The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and ...translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.
Three‐dimensional (3D) printing, or additive manufacturing, technology has rapidly penetrated the medical device industry over the past several years, and innovative groups have harnessed it to ...create devices with unique composition, structure, and customizability. These distinctive capabilities afforded by 3D printing have introduced new regulatory challenges. The customizability of 3D‐printed devices introduces new complexities when drafting a design control model for FDA consideration of market approval. The customizability and unique build processes of 3D‐printed medical devices pose unique challenges in meeting regulatory standards related to the manufacturing quality assurance. Consistent material powder properties and optimal printing parameters such as build orientation and laser power must be addressed and communicated to the FDA to ensure a quality build. Postprinting considerations unique to 3D‐printed devices, such as cleaning, finishing and sterilization are also discussed. In this manuscript we illustrate how such regulatory hurdles can be navigated by discussing our experience with our group's 3D‐printed bioresorbable implantable device.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Expanded access (EA) provides a pathway for the clinical use of investigational products (drugs, biologics, and medical devices) for patients who are without satisfactory therapeutic options and for ...whom a clinical trial is not available. Academic medical centers (AMCs) are likely to encounter EA requests, but it is unknown what support is available at these institutions for physicians seeking EA for patients.
A landscape assessment was conducted at AMCs, focused on those within the Clinical and Translational Science Awards (CTSA) consortium.
Forty-seven responses were evaluated including 42 CTSA hubs. The large majority (43 of 47 respondents) reported using single-patient EA, while 37 reported multi-patient industry sponsored EA and 37 reported multi-patient investigator-initiated EA. Only half reported central tracking of EA requests. Support was available at 89% of sites for single-patient EA but less often for multi-patient EA. Types of support varied and were focused largely on the initial submission to the FDA.
Use of and support for EA is widespread at AMCs, with support focused on single-patient requests. Gaps in support are common for activities after initial submission, such as FDA reporting and data collection.
Background: A high prevalence of obstructive sleep apnea (OSA) symptoms was reported in patients with asthma. Our goal was to evaluate
factors associated with habitual snoring and OSA risk in these ...patients.
Methods: Patients with asthma were surveyed at specialty clinics with the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ)
and questions about the frequency of asthma symptoms (National Asthma Education and Prevention Program guidelines), followed
by medical record review. SA-SDQ scores ⥠36 for men and ⥠32 for women defined high OSA risk. Logistic regression was used
to model associations with habitual snoring and high OSA risk.
Results: Among 244 patients, 37% snored habitually and 40% demonstrated high OSA risk. Independent predictors of habitual snoring
included gastroesophageal reflux disease (GERD) odds ratio (OR), 2.19; 95% confidence interval (CI), 1.19 to 4.02 and use
of an inhaled corticosteroid (ICS) OR, 2.66; 95% CI, 1.05 to 6.72. High OSA risk was predicted by asthma severity step (OR,
1.59; 95% CI, 1.23 to 2.06), GERD (OR, 2.70; 95% CI, 1.51 to 4.83), and ICS use (OR, 4.05; 95% CI, 1.56 to 10.53). Linear,
dose-dependent relationships of ICS with habitual snoring and high OSA risk were seen (p = 0.004 and p = 0.0006, respectively).
Women demonstrated a 2.11 times greater odds for high OSA risk (95% CI, 1.10 to 4.09) when controlling for the above covariates.
Conclusions: Symptoms of OSA in patients with asthma are predicted by asthma severity, coexistent GERD, and use of an ICS in a dose-dependent
fashion. The well-recognized male gender predominance for OSA symptoms is not apparent in these patients. Further exploration
of these relationships may help to explain the increased prevalence of OSA in asthma and provide new insights into the reported
female predominance of asthma morbidity.
With no approved treatments for COVID-19 initially available, the Food and Drug Administration utilized multiple preapproval pathways to provide access to investigational agents and/or medical ...devices: Expanded Access, Emergency Use Authorizations, and Clinical Trials. Regulatory units within an Academic Medical Center (AMC), including those part of the Clinical and Translational Science Award (CTSA) consortium, have provided support for clinicians in navigating these options prior to the pandemic. As such, they were positioned to be a resource for accessing therapies during the COVID-19 public health emergency.
A small survey and a follow-on poll of the national Investigational New Drug (IND)/Investigational Device Exemption (IDE) Workgroup were conducted in October and December 2020 to determine whether CTSA regulatory units assisted in facilitating access to COVID-19 therapies and the extent of pandemic-related challenges these units faced.
Fifteen survey and 21 poll responses were received, which provided insights into the demands placed on these regulatory support units due to the pandemic and the changes required to provide critical support during this and future crises. Key changes and lessons learned included the importance of regulatory knowledge to support the institutional response, the critical need for electronic submission capacity for Food and Drug Administration (FDA) documents, and the nimble reallocation of regulatory and legal resources to support patient access to investigational agents and/or medical devices during the pandemic.
AMC- and CTSA-based regulatory units played a meaningful role in the COVID-19 pandemic but further unit modifications are needed for enabling more robust regulatory support in the future.
Sleep apnea affects more than half of patients with acute ischemic stroke and is associated with poor stroke outcome. This pilot study assessed the feasibility of a randomized, sham-controlled ...continuous positive airway pressure (CPAP) trial in subjects with acute ischemic stroke. Subjects identified with sleep apnea based on an apnea-hypopnea index ≥5 on overnight polysomnography or portable respiratory monitoring within 7 days of onset of stroke symptoms were randomized to receive active or sham CPAP for a 3-month period. Objective usage was ascertained by compliance data cards. Subjects, treating physicians, and outcome assessors were masked to intervention allocation. Among 87 subjects who provided consent, 74 were able to complete sleep apnea screening, 54 (73%) of whom had sleep apnea. Thirty-two subjects agreed to randomization. Of the 15 subjects who commenced active titration, 11 (73%) took the device home, and 8 (53%) completed the 3-month follow-up. Of the 17 subjects who commenced sham titration, 11 (65%) took the sham device home and completed the 3-month follow-up. The median cumulative usage hours over the 90 days were similar in the active group (53 hours; interquartile range, 22-173 hours) and the sham group (74 hours; interquartile range, 17-94 hours), and blinding to subject condition was successfully maintained. This first-ever randomized, sham-controlled trial of CPAP in patients with recent stroke and sleep apnea demonstrates that sham treatment can be an effective placebo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The U.S. federal government provides two tracks for eligible patients to obtain access outside clinical trials to investigational interventions currently under study for potential clinical benefits: ...the Food and Drug Administration’s expanded access pathway and the pathway created by the more recent Right to Try Act. In this issue of the Hastings Center Report, with a critical focus on patients, industry, and the research enterprise, Kelly Folkers and colleagues frame the inherent challenges that these pathways are meant to solve and have also inadvertently created. But an additional key focus is how the relevant situations should be managed at the bedside and how the system risks both inefficient and inequitable access to options at the institutional level. Although either pathway could be helpful to patients, the challenges of having the pathways coexist are greater than the sum of their parts. Individual clinicians represent the front line of the regulatory and eligibility challenges of expanded access and right to try, making clinical education a critical component of a comprehensive approach to using them well. But it is medical institutions that must take the lead on supporting access to investigational options in the most equitable and effective manner possible.
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BFBNIB, DOBA, FZAB, GIS, IJS, INZLJ, IZUM, KILJ, NLZOH, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ, ZRSKP
OBJECTIVES/GOALS: Physicians can request the clinical use of investigational products for their patients through an FDA pathway called Expanded Access (EA). Most evaluations of EA focus on the FDA ...submission only. We sought to evaluate these requests through the full academic medical center process. METHODS/STUDY POPULATION: Through the Transforming Expanded Access to Maximize Support and Study grant, we reviewed regulatory records for single-patient EA requests at four institutions (Duke University, University of Rochester, University of Michigan, and University of Texas Southwestern) which occurred between June 1, 2021 and February 28, 2023. Key data was collected, including the investigational product requested, submission and approval dates, urgency of request, and indication for treatment. Descriptive statistics were performed with Microsoft Excel. RESULTS/ANTICIPATED RESULTS: A total of 405 EA requests were identified, of which 319 (78.8%) were for drugs, 59 (14.6%) for biologics, and 27 (6.7%) for medical devices. The majority were characterized as non-emergency (60.7%), but the proportion of emergency to non-emergency cases varied considerably when stratified by year, with a peak in emergency cases in 2020. The most common products included therapies for COVID-19 and Mpox. Median time to obtain all approvals for treatment was 7 days for emergency cases and 28 days for non-emergency. The FDA review took the least time, with a median of 1 day in non-emergency cases. Full board approval from an institutional review board in non-emergency cases was 7 days. DISCUSSION/SIGNIFICANCE: These results generally align with previous reports on EA submissions received by the FDA. The timelines for the EA process represent an important benchmark both for treatment planning and institutional improvement.
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