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Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study

['Jonathon W. Senefeld', 'Department Of Anesthesiology', 'Perioperative Medicine', 'Mayo Clinic', 'Rochester', 'Minnesota', 'United States Of America', 'Patrick W. Johnson', 'Department Of Quantitative Health Sciences', 'Jacksonville']

Date: 2022-01 

Abstract Background The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. Methods and findings Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician–principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had—or were at risk of progression to—severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. Conclusions These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. Trial registration ClinicalTrials.gov NCT#: NCT04338360.

Author summary Why was this study done? There was a public health need to provide expedited and broad access to convalescent plasma for the treatment of coronavirus disease 2019 (COVID-19) during the early stages of this public health emergency in the United States.

Convalescent plasma was initially administered through regulatory pathways that required per-patient approval, resulting in substantial administrative time.

The Expanded Access Program (EAP) was initiated to provide broad access to COVID-19 convalescent plasma and to provide a framework for standardized collection of data describing the safety profile of convalescent plasma. What did the researchers do and find? The EAP provided rapid and broad access to convalescent plasma throughout the US and some US territories and was effective at providing therapy for demographic groups that were severely affected by COVID-19.

In addition, the data provide evidence supporting that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19. What do these findings mean? The study design of the EAP may serve as an example for future efforts in response to a rapidly developing infectious disease when broad access to a treatment is needed in areas and demographic groups that are often poorly represented in clinical trials.

Citation: Senefeld JW, Johnson PW, Kunze KL, Bloch EM, van Helmond N, Golafshar MA, et al. (2021) Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study. PLoS Med 18(12): e1003872. https://doi.org/10.1371/journal.pmed.1003872 Academic Editor: Cynthia So‐Osman, Sanquin Blood Bank, NETHERLANDS Received: February 1, 2021; Accepted: November 18, 2021; Published: December 20, 2021 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability: The authors are not permitted to share the data that support the findings of this study directly. Individual participant data underlying the results reported in this publication, along with a data dictionary, may be made available to approved investigators for secondary analyses following the completion of the objectives of the United States Expanded Access Program to COVID-19 convalescent plasma. Limited and de-identified data sets will be deposited into a research data repository and may be shared with investigators under controlled access procedures as approved by the Mayo Clinic Institutional Review Board. A scientific committee will review requests for the conduct of protocols approved or determined to be exempt by an Institutional Review Board. Requestors may be required to sign a data use agreement. Data sharing must be compliant with all applicable Mayo Clinic policies. Interested parties may contact uscovidplasma@mayo.edu or visit www.uscovidplasma.org. Funding: This project has been funded in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096. Additionally, this study was supported in part by National Center for Advancing Translational Sciences (NCATS) grant UL1TR002377, National Heart, Lung, and Blood Institute (NHLBI) grant 5R35HL139854 (to MJJ) and grant 1F32HL154320 (to JWS), Natural Sciences and Engineering Research Council of Canada (NSERC) PDF-532926-2019 (to SAK), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 5T32DK07352 (to CCW), National Institute of Allergy and Infectious Disease (NIAID) grants R21 AI145356, R21 AI152318 and R21 AI154927 (to DF), R01 AI152078 9 (to AC), National Heart Lung and Blood Institute RO1 HL059842 (to AC), National Institute on Aging (NIA) U54AG044170 (to SEB), Schwab Charitable Fund (Eric E Schmidt, Wendy Schmidt donors), United Health Group, National Basketball Association (NBA), Millennium Pharmaceuticals, Octapharma USA, Inc, and the Mayo Clinic. The principal investigator (M.J.J.) served as the regulatory sponsor. Many of the authors (JWS, PWJ, KLK, NvH, MAG, SAK, AMK, MAS, JCDS, CCW, KAB, CMvB, JRS, JLW, MMP, MRB, MAW, BR, SEB, JRAS, RFR, VH, ERW, AJC, KFL, JGR, KJA, MNPV, JJD, RJR, PRB, JEB, ZAB, MCP, MJJ, RSW, REC, DF) were full- or part-time employees of one of the study sponsors (Mayo Clinic) and were involved in study design, data analysis, data interpretation, and/or writing of the manuscript. All other funders had no role in the design and conduct of the study, collection, management, and analysis of the data. The primary funder (the US Biomedical Advanced Research and Development Authority, BARDA) provided input to and approval of other aspects of the study, including a review of the interpretation of the data and approval of the manuscript prior to submission. All other funders had no role in the review or approval of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: BARDA, Biomedical Advanced Research and Development Authority; COVID-19, coronavirus disease 2019; EAP, Expanded Access Program; eIND, emergency investigational new drug; EUA, emergency use authorization; FDA, Food and Drug Administration; ICU, intensive care unit; IND, investigational new drug; IRB, institutional review board; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TACO, transfusion-associated circulatory overload; TRALI, transfusion-related acute lung injury

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), spread rapidly across the United States (US) after confirmation of the first cases of COVID-19 in the US in December 2019 and January 2020 [1]. By March of 2020, community transmission was occurring in major metropolitan areas in the Northeast US, where hospitals became overwhelmed with admissions for severe or life-threatening COVID-19 [1]. Although most of those who are infected have few or no symptoms despite high SARS-CoV-2 viral loads [2], approximately 2% to 7% [3–5] develop hypoxemia and severe COVID-19 leading to hospitalization and the need for supplemental oxygen support [6]. Severe cases of COVID-19 can lead to respiratory failure, which is among the leading causes of death in persons with COVID-19 [7]. The treatment of patients with COVID-19 is primarily supportive [8]. During the early stages of this public health emergency, evidence-based treatments were few, but immunomodulatory agents and antivirals were viewed as promising therapeutic strategies for patients with COVID-19 [9,10]. Passive immunotherapy using convalescent plasma or serum had been used previously to treat diverse infectious diseases [11–13], including severe acute respiratory syndrome coronavirus 1 infection (SARS-CoV-1) [14]. Further, early studies undertaken during the COVID-19 pandemic suggested the potential efficacy of convalescent plasma in the treatment of COVID-19 [15–17]. In late March and early April of 2020, COVID-19 convalescent plasma began to be administered to patients under single-patient emergency investigational new drug (eIND) applications while randomized clinical trials of COVID-19 convalescent plasma were in various stages of development and enrollment. Neither the single eIND process nor the speed at which clinical trials could be implemented was meeting the need to provide access to COVID-19 convalescent plasma for most patients. For example, one institution in New York City had 45 eIND applications submitted to and approved by the US Food and Drug Administration (FDA) in a 2-week period in late March 2020 [18]. The single-patient eIND application process requires substantial administrative support from local institutions and the US FDA, limiting widespread access for patients to convalescent plasma [19,20]. Additionally, clinical trials often have inclusion criteria that are restricted to a specific geographical region or disease status (e.g., hospitalized, but not with severe disease) and have exclusion criteria (e.g., prisoners or recipients of solid organ transplant). Thus, a different regulatory pathway for obtaining access to COVID-19 convalescent plasma and comprehensively studying the safety of convalescent plasma for the treatment of COVID-19 was needed. To provide access to COVID-19 convalescent plasma treatment and provide a framework for standardized safety data collection, Mayo Clinic initiated the Expanded Access Program (EAP) for COVID-19 convalescent plasma. The primary objective of the EAP was to provide access to convalescent plasma for hospitalized patients in the US with severe or life-threatening COVID-19 [21]. The EAP started as a national registry approved to register 5,000 patients, but due to the extraordinary national demand for COVID-19 convalescent plasma, enrollment goals were extended in collaboration with the US FDA and the Biomedical Advanced Research and Development Authority (BARDA), with the aim of the EAP becoming a broad national program obviating the need for individual-patient investigational new drug (IND) applications. We herein assess the extent to which the EAP was successful in terms of providing access to COVID-19 convalescent plasma by presenting demographic, geographical, and chronological characteristics of patients in the EAP alongside publicly available data of state-level patterns in COVID-19. Additionally, we analyzed key safety metrics following transfusion of convalescent plasma.

Methods As described previously [22–24], the EAP was a national registry for hospitalized patients with COVID-19. Collaborative support was provided by the US BARDA and FDA; funding to support the study infrastructure and study-related costs at participating sites was provided under contract from BARDA. Mayo Clinic served as the academic research organization coordinating the national registry. The Mayo Clinic institutional review board (IRB), the central IRB for the registry, approved the protocol (IRB #20–0033412, ClinicalTrials.gov NCT04338360) and all amendments, and provided regulatory oversight for all sites and investigators. The principal investigator (MJJ) was the regulatory sponsor. A data and safety monitoring board oversaw the safety analyses and advised the regulatory sponsor and the Mayo Clinic IRB on risk. Study data were deposited with the US FDA. The study used a prospective protocol and statistical analysis plan (as previously described [22]), with changes to both plans during the study period associated with the EAP. Full details of the study design, conduct, oversight, and analyses are provided in the protocol and statistical analysis plan (S1 Text). This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist). Patients Patients were eligible for enrollment in the EAP if they were aged 18 years or older, were hospitalized with a laboratory-confirmed diagnosis of or suspected/probable infection with SARS-CoV-2, and either had or were judged by a healthcare provider to be at high risk of progression to severe or life-threatening COVID-19. Severe COVID-19 was defined by 1 or more of the following: dyspnea, respiratory frequency ≥ 30/minute, blood oxygen saturation ≤ 93%, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen < 300, and lung infiltrates > 50% within 24 to 48 hours of hospital admission. Life-threatening COVID-19 was defined as 1 or more of the following: respiratory failure, septic shock, and multiple organ dysfunction or failure. To maximize access to COVID-19 convalescent plasma, no exclusion criteria were used, thereby enabling access for populations of vulnerable adults who may not be eligible for clinical trials, including pregnant women and prisoners. Enrollment All hospitals and acute care facilities in the US and its territories, and any physician licensed in the US, were allowed to register for participation provided they agreed to adhere to the treatment protocol, which was available online [21], as well as US FDA and state regulations. All patient registration was facilitated through the central study website [25]. A single consent form, available in 8 languages, was used by all participating sites. Prior to patient enrollment, written informed consent was obtained from the patient or a legally authorized representative, or by means of an emergency consent process for patients in a condition that warranted this process. Criteria for emergency consent were consistent with the federal regulations governing emergency consent [26]. Early COVID-19 convalescent plasma safety reports and details on convalescent plasma transfusion antibody titers have been described elsewhere [22–24]. Distribution and transfusion of COVID-19 convalescent plasma Eligibility for donation of COVID-19 convalescent plasma was established by the US FDA. In brief, convalescent plasma was donated by individuals with evidence of past SARS-CoV-2 infection, as determined by a positive molecular diagnostic test for COVID-19 (i.e., at time of illness) or a positive serological test. A minimum antibody titer against SARS-CoV-2 was not required for convalescent plasma administration under the EAP, in part because there was no readily deployable assay early in the pandemic. Donation was required to be at least 14 days following resolution of COVID-19 symptoms. The eligibility criteria for donation of convalescent plasma changed over the course of the EAP, including relaxation of a requirement for negative testing (e.g., nasopharyngeal swab) for those donating less than 28 days after resolution of symptoms. Convalescent plasma donors had to satisfy all requirements for allogeneic blood donation, including measures to mitigate transfusion-related acute lung injury (TRALI). COVID-19 convalescent plasma was collected by US FDA–licensed or–registered blood collectors (i.e., blood centers or hospital-based collection facilities) using the standard blood collection center procedures for plasma collection that predated COVID-19. The units of convalescent plasma were labeled using a facility-specific ISBT 128 code, which enabled tracking of the blood product from source to patient. After a patient was enrolled, convalescent plasma was ordered directly from a participating blood collector and transfused in accordance with the participating institutions’ transfusion guidelines. Initially, the EAP protocol restricted transfusion to a maximum volume of 400 mL of ABO-compatible convalescent plasma. On May 23, 2020, it became permissible to follow institutional transfusion guidelines (e.g., transfusion of group O units with low-titer anti-A), and repeated dosing of convalescent plasma was allowed. The units of convalescent plasma were tracked from collection through distribution and transfusion. This allowed for comparison of patient enrollment against utilization by location over time. The origin and the distribution of convalescent plasma were mapped using the facility identification code embedded in the ISBT 128 code label of the units of COVID-19 convalescent plasma. Study data Demographic and clinical characteristics of enrolled patients were collected using the Research Electronic Data Capture (REDCap) system (version 9.1.15–10.0.33; Vanderbilt University, Nashville, TN) [27,28]. The online case report forms were designed to optimize convenience. Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, white) and ethnicity (Hispanic/Latino or not Hispanic/Latino) were reported in categories by site personnel in a manner consistent with guidelines provided by the US Office of Management and Budget [29]. The database was updated as needed to fulfill the requirements of the EAP IRB and the data collection requirements of BARDA. As the original goal of data collection was to determine safety among 5,000 patients, updates were needed to capture additional clinical data as enrollment expanded and the study progressed. Additionally, in response to surges in COVID-19 infection rates, data collection instruments were simplified by requiring less detailed demographic and clinical information about transfused patients. Enrollment into the EAP was stopped after the US FDA issued an emergency use authorization (EUA) for COVID-19 convalescent plasma on August 23, 2020. Data clarification requests were sent to participating investigators as needed until the database was locked to further data changes on December 16, 2020. All versions of the study protocol, case report forms with completion instructions, and the informed consent form are publicly available on the study website [25]. COVID-19 epidemiological data sources In order to contextualize whether the patients enrolled in the EAP were reflective of the US population, race and ethnicity data for each state and US territory were retrieved from the US Census Bureau [30], using the same race and ethnicity categories that were collected in the EAP. Confirmed COVID-19 infection rates per day for each US state were obtained from the New York Times database [31]. Hospital referral regions are regional healthcare markets defined by where most residents within that region have their hospitalization stays. The 306 hospital referral regions in the US were retrieved from the Dartmouth Atlas of Health Care [32]. Data on region type (metropolitan, micropolitan, or neither) were obtained from US Census Bureau data [30] and the 2010 Office of Management and Budget standards that define metropolitan and micropolitan areas based on statistical assessments [33]. Micropolitan areas were defined as areas with a population of at least 10,000 and less than 50,000 residents. The US regions of Northeast, South, Midwest, and West were delineated using commonly used regions [34]. Characteristics of US hospitals were retrieved from American Hospital Directory [35] and the Centers for Medicare & Medicaid Services [36]. The potential limitations of the data sources are described in the Discussion. Serious transfusion reactions. All serious transfusion reactions were reported by the treating physicians and independently adjudicated over the course of the study by the IND sponsor and trained designees using National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol criteria [37]. Serious transfusion reactions were defined as transfusion-associated circulatory overload (TACO), TRALI, severe allergic reaction, hypotensive reaction, or death. By definition, all serious transfusion reactions occurred within 6 hours of the COVID-19 convalescent plasma transfusion. The attribution categories used for evaluating the relatedness of serious transfusion reactions to COVID-19 convalescent plasma transfusion included unrelated, possibly related, probably related, and definitely related. Serious transfusion reactions were collected using case report forms completed 4 hours and 7 days after transfusion, with additional forms used to report more serious adverse event information when needed. Statistical considerations. To provide a comprehensive report of enrollment data for the EAP program, descriptive statistics are presented for demographic and clinical variables of interest. To examine enrollment in the EAP over time, dot plots are used to show the number of enrollments, for each US state individually and aggregated by region, by day of the study. Additionally, EAP enrollment was compared to the number of confirmed COVID-19 cases per state over the duration of the study. During the window of EAP enrollment, a moving 7-day average was calculated for daily enrollments and COVID-19 cases within each state that enrolled more than 10 patients in total in the EAP. To compare and visualize relative patterns, these averages were scaled between 0 (lowest cases/enrollments) and 1 (peak cases/enrollments) and overlaid on a geofaceted graph. The geofaceted graph contains 1 cell for each US state that is placed at approximately the same location on the graph as the corresponding geographical location of the state on a map. Differences in geographical access to convalescent plasma through the EAP were assessed by examining enrollment across micropolitan and metropolitan areas and the number of hospitals enrolling patients in each hospital referral region in the US. Crude mortality (observed number of deaths divided by the number of transfused patients) is presented across a range of patient and region characteristics. For this analysis, crude mortality was summarized with 95% confidence intervals; no tests for differences among or between levels were performed. All data were processed using R version 3.6.2.

Discussion Principal findings The US EAP successfully provided access to COVID-19 convalescent plasma to over 105,000 patients, of whom nearly 95,000 patients were transfused with convalescent plasma over the course of 5 months. The EAP provided an efficient model for population-wide procurement, distribution, and infusion of convalescent plasma under a research protocol in a time of crisis. At its conclusion, the program was responsible for the largest number of transfusions of convalescent plasma for a single infectious disease to date. The EAP was initiated to respond to an emerging public health crisis. Both the scale and speed of execution of the program were notable: Over 25,000 hospitalized patients with COVID-19 were transfused with convalescent plasma within the first 11 weeks following the program’s inception. Access to convalescent plasma closely kept pace with increases in confirmed US COVID-19 infections per state over time, and there was substantial inclusion of vulnerable racial and ethnic minority populations. Geographically, enrollment in the EAP occurred in all US states, the District of Columbia, and the US territories of Puerto Rico and the US Virgin Islands. Patients were enrolled from all but 5 of the US national hospital referral regions, and substantial enrollment occurred in both metropolitan and non-metropolitan areas. The rate of serious transfusion reactions was objectively low. The crude 30-day mortality rate in this high-risk patient population was 25.2%. Despite the potential risks associated with plasma transfusion in critically ill patients, these data provide evidence supporting the safety of COVID-19 convalescent plasma. Demographic, chronological, and geographical characteristics of patients enrolled in the EAP. Demographic characteristics of the complete enrolled EAP cohort showed substantial enrollment among patients 60 years of age or older (57.8%), male patients (58.4%), patients of African American or Black race (18.2%), and patients of Hispanic or Latino ethnicity (37.2%). African American or Black race and Hispanic or Latino ethnicity make up 13.4% and 18.5% of the US population, respectively [30]. Previous studies have found that older [39,40], male [40], African American or Black race [39,41,42], and Hispanic or Latino [42] individuals are at higher risk of hospitalization for severe or life-threatening COVID-19. The presented enrollment results from the EAP highlight that this program was able to provide access to COVID-19 convalescent plasma to demographic groups that have experienced the largest disease burden from the US COVID-19 epidemic. Participation in the EAP (both enrollments and transfusions) per day closely tracked the number of cases reported by state as the COVID-19 epidemic developed. Participation during April and May 2020 was high in Northeastern states, whereas in July and August participation peaked in the Southern region of mainland US, in line with the development of “hotspots” in these regions over time [43]. An increase in enrollment in Midwestern states was observed during August 2020, and this increase was also closely associated with an increase in confirmed COVID-19 cases in that region. Although there was widespread participation across US states and territories, there were fewer than 10 patients enrolled in both Vermont (n = 1) and Wyoming (n = 9), representing a small fraction of the total COVID-19 cases in those states. Given that there were no registered clinical trials involving COVID-19 convalescent plasma in these 2 states during the time of the EAP, there may have been regulatory or administrative barriers to participation in trials involving experimental therapeutics for COVID-19. The EAP data reveal a gap between the number of enrolled and the number of transfused patients, particularly during the initial peak of each “wave” of the COVID-19 pandemic. This gap appears to represent the few days required to establish the local/regional infrastructure necessary to set up the collection and transfusion of convalescent plasma. Convalescent plasma was also shared between regions when the epidemic intensified in a certain region. Strengths and limitations. The US EAP for COVID-19 convalescent plasma aimed to provide access to a treatment possibly providing benefit. Many of the trials of convalescent plasma experienced delays due to the unique challenges inherent to undertaking complex research during a public health crisis [44]. The EAP rapidly provided access to important information on the safety of COVID-19 convalescent plasma [23,24] while also providing signals of efficacy through exploratory analyses [22]. One of the federal requirements for an EAP is that it should not interfere with pivotal trials [45]. The EAP for COVID-19 convalescent plasma continuously transmitted data to the US FDA for ongoing evaluation of consistency with federal requirements for an EAP, and the program was not discontinued until the issuance of an EUA, which obviated the need for a convalescent plasma EAP. Numerous challenges were encountered during the development and implementation of this national registry. In the context of competing demands on healthcare resources during the COVID19 pandemic [46], this national registry used a modern design with creative solutions to overcome the epidemiological and logistical challenges of the pandemic [47]. Creative solutions included a central academic IRB for oversight, streamlined registration for sites and physicians, simple online data collection forms, a robust support center that was accessible via email or telephone, minimal patient exclusion criteria, few restrictions on concomitant therapies, and no initiation or monitoring site visits. Several important limitations resulted from this design, however, including impact on data collection during “waves” (i.e., large increases in the number of cases of COVID-19 in the US) of the pandemic, unavailable data due to abridged data collection forms, and missing data due to the nature of a national registry. Additionally, the EAP was designed to provide access to convalescent plasma at hospitals and acute care facilities that were not already part of a clinical trial or did not have the infrastructure to support complex clinical trials. This registry also did not require training of the local investigators or study team members. This pragmatic approach did not ensure the highest quality of data nor completeness of data. Implications for clinical practice and public policy. The success of the EAP in providing rapid access to convalescent plasma, combined with evidence supporting the safety of COVID-19 convalescent plasma, indicates that convalescent plasma is a “common sense” therapeutic that can be mobilized for future infectious disease outbreaks using the EAP methods as a model. In this regard it is noteworthy, given that COVID-19 convalescent plasma clinical trials were limited to only a few institutions, that most patients treated with plasma would have had no access without the EAP or single-patient eIND applications. The high use of convalescent plasma within the EAP indicates a high level of acceptance for this therapy by patients and frontline physicians despite the absence of high-quality data for its clinical efficacy. The EAP design was particularly effective in providing access to a potentially effective treatment in minority demographic groups and rural areas that are often underrepresented in US randomized controlled trials [48,49]. Conclusion The EAP provided rapid and broad access to convalescent plasma throughout the US and some US territories and was effective at providing therapy for demographic groups that were severely affected by COVID-19. Over time, the EAP provided access to convalescent plasma in response to sudden and exponential changes in SARS-CoV-2 infection rates. Data gathered from the EAP established that COVID-19 convalescent plasma was generally safe [23,24], and the EAP provided key efficacy data that were an important component of the scientific evidence considered by the US FDA in the decision to issue an EUA [22] for convalescent plasma in the treatment of hospitalized adults with COVID-19. Hence, this program established that it is possible to obtain relevant and actionable safety and efficacy data during pandemic conditions. The efficient study design of the EAP may serve as an example for future efforts when broad access to a treatment is needed in response to a rapidly developing infectious disease, providing access in areas typically underrepresented in clinical studies and thereby allowing capture of demographic groups that are often poorly represented in clinical trials.

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