FDA Implementation of the Expanded Access Program in the United States

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a difficult to predict, and potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). VOD/SOS develops via a pathophysiologic cascade, and VOD/SOS with multi-organ dysfunction (MOD)/multi-organ failure (MOF) may be associated with >80% mortality. Defibrotide was recently approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and is approved in the European Union to treat severe hepatic VOD/SOS post-HSCT. In the United States, defibrotide had been available through an expanded-access program. Methods Patients in the expanded-access program were diagnosed with VOD/SOS by investigators using Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of the following: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of the following: total bilirubin >2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy; elevated bilirubin was not required for patients with biopsy or who met modified Seattle criteria by presence of hepatomegaly with ascites/weight gain. This program included patients with or without MOD/MOF (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Here, Day +100 survival post-HSCT is explored post hoc based on 4 bilirubin-level categories at time of study entry; together these categories have been defined as 1 of the criteria in the proposed VOD/SOS grading scale for adults from the European Society for Blood and Marrow Transplantation (EBMT; ≥2 mg/dL to <3 mg/dL, ≥3 mg/dL to <5 mg/dL, ≥5 mg/dL to <8 mg/dL, and ≥8 mg/dL [Mohty M et al. Bone Marrow Transplant. 2016;51:906-912]). It is important to note that bilirubin <2 mg/dL is not part of the proposed EBMT criteria for VOD/SOS in adults. Results Among 756 post-HSCT patients enrolled through April 18, 2015, who received ≥1 dose of defibrotide, 427 also had MOD/MOF. Median age was lowest in patients with bilirubin <2 mg/dL (5 years). By comparison, median age in patients with bilirubin ≥2 to <3 mg/dL (56% of all patients) was 16 years; for bilirubin ≥3 to <5 mg/dL, median age was 13 years; and for the 2 small groups with bilirubin ≥5 to <8 or ≥8 mg/dL, median ages were 15 and 16.5 years, respectively. Day +100 survival in the overall HSCT population of the expanded-access program was 55.4% by Kaplan-Meier estimate. The survival rate was 81.4% in patients with bilirubin <2 mg/dL; for patients with bilirubin levels ≥2 mg/dL, who tended to be older, survival estimates decreased (Table). Day +100 survival patterns by bilirubin level were generally similar in the subgroups of patients with and without MOD/MOF (Table). Overall, 515 post-HSCT patients (67%) reported ≥1 adverse event (AE). Serious AEs were reported by 386 patients (50%), and AEs leading to death occurred in 250 patients (33%). Among all AEs, 158 patients (21%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication. Conclusions Overall, higher bilirubin levels were associated with worse Day +100 outcomes (with the exception of the ≥5 to <8 mg/dL group, which represented only 5% of patients, and so has limited validity). However, interpretation of these results has to be treated with caution because only a single criterion from the EBMT guidelines was analyzed and because potentially confounding interactions (eg, age) were not assessed. Across all bilirubin-level categories, VOD/SOS with MOD/MOF was consistently associated with worse outcomes than VOD/SOS without MOD/MOF. These results further support the importance of identifying VOD/SOS earlier and suggest that diagnosis and treatment of VOD/SOS, before bilirubin becomes markedly elevated, may be associated with improved outcomes. Support: Jazz Pharmaceuticals. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kernan:Gentium: Research Funding; The National Cancer Institute of the National Institutes of Health: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer:GentiumSpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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

PLoS Medicine ◽

10.1371/journal.pmed.1003872 ◽

2021 ◽

Vol 18 (12) ◽

pp. e1003872

Author(s):

Jonathon W. Senefeld ◽

Patrick W. Johnson ◽

Katie L. Kunze ◽

Evan M. Bloch ◽

Noud van Helmond ◽

...

Keyword(s):

United States ◽

Clinical Trials ◽

The United States ◽

Registry Study ◽

National Hospital ◽

Expanded Access Program ◽

Hospital Referral ◽

Life Threatening ◽

Widespread Access ◽

Access Program

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.

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Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) Post-Hematopoietic Stem Cell Transplantation (HSCT) in Patients with Acute Leukemias: A Subgroup Analysis from the Defibrotide Expanded-Access Program

Blood ◽

10.1182/blood.v128.22.3412.3412 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3412-3412

Author(s):

Paul G. Richardson ◽

Angela R. Smith ◽

Brandon M. Triplett ◽

Nancy A. Kernan ◽

Stephan A. Grupp ◽

...

Keyword(s):

Board Of Directors ◽

Stock Options ◽

Research Funding ◽

The United States ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Expanded Access ◽

Expanded Access Program ◽

Kaplan Meier ◽

Access Program

Abstract Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning for hematopoietic stem cell transplant (HSCT). Reported mean incidence of VOD/SOS following HSCT is an estimated 13.7% (range 0%-62.3%). VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Endothelial cell (EC) damage, triggered by cytotoxic chemotherapeutic conditioning regimens and a prothrombotic-hypofibrinolytic state, is a critical factor in the pathophysiology of VOD/SOS. In the United States, defibrotide is approved for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT, and in the European Union, defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT. Prior to its approval, defibrotide had been available in the United States through an expanded-access program. Here, Day +100 post-HSCT survival and safety are analyzed for the 2 largest primary-disease subgroups in that study: acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Methods Patients in the expanded-access program had VOD/SOS diagnosed by Baltimore criteria (bilirubin ≥2 mg/dL and ≥2 of: hepatomegaly, ascites, ≥5% weight gain), modified Seattle criteria (≥2 of: total bilirubin >2 mg/dL, hepatomegaly, or ascites and/or ≥5% weight gain [in this study]), or biopsy, and this study included patients with or without MOD (defined by renal and/or pulmonary dysfunction). Defibrotide 25 mg/kg/day was given in 4 divided doses for a recommended ≥21 days. Results A total of 867 patients were enrolled in the safety population of the expanded-access program through April 18, 2015, including 476 patients with MOD. The primary diseases affecting 5% or more of the safety population at baseline were AML, 25.7% (222/867); ALL, 23.4% (202/867); neuroblastoma, 8.5% (73/867); and myelodysplastic syndrome, 5.7% (27/867). Data were available for 756 post-HSCT patients who received ≥1 dose of defibrotide. Of those patients, 207 (27.4%) patients had AML and 152 (20.1%) patients had ALL as their primary disease. Of the AML patients, 49.8% (103/207) were male, and 50.2% (104/207) were female; median age at HSCT was 23 years (range: 0.5, 74.0 years); and all had allogeneic HSCT. Among the ALL patients, 62.5% (95/152) were male, and 37.5% (57/152) were female; median age at HSCT was 16 years (range: 0.3, 68.0 years); and all had allogeneic HSCT. At Day +100 post-HSCT, observed survival was 45.4% (94/207) among AML patients and 42.8% (65/152) among ALL patients; 50.7% (105/207) and 52.0% (79/152), respectively, had died; and status was not available (ie, no HSCT date recorded, did not have sufficient follow-up, or their data were not available) for 3.9% (8/207) and 5.3% (8/152), respectively. For AML patients, Kaplan-Meier estimated survival rate was 47.8% (95% confidence interval [CI], 40.7%-54.5%; Figure 1); among ALL patients, Kaplan-Meier estimated survival rate was 46.0% (95% CI, 37.7%-53.9%; Figure 2). Adverse events (AEs) occurred in 76.8% (159/207) of AML patients and 64.5% (98/152) of ALL patients, with serious AEs in 57.5% (119/207) and 52.6% (80/152), respectively. Treatment-related AEs, as assessed by investigators, occurred in 21.7% (45/207) of AML patients and 17.1% (26/152) of ALL patients (>2% in either group [all <4%]: pulmonary hemorrhage, epistaxis, gastrointestinal hemorrhage, hypotension). Treatment-related AEs leading to discontinuation developed in 14.5% (30/207) of AML patients and 8.6% (13/152) of ALL patients (>2% in either group [all <3%]: pulmonary hemorrhage, gastrointestinal hemorrhage); treatment-related deaths occurred in 3.4% (7/207) of AML patients and 2.6% (4/152) of ALL patients, respectively, with none occurring in >1 patient in either subgroup. Conclusions The Day +100 survival rates and safety profile for the AML and ALL subgroups in the expanded-access program were consistent with prior defibrotide studies and analyses of the overall HSCT population in this study. Kaplan-Meier estimates of survival at Day +100 were similar between the AML (47.8%) and ALL (46.0%) subgroups. Taken together, these subgroup results affirm the overall efficacy and safety profile of defibrotide in post-HSCT patients with VOD/SOS and underlying acute leukemia. Support: Jazz Pharmaceuticals. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kernan:The National Cancer Institute of the National Institutes of Health: Research Funding; Gentium: Research Funding. Grupp:Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees.

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Tazemetostat Expanded Access Program for Adults With Epitheliloid Sarcoma

Case Medical Research ◽

10.31525/ct1-nct04225429 ◽

2020 ◽

Author(s):

Keyword(s):

Expanded Access ◽

Expanded Access Program ◽

Access Program

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IPILIMUMAB IN PATIENTS WITH DISSEMINATED MELANOMA: THE N.N. PETROV NATIONAL MEDICAL RESEARCH CENTER OF ONCOLOGY EXPANDED ACCESS PROGRAM EXPERIENCE

Problems in oncology ◽

10.37469/0507-3758-2018-64-3-388-393 ◽

2018 ◽

Vol 64 (3) ◽

pp. 388-393

Author(s):

Yekaterina Anokhina ◽

V. Rubinchik ◽

Yekaterina Yaremenko ◽

Gulfiya Teletaeva ◽

Dilorom Latipova ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Medical Research ◽

Research Center ◽

Expanded Access ◽

Risk Of Death ◽

National Medical ◽

Expanded Access Program ◽

Access Program

Ipilimumab (IPI) provides a ten-year overall survival in almost 20 % of selected patients participated in several phase II-III trials. However, the expanded access program (EAP) looks more like routine practice than like clinical trials& This is why the results of such application could be different. Here we present the long-term follow-up data of single center EAP. Ninety-six patients with disseminated melanoma progressing after at least one lines of drug therapy were included at the N.N. Petrov National Medical Research Center of Oncology. Sixty-seven (70 %) patients had stage IV M1c, 35 patients (36 %) had elevated LDH before initiating IPI therapy. All patients received IPI 3 mg / kg IV every 3 weeks for a maximum of 4 cycles. Totally, 320 cycles (mean - 3.3 per patient) were conducted. Grade 3-4 immuno-mediated adverse events (imAE) observed in 18 (19 %) patients. Three patients died of adverse events, possibly associated with ongoing therapy. The median time to progression was 3 (95 % CI, 2.4 to 3.5) mo., the median overall survival was 13 (95 % CI, 8.3 to17.6) mo. Previous immunotherapy with dendritic cell vaccines decreased the risk of death by 48 % (Log-rank p = 0.049). The wild type BRAF status increased three-year overall survival from 29 to 68 % (p = 0.042). Our data confirms long-term safety and efficacy of IPI in patients with pretreated disseminated melanoma in the close to real practice setting.

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