This letter is in response to your request that the Food and Drug Administration (FDA) issue an Emergency Use Authorization (EUA) for emergency use of COVID-19 convalescent plasma for the treatment of hospitalized patients with Coronavirus Disease 2019 (COVID-19), as described in the Scope of Authorization (Section II) of this letter, pursuant to Section 564 of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 360bbb-3). On February 4, 2020, pursuant to Section 564(b)(1)(C) of the Act, the Secretary of the Department of Health and Human Services (HHS) determined that there is a public health emergency that has a significant potential to affect national security or the health and security of United States citizens living abroad, and that involves the virus that causes COVID-19 (the virus was later named SARS-CoV-2). 1 On March 27, 2020, on the basis of such determination, the Secretary of HHS declared that circumstances exist justifying the authorization of emergency use of drugs and biological products during the COVID-19 pandemic, pursuant to Section 564 of the Act, subject to the terms of any authorization issued under that section. 2 COVID-19 convalescent plasma is human plasma collected from individuals whose plasma contains anti-SARS-CoV-2 antibodies, and who meet all donor eligibility requirements (21 CFR 630.10 and 21 CFR 630.15) and qualifications. It is an investigational product and is not currently approved or licensed for any indication. Based on review of historical evidence using convalescent plasma in prior outbreaks of respiratory viruses, certain preclinical evidence, results from small clinical trials of convalescent plasma conducted during the current outbreak, and data obtained from the ongoing National Convalescent Plasma Expanded Access Protocol (EAP)
Two Artemis-deficient (mArt-/-) mouse models, independently generated on 129/SvJ backgrounds have the expected T-B-NK+SCID phenotype. However, they fail to mimic the human disease due to CD4+ T-cell leakiness. Moreover, immune reconstitution in these leaky mouse models following hematopoietic stem cell transplantation (HSCT) is more easily achieved than that seen in Artemis-deficient humans. To develop a more clinically relevant animal model we backcrossed the mArt-/- mutation onto the C57Bl/6 (B6) background (99.9%) resulting in virtually no CD4+ T-cell leakiness compared to 129/SvJ mArt-/- mice (0.3±0.25% vs 19.5±15.1%, p<0.001). The non-leaky mouse was also uniquely resistant to engraftment using allogeneic mismatched HSC, comparable to what is seen with human Artemis deficiency. The genetic background also influenced Artemis-associated radiation sensitivity with differing degrees of x-ray hypersensitivity evident in 129/SvJ and B6 backgrounds with both the mArt-/- and mArt-/+ genotypes. Our results indicate that immunogenic and DNA repair phenotypes associated with Artemis deficiency are significantly altered by genetic background, which has important implications for SCID diagnosis and treatment. Moreover, the B6 mArt-/- mouse is a more accurate model for the human disease, and a more appropriate system for studying human Artemis-deficiency and for developing improved transplant and gene therapy regimens for the treatment of SCID children.
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