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.

Successful Treatment of Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Patients With Immunodeficiency With Extended Nirmatrelvir/Ritonavir: Case Series.

Immunocompromised patients with B-cell deficiencies are at risk for prolonged symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We describe 4 patients treated for B-cell malignancies with B-cell-depleting therapies who developed persistent SARS-CoV-2 infection and had resolution of symptoms following an extended course of nirmatrelvir/ritonavir.

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.

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.

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.