C. jejuni cells on stainless steel coupons. All isolates had significantly higher counts when incubated at 42°C compared to room temperature, regardless of oxygen level (P < 0.001). Furthermore, stronger biofilm density was observed at 42°C compared to room temperature, regardless of oxygen level. These findings underscore the influence of temperature on the biofilm forming ability of C. jejuni. The ability of these field isolates to form biofilms under various environmental conditions suggests a heightened potential for surface colonization and increased infection risk in poultry processing facilities.

Lessons From Insulin: Policy Prescriptions for Affordable Diabetes and Obesity Medications.

Escalating insulin prices have prompted public scrutiny of the practices of drug manufacturers, pharmacy benefit managers, health insurers, and pharmacies involved in production and distribution of medications. As a result, a series of policies have been proposed or enacted to improve insulin affordability and foster greater equity in access. These policies have implications for other diabetes and obesity therapeutics. Recent legislation, at both the state and federal level, has capped insulin out-of-pocket payments for some patients. Other legislation has targeted drug manufacturers directly in requiring rebates on drugs with price increases beyond inflation rates, an approach that may restrain price hikes for existing medications. In addition, government negotiation of drug pricing, a contentious issue, has gained traction, with the Inflation Reduction Act of 2022 permitting limited negotiation for certain high expenditure drugs without generic or biosimilar competition, including some insulin products and other diabetes medications. However, concerns persist that this may inadvertently encourage higher launch prices for new medications. Addressing barriers to competition has also been a priority such as through increased enforcement against anticompetitive practices (e.g., "product hopping") and reduced regulatory requirements for biosimilar development and market entry. A novel approach involves public production, exemplified by California's CalRx program, which aims to provide biosimilar insulins at significantly reduced prices. Achieving affordable and equitable access to insulin and other diabetes and obesity medications requires a multifaceted approach, involving state and federal intervention, ongoing policy evaluation and refinement, and critical examination of corporate influences in health care.

Medicare Part B and Part D drug eligibility for center for Medicare and Medicaid Services price negotiation under the Inflation Reduction Act: estimates using 2016-2019 data.

Background: To reduce Medicare prescription drug expenditures, the 2022 Inflation Reduction Act (IRA) allows the Centers for Medicare & Medicaid Services (CMS) to directly negotiate with drug manufacturers on Medicare prices of high-expenditure drugs (≥$200m annual spending) which meet certain eligibility criteria. However, it is unclear what proportion of high-expenditure drugs covered by Medicare, and attributable annual drug spending, would typically be eligible for CMS negotiations in a given year. Methods: We used historical Medicare drug spending data to determine how many high-expenditure drugs, and attributable drug spending, would have been eligible for CMS negotiations had the IRA been in effect from 2016-2019, while also determining which of the IRA's eligibility criteria is most restrictive. Results: From 2016-2019, approximately one third (33.3% for Part B, 32.4% for Part D) of high-expenditure Medicare drugs would have been eligible for negotiation, with ineligible drugs accounting for 75.2% and 63.8% of spending on high-expenditure drugs in Medicare Part B and D, respectively. Most ineligible high-expenditure drugs were ineligible because they launched too recently. From 2016-2019, between 59 and 74 high-expenditure drugs were eligible per year, indicating that in some years there may not be enough eligible drugs for CMS to negotiate on the maximum number of drugs allowable by law. Conclusions: The IRA's current eligibility criteria may restrict CMS from being able to negotiate drug prices on approximately two-thirds of the high-expenditure drugs covered by Medicare and may not allow CMS to negotiate on the maximum number of drugs allowable by law. Congress could consider relaxing eligibility requirements for price negotiation, such as those pertaining to launch date recency, to ensure there are a sufficient number of high-expenditure drugs eligible for negotiation or make certain ineligible drugs contributing to significant annual Medicare spending eligible for negotiation on a case-by-case basis.

Implications for Public Health Regulation if Chevron Deference Is Overturned.

This Viewpoint describes implications for medicine and public health if the US Supreme Court decides to overturn or narrow Chevron deference.

Phenotypic virulence characterization of avian pathogenic Escherichia coli (APEC) isolates from broiler breeders with colibacillosis in Mississippi.

AIMS: In this study, we evaluated the phenotypic virulence characteristics of avian pathogenic Escherichia coli (APEC) isolates from broiler breeders with colibacillosis in Mississippi. Also, the relationship between phenotypic and genotypic virulence patterns was determined. METHODS AND RESULTS: Twenty-eight APEC isolated from lesions of broiler breeders diagnosed with colibacillosis were used for embryo lethality assay and chick challenge study. The percentage of embryo mortality following embryo lethality assay and pathogenicity score following the chick challenge study were used to categorize the isolates based on virulence. Pearson correlation analysis was performed to determine the relationship between embryo mortality, chick pathogenicity, and the presence of virulence-associated genes in the isolates. Overall, 39.3% of the isolates were highly virulent and 3.5% were avirulent, following both assays. There existed a positive correlation between embryo mortality and chick pathogenicity (r = 0.73, P < .01), as well as percentage embryo mortality and pathogenicity score with the presence of some virulence genes. CONCLUSIONS: Even though all the APEC were isolated from lesions of diseased breeders, the virulence potential varied from being avirulent to highly virulent. Further, we identified a positive relationship between phenotypic virulence and the frequency of virulence-associated genes.

Pivotal Trial Demographic Representation and Clinical Development Times for Oncology Therapeutics.

This study evaluates whether FDA-approved novel cancer therapeutics supported by pivotal trials with adequate representation of minoritized groups were associated with slower clinical development times than those with inadequate representation.

Association of health benefits and harms of Christmas dessert ingredients in recipes from The Great British Bake Off: umbrella review of umbrella reviews of meta-analyses of observational studies.

OBJECTIVE: To determine the health benefits and harms of various ingredients in Christmas desserts from The Great British Bake Off. DESIGN: Umbrella review of umbrella reviews of meta-analyses of observational studies. DATA SOURCES: The Great British Bake Off website, Embase, Medline, and Scopus. INCLUSION CRITERIA: Umbrella reviews of meta-analyses of observational studies evaluating the associations between Christmas dessert ingredients and the risk of death or disease. MAIN OUTCOME MEASURES: Proportion of protective and harmful summary associations between ingredient groups from The Great British Bake Off Christmas dessert recipes and the risk of death or disease. RESULTS: 48 recipes for Christmas desserts (ie, cakes, biscuits, pastries, and puddings and desserts) were provided on The Great British Bake Off website with 178 unique ingredients that were collapsed into 17 overarching ingredient groups. A literature search identified 7008 titles and abstracts, of which 46 eligible umbrella reviews reported 363 unique summary associations between the ingredient groups and risk of death or disease. Of these summary associations, 149 (41%) were significant, including 110 (74%) that estimated that the ingredient groups reduced the risk of death or disease and 39 (26%) that increased the risk. The most common ingredient groups associated with a reduced risk of death or disease were fruit (44/110, 40%), coffee (17/110, 16%), and nuts (14/110, 13%), whereas alcohol (20/39, 51%) and sugar (5/39, 13%) were the most common ingredient groups associated with increased risk of death or disease. CONCLUSIONS: Recipes for Christmas desserts from The Great British Bake Off often use ingredient groups that are associated with reductions, rather than increases, in the risk of death or disease. This Christmas, if concerns about the limitations of observational nutrition research are set aside, you can have your cake and eat it too.

Avian Pathogenic Escherichia coli (APEC) in Broiler Breeders: An Overview.

Poultry meat is one of the major animal protein sources necessary to meet the global protein demand. Sustainability in broiler production is the key to achieving its continuous supply, and broiler breeders play a critical role in maintaining this sustainability by providing good quality chicks. Colibacillosis, the disease caused by avian pathogenic Escherichia coli (APEC), causes severe economic losses to the poultry industry globally. Moreover, APEC causes an additional burden among broiler breeders, such as a decrease in egg production and mortality among these birds. There is vertical transmission of APEC to the broiler chicks through eggs, resulting in increased first-week mortality and subsequent horizontal transmission at the hatchery. In this regard, the vertical transmission of antibiotic resistance genes is another concern that needs attention. Controlling several diseases in broiler breeders would possibly reduce the first-week mortality in chicks, thereby maintaining the production level. For that, constant monitoring of the bacterial populations is critical. Moreover, amidst the increased antibiotic resistance pattern, more focus on alternative treatment strategies like vaccines, probiotics, and bacteriophages is necessary. Future research focusing on strategies to mitigate APEC in broiler breeders would be one of the finest solutions for sustainable broiler production.

Feasibility of Emulating Clinical Trials Supporting US FDA Supplemental Indication Approvals of Drugs and Biologics.

This cross-sectional study evaluates the supporting clinical trials for supplemental new drug applications and supplemental biologics license applications from 2017 to 2019.

Aerotolerance and Multi-Locus Sequence Typing of Campylobacter jejuni Isolated from Commercial Broiler Processing Plants.

Campylobacter jejuni is one of the leading causes of acute diarrhea in the United States. Despite being a microaerophilic pathogen, C. jejuni continues to endure within the domain of food production, especially in poultry processing. Recent research on aerotolerance indicates that close monitoring of this pathogen is necessary. A total of 40 C. jejuni isolates previously obtained from commercial broiler processing plants were analyzed for aerotolerance and genetic diversity. In addition, the effect of aerotolerance and storage time (days) on the survival of C. jejuni on broiler drumsticks at refrigeration (4 °C) and freezing conditions (-20 °C) was also evaluated. Out of 40 isolates, 25 (62.5%) were aero-sensitive (AS), 10 (25%) were intermediately aerotolerant (IAT), and 5 (12.5%) were hyper aerotolerant (HAT). The isolates belonged to four clonal complexes (CCs) and six sequence types, with the majority of isolates assigned to the CC-353 clonal complex. C. jejuni counts were reduced by 0.40 log CFU/g after 7 days at 4 °C and by 1.50 log CFU/g after 14 days at -20 °C, respectively, irrespective of aerotolerance (p < 0.001). At both refrigeration (p < 0.013) and freezing (p < 0.001), HAT showed greater reductions as compared to AS and IAT. These findings suggest that both refrigeration and freezing reduce C. jejuni counts.

Effects of a Sprinkler and Cool Cell Combined System on Cooling Water Usage, Litter Moisture, and Indoor Environment of Broiler Houses.

Climate change is a serious challenge to food production around the world. Sustainability and water efficiency are critical to a poultry industry faced with global production concerns including increased demands for high-quality, affordable animal protein and greater environmental pressures resulting from rising global temperatures, flock heat stress, and limits on water availability. To address these concerns, a commercial sprinkler system used in combination with a cool cell system was evaluated against a cool cell system alone for two summer flocks of heavy broilers at Mississippi State University to determine effects of sprinkler technology on cooling water usage, litter moisture, and in-house environments. Environmental data were calculated and recorded throughout the flocks. The combination house exhibited a 2.2 °C (4 °F) increase in daily maximum temperature, lower coincident relative humidity, and a 64% (62,039 L/flock) reduction in average cooling water usage over the cool cell-only house. Litter moisture for the combination house tended to be numerically lower but showed no significant difference at several time points between and across flocks. A combined sprinkler/cool cell system reduced cooling water use by 64% over two flocks compared to a cool cell alone system and decreased in-house relative humidity levels.

Use of Expedited Regulatory Programs and Clinical Development Times for FDA-Approved Novel Therapeutics.

This cross-sectional study evaluates the duration between application to US Food and Drug Administration (FDA) and approval for new drugs and biologics in the US from 2015 to 2022.