Real-World Data Collection from Expanded Access Case Studies for the Treatment of Nontuberculous Mycobacterial Infection with Clofazimine.

Background: Due to its indolent nature, nontuberculous mycobacteria (NTM) are increasing in global prevalence as a cause of pulmonary infections and are difficult to treat with traditional antibiotics. Here, we study the repurposing of clofazimine (CFZ) to treat NTM through expanded access in a single health system. Our main objectives are to describe the feasibility of accessing and analyzing expanded access data and to generate hypotheses regarding CFZ use in NTM treatment. Methods: A retrospective chart review was performed on patients within a single health system who had been approved for expanded access of clofazimine or who received it through an outside hospital for NTM treatment. Data were collected on patients' baseline demographics, details of their NTM infection, concomitant therapies, and results as of 30 June 2021. Results: A total of 55 patients were identified upon initial review as potentially receiving CFZ for NTM infection. After excluding 19 patients who did not initiate CFZ, data from the remaining 36 patients were collected and summarized. The median age at which patients were diagnosed with NTM was 51.3 years old, with a median BMI of 21.2 kg/m2. Patients were more likely to be female (64%), have a baseline lung disease (72%), and 52% were current or former smokers at the time of their diagnosis. The most common species isolated was M. avium complex (47%) followed by M. abscessus (36%), with the most common site of infection being the lung (78%). The majority of patients presented with productive cough with excess sputum production followed by pulmonary nodules and bronchiectasis present on radiograph. Conclusions: This study demonstrated the difficulty of collecting retrospective real-world data via electronic healthcare records on symptoms, side effects, and radiography from patients who obtained a drug through expanded access. Based on the findings of this study, we recommend further research into the potential use of CFZ in patients with M. abscessus pulmonary infections.

National landscape assessment of academic medical center support for expanded access to investigational products.

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. METHODS: A landscape assessment was conducted at AMCs, focused on those within the Clinical and Translational Science Awards (CTSA) consortium. RESULTS: 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. CONCLUSION: 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.

Adapting an Expanded Access program to enable investigational treatments for COVID-19.

Retrospective case studies of initiatives supported by the National Institutes of Health's Clinical and Translational Science Award (CTSA) hubs can be used to identify facilitators and barriers of translational science. This case study investigates how a CTSA Expanded Access program adapted to changing FDA guidance issued in 2020 to support clinicians' treatment of COVID-19 patients in Michigan. We studied how this program changed throughout the pandemic to support physicians' requests for remdesivir, convalescent plasma, and other uses of unapproved drugs and novel medical devices. A protocol for retrospective translational science case studies of health interventions developed by CTSA evaluators was used for this case study. Data collection methods included seven interviews and a review of institutional data, peer-reviewed publications, news stories, and other public records. The barriers identified include evolving guidance, misalignment of organizational operations, and the complexity of the research infrastructure. The facilitators of translation include collaboration between research and care teams, increasing engagement with a broad network of supporters, and ongoing professional development for research staff. The findings of this case study can be used to inform future investigations of the principles underlying the translational process.

Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19.

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.

Role of CTSA institutes and academic medical centers in facilitating preapproval access to investigational agents and devices during the COVID-19 pandemic.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19.

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 10-15 years 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 FDA-approved compounds and clinical candidates, we identified 17 dose-responsive compounds with in vitro antiviral efficacy in human liver Huh7 cells and confirmed antiviral efficacy in human colon carcinoma Caco-2, human prostate adenocarcinoma LNCaP, and in a physiologic 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 classically 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.

The Critical Role of Medical Institutions in Expanding Access to Investigational Interventions.

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.

Pacemaker recycling: A notion whose time has come.

The purpose of this paper is to summarize the need, feasibility, safety, legality, and ethical perspectives of pacemaker reutilization in low- and middle-income countries (LMICs). It will also describe, in-depth, Project My Heart Your Heart (PMHYH) as a model for pacemaker reuse in LMICs. The primary source of the discussion points in this paper is a collection of 14 publications produced by the research team at the University of Michigan and its collaborative partners. The need for pacemaker reutilization in LMICs is evident. Numerous studies show that the concept of pacemaker reutilization in LMICs is feasible. Infection and device malfunction are the main concerns in regard to pacemaker reutilization, yet many studies have shown that pacemaker reuse is not associated with increased infection risk or higher mortality compared with new device implantation. Under the right circumstances, the ethical and legal bases for pacemaker reutilization are supported. PMHYH is a proof of concept pacemaker donation initiative that has allowed funeral home and crematory directors to send explanted devices to an academic center for evaluation and re-sterilization before donation to underserved patients in LMICs. The time is now to pursue large-scale studies and trials of pacemaker reuse for the betterment of society. PMHYH is leading the way in the effort and is poised to conduct a prospective randomized, non-inferiority, multicenter study to confirm the clinical efficacy and safety of pacemaker reuse, for clinical and legal support.

Cleaning and Sterilization of Used Cardiac Implantable Electronic Devices With Process Validation: The Next Hurdle in Device Recycling.

OBJECTIVES: This study sought to develop a validated, reproducible sterilization protocol, which could be used in the reprocessing of cardiac implantable electronic devices (CIEDs). BACKGROUND: Access to cardiac CIED therapy in high-income and in low- and middle-income countries varies greatly. CIED reuse may reduce this disparity. METHODS: A cleaning and sterilization protocol was developed that includes washing CIEDs in an enzymatic detergent, screw cap and set screw replacement, brushing, inspection, and sterilization in ethylene oxide. Validation testing was performed to assure compliance with accepted standards. RESULTS: With cleaning, the total mean bioburden for each of 3 batches of 10 randomly chosen devices was reduced from 754 to 10.1 colony-forming units. After sterilization with ethylene oxide, with 3 half-cycle and 3 full-cycle processes, none of the 90 biological indicator testers exhibited growth after 7 days. Through cleaning and sterilization, protein and hemoglobin concentrations were reduced from 99.2 to 1.42 µg/cm2 and from 21.4 to 1.03 µg/cm2, respectively. Mean total organic carbon residual was 1.44 parts per million (range 0.36 to 2.9 parts per million). Endotoxin concentration was not detectable at the threshold of <0.03 endotoxin units/ml or <3.0 endotoxin units/device. Cytotoxicity and intracutaneous reactivity tests met the standards set by the Association for Advancement of Medical Instrumentation and the International Organization for Standardization. CONCLUSIONS: CIEDs can be cleaned and sterilized according to a standardized protocol achieving a 12-log reduction of inoculated product, resulting in sterility assurance level of 10-6.

Regulatory Considerations in the Design and Manufacturing of Implantable 3D-Printed Medical Devices.

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.

Access to Investigational Drugs: FDA Expanded Access Programs or "Right-to-Try" Legislation?

PURPOSE: The Food and Drug Administration Expanded Access (EA) program and "Right-to-Try" legislation aim to provide seriously ill patients who have no other comparable treatment options to gain access to investigational drugs and biological agents. Physicians and institutions need to understand these programs to respond to questions and requests for access. METHODS: FDA EA programs and state and federal legislative efforts to provide investigational products to patients by circumventing FDA regulations were summarized and compared. RESULTS: The FDA EA program includes Single Patient-Investigational New Drug (SP-IND), Emergency SP-IND, Intermediate Sized Population IND, and Treatment IND. Approval rates for all categories exceed 99%. Approval requires FDA and Institutional Review Board (IRB) approval, and cooperation of the pharmaceutical partner is essential. "Right-to-Try" legislation bypasses some of these steps, but provides no regulatory or safety oversight. CONCLUSION: The FDA EA program is a reasonable option for patients for whom all other therapeutic interventions have failed. The SP-IND not only provides patient access to new drugs, but also maintains a balance between immediacy and necessary patient protection. Rather than circumventing existing FDA regulations through proposed legislation, it seems more judicious to provide the knowledge and means to meet the EA requirements.

Sleep apnea treatment after stroke (SATS) trial: is it feasible?

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.

Predictors of habitual snoring and obstructive sleep apnea risk in patients with asthma.

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 >or= 36 for men and >or= 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.

Sleep staging and respiratory events in refractory epilepsy patients: Is there a first night effect?

PURPOSE: We performed this analysis of possible first night effects (FNEs) on sleep and respiratory parameters in order to evaluate the need for two serial night polysomnograms (PSGs) to diagnose obstructive sleep apnea (OSA) in epilepsy patients. METHODS: As part of a pilot multicenter clinical trial investigating the effects of treating sleep apnea in epilepsy, two nights of PSG recording were performed for 40 patients with refractory epilepsy and OSA symptoms. Sleep architecture was examined in detail, along with respiratory parameters including apnea/hypopnea index (AHI) and minimum oxygen saturation. Analysis included two-tailed t-tests, Wilcox sign rank analysis, and Bland Altman measures of agreement. RESULTS: Total sleep time differed between the two nights (night 1,363.8 min + 59.4 vs. 386.3 min + 68.6, p = 0.05). Rapid eye movement (REM) sleep and percentage of REM sleep were increased during night two (night 1: 12.3% + 5.9 vs. night 2: 15.5% + 6.2, p = 0.007), and the total minutes of slow-wave sleep (SWS) were increased (night 1: 35.6 + 60.7 vs. night 2: 46.4 + 68.1, p = 0.01). No other sleep or respiratory variables differed between the two nights. Given an AHI inclusion criterion of five apneas per hour, the first PSG identified all but one patient with OSA. DISCUSSION: Respiratory parameters showed little variability between the first and second nights. Sleep architecture was mildly different between the first and second PSG night. Performing two consecutive baseline PSGs to diagnose OSA may not be routinely necessary in this population.

Correlates of daytime sleepiness in patients with asthma.

BACKGROUND AND PURPOSE: Patients with asthma often complain of daytime sleepiness, which is usually attributed to a direct effect of asthma on nocturnal sleep quality. We investigated this and other potential explanations for daytime sleepiness among asthmatics. PATIENTS AND METHODS: One hundred fifteen adult asthmatics were assessed for perceived daytime sleepiness (one question item), subjective sleepiness (Epworth Sleepiness Scale score, ESS), obstructive sleep apnea risk (Sleep Apnea scale score within Sleep Disorders Questionnaire, SA-SDQ), asthma severity step, relevant comorbid conditions, and current asthma medications. RESULTS: Among all subjects, 55% perceived excessive daytime sleepiness and 47% had ESS>10. Most subjects reported snoring (n=99, or 86%) and many snored habitually (n=44, 38%). The ESS correlated with SA-SDQ (P<0.0001), male gender (P=0.01), and asthma severity step (P=0.04). In a multiple regression model, the ESS was independently associated with SA-SDQ (P=0.0003) and male gender (P=0.02), but not with asthma severity step (P=0.51). There were no correlations between ESS and age, body mass index (BMI), forced expiratory volume in one second as percent of predicted value (FEV(1)%), comorbidities, or medication used to treat asthma. CONCLUSIONS: Sleepiness is common in asthmatics and may reflect occult obstructive sleep apnea more often than effects of asthma itself, other comorbid conditions, or asthma medications.