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Defining a Regulatory Strategy for ATMP/Aerosol Delivery Device Combinations in the Treatment of Respiratory Disease.

ABSTRACT: Advanced Therapeutic Medicinal Products (ATMP) are a heterogenous group of investigational medicinal products at the forefront of innovative therapies with direct applicability in respiratory diseases. ATMPs include, but are not limited to, stem cells, their secretome, or extracellular vesicles, and each have shown some potential when delivered topically within the lung. This review focuses on that subset of ATMPs. One key mode of delivery that has enabling potential in ATMP validation is aerosol-mediated delivery. The selection of the most appropriate aerosol generator technology is influenced by several key factors, including formulation, patient type, patient intervention, and healthcare economics. The aerosol-mediated delivery of ATMPs has shown promise for the treatment of both chronic and acute respiratory disease in pre-clinical and clinical trials; however, in order for these ATMP device combinations to translate from the bench through to commercialization, they must meet the requirements set out by the various global regulatory bodies. In this review, we detail the potential for ATMP utility in the lungs and propose the nebulization of ATMPs as a viable route of administration in certain circumstances. Further, we provide insight to the current regulatory guidance for nascent ATMP device combination product development within the EU and US.

SUBMITTER: Woods N

PROVIDER: S-EPMC7601063 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Defining a Regulatory Strategy for ATMP/Aerosol Delivery Device Combinations in the Treatment of Respiratory Disease.

Woods Niamh N MacLoughlin Ronan R

Pharmaceutics 20200926 10

Advanced Therapeutic Medicinal Products (ATMP) are a heterogenous group of investigational medicinal products at the forefront of innovative therapies with direct applicability in respiratory diseases. ATMPs include, but are not limited to, stem cells, their secretome, or extracellular vesicles, and each have shown some potential when delivered topically within the lung. This review focuses on that subset of ATMPs. One key mode of delivery that has enabling potential in ATMP validation is aeroso ...[more]

PMID: 32993197

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Project description:BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 μm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.

Project description:BackgroundSpurred by the Coronavirus infectious disease 2019 pandemic, aerosol containment devices (ACDs) were developed to capture infectious respiratory aerosols generated by patients at their source. Prior reviews indicated that such devices had low evidence of effectiveness, but did not address how ACDs should be evaluated, how well they should perform, nor have clearly defined performance standards. Towards developing design criteria for ACDs, two questions were posed: 1) What characteristics have guided the design of ACDs? 2) How have these characteristics been evaluated?MethodsA scoping review was performed consistent with PRISMA guidelines. Data were extracted with respect to general study information, intended use of the device, device design characteristics and evaluation.ResultsFifty-four articles were included. Evaluation was most commonly performed with respect to device aerosol containment (n = 31, 61%), with only 5 (9%), 3 (6%) and 8 (15%) formally assessing providing experience, patient experience and procedure impact, respectively. Nearly all of the studies that explored provider experience and procedure impact studied intubation. Few studies provided a priori performance criteria for any evaluation metric, or referenced any external guidelines by which to bench mark performance.ConclusionWith respect to aerosol containment, ACDs should reduce exposure among HCP with the device compared with the absence of the device, and provide ≥90% reduction in respirable aerosols, equivalent in performance to N95 filtering facepiece respirators, if the goal is to reduce reliance on personal protective equipment. The ACD should not increase awkward or uncomfortable postures, or adversely impact biomechanics of the procedure itself as this could have implications for procedure outcomes. A variety of standardized instruments exist to assess the experience of patients and healthcare personnel. Integration of ACDs into routine clinical practice requires rigorous studies of aerosol containment and the user experience.

Dataset Information

Defining a Regulatory Strategy for ATMP/Aerosol Delivery Device Combinations in the Treatment of Respiratory Disease.

Publications

Defining a Regulatory Strategy for ATMP/Aerosol Delivery Device Combinations in the Treatment of Respiratory Disease.

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