IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival. APPROACH AND RESULTS: Subjects with a clinical diagnosis of severe AH (Model for End-Stage Liver Disease [MELD] >20, Maddrey discriminant function [MDF] >32) were randomized to receive methylprednisolone (PRED; 28 days) or a combination of anakinra (14 days) plus pentoxifylline (28 days) plus zinc (COMB; 180 days). The primary endpoint was survival at 180 days. The study was designed in 2013, initiated in October 2014, and completed in March 2018. Five hundred patients were screened to randomize 104 subjects with a clinical diagnosis of AH with a MELD score >20. Fifty-three patients were randomized into the COMB and 50 to the PRED treatment; 1 dropped out of the study before randomization. Mean age was 45.3 ± 10.4 years; 60.6% were males, 92.3% White, and mean MELD 25.7 ± 3.9. Kaplan-Meier survival estimate at 180 days was 67.9% in COMB and 56% in PRED (HR = 0.69; p = 0.3001). Survival curves separated by 90 days (COMB, 69.8%; PRED, 58.0%; HR = 0.69; p = 0.28). Survival at 28 days was similar between the COMB (83.4%) and PRED groups (81.2%; HR = 0.91; p = 0.85). There were no unexpected serious adverse events, and incidence of infection was comparable between groups. MELD 20-25 and MELD >26 strata showed nonsignificant treatment effects in favor of COMB. CONCLUSIONS: A combination of anakinra, pentoxifylline plus zinc provides similar survival benefits compared to corticosteroid therapy in severe AH.

Experience, Perceptions, and Recommendations Concerning COVID-19-Related Clinical Research Adjustments.

BACKGROUND: During the COVID-19 public health emergency, the FDA and NIH altered clinical trial requirements to protect participants and manage study conduct. Given their detailed knowledge of research protocols and regular contact with patients, clinicians, and sponsors, clinical research professionals offer important perspectives on these changes. METHODS: We developed and distributed an anonymous survey assessing COVID-19-related clinical trial adjustment experiences, perceptions, and recommendations to Clinical Research Office personnel at the Harold C. Simmons Comprehensive Cancer Center. Responses were compared using the Fisher exact test. RESULTS: A total of 94 of 109 contacted research personnel (87%) responded. Among these individuals, 58% had >5 years' professional experience in clinical research, and 56% had personal experience with a COVID-19-related change. Respondents perceived that these changes had a positive impact on patient safety; treatment efficacy; patient and staff experience; and communication with patients, investigators, and sponsors. More than 90% felt that positive changes should be continued after COVID-19. For remote consent, telehealth, therapy shipment, off-site diagnostics, and remote monitoring, individuals with personal experience with the specific change and individuals with >5 years' professional experience were numerically more likely to recommend continuing the adjustment, and these differences were significant for telehealth (P=.04) and therapy shipment (P=.02). CONCLUSIONS: Clinical research professionals perceive that COVID-19-related clinical trial adjustments positively impact multiple aspects of study conduct. Those with greatest experience-both specific to COVID-19-related changes and more generally-are more likely to recommend that these adjustments continue in the future.

Warning letters to sponsor-investigators at academic health centres - the regulatory "canaries in a coal mine".

PURPOSE: This study highlights Warning Letter (WL) findings issued to sponsor-investigators (S-Is) by the Food and Drug Administration (FDA). METHODS: The online index of WLs issued from October 1, 2007 through September 30, 2012 was reviewed [1]. Through a manual screening process, letters were evaluated if specifically issued to 'clinical investigators', 'sponsors' or 'sponsor-investigators'. A particular focus was given to S-Is at Academic Health Centres (AHCs). Each letter was scored for the presence of violations in 40 general regulatory categories. RESULTS: A review of FDA WLs issued over a five-year period (FDA Fiscal Years 2008-2012) revealed that WLs to S-Is represent half of the WLs issued to all sponsors (16 of 32 letters). A review of these letters indicates that S-Is are not aware of, or simply do not meet, their regulatory responsibilities as either investigators or sponsors. In comparing total sponsor letters to those of S-Is, the most cited violation was the same: a lack of monitoring. A review of publicly available inspection data indicates that these 16 letters merely represent the tip of the iceberg. CONCLUSION: This review of the WL database reveals the potential for serious regulatory violations among S-Is at AHCs. Recent translational funding initiatives may serve to increase the number of S-Is, especially among Academic Health Centres (AHCs) [2]; thus, AHCs must become aware of this S-I role and work to support investigators who assume both roles in the course of their research.

Longitudinal Experience With and Impressions of COVID-19-Related Clinical Research Changes.

PURPOSE: The COVID-19 pandemic has led to profound changes in clinical research, including remote consent, telehealth, off-site procedures, shipment of therapy, and remote study monitoring. We assessed longitudinal perceptions of these adjustments among clinical research professionals. METHODS: We distributed an anonymous survey assessing experiences, perceptions, and recommendations regarding COVID-19-related clinical research adjustments to cancer clinical research office personnel in May 2020 and again in November 2020. Responses were compared using Fisher's exact and Mann-Whitney U tests. RESULTS: A total of 90 of 102 invited research personnel (88%) responded. Fifty-three (59%) reported participating in both initial and follow-up surveys. The proportion of respondents reporting personal experience with COVID-19-related adjustments increased over time, particularly for remote initial consent (29% v 4%), remote reconsent (24% v 9%), and remote study monitoring (36% v 22%). Perceived impact of COVID-19-related adjustments on data quality (P = .02) and patient experience (P = .002) improved significantly. However, perceived effect on patient safety (P = .02) and respondent's experience (P = .09) became less favorable. Individuals with personal experience with the adjustment were more likely to recommend continuing remote consent (62% v 38%; P = .04), remote monitoring (69% v 45%; P = .05), and therapy shipment (67% v 35%; P = .01) after the COVID-19 pandemic, with nonsignificant trends for off-site diagnostics (44% v 24%; P = .13) and telehealth visits (66% v 45%; P = .08). CONCLUSION: More than 6 months into the global pandemic, perceptions of COVID-19-related clinical research changes remain favorable. Experienced individuals are more likely to recommend that these changes continue in the future.

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.

Understanding FDA regulatory requirements for investigational new drug applications for sponsor-investigators.

Clinical investigators invoke a number of specific regulatory requirements if their study includes use of a pharmaceutical agent. Studies using a drug that has not been approved by the Food and Drug Administration (FDA) or for indications not in the approved labeling may require filing an Investigational New Drug (IND) application with the FDA. If a study meets specific regulatory exemption criteria, then an IND may not be needed. Individual investigators may meet the FDA definition of a sponsor-investigator, in which case the application process is generally less complicated than for commercial sponsors, and this review addresses only this circumstance. Filing an IND requires completion of 3 sets of forms: 1 detailing the study (FDA Form 1571), 1 providing information about the investigator and study site (FDA Form 1572), and 1 certifying that the study is registered in the national database of clinical trials (FDA Form 3674). If the IND is approved, the study may begin 30 days after the FDA acknowledges receipt and assigns an IND. If the FDA requires additional information or if the study is placed on a "clinical hold," the study must not proceed. While the IND is active, the investigator must also continue to meet a set of regulations for monitoring the study and reporting to the FDA.

Via media: Role and responsibilities of the independent safety officer.

Every research study that includes volunteer participants requires safety assurances in proportion to the risks of the study. Investigator-initiated clinical research can present unique regulatory challenges particularly for studies with a risk profile that warrants more oversight than minimal risk but less than for large, commercial, or high-risk research. The use of an independent safety officer (ISO) offers a middle way of right-sizing oversight to match the risk. ISOs are clinicians or researchers with relevant expertise who are independent of the investigator and the research study. Their relationship to the study is defined by a formal charter which is aligned with the protocol and Data and Safety Monitoring Plan to address the oversight process, responsibilities of the ISO, and clearly describe the variables to be monitored. The ISO responsibilities include reviewing safety data, adverse events, recruitment, demographics, study progress, data quality, protocol changes, and any new scientific information that pertains to the trial. Finally, the ISO reports in their review on any significant findings may propose modifications to the study or a need to stop the trial.

Count me in: using a patient portal to minimize implicit bias in clinical research recruitment.

OBJECTIVE: Determine whether women and men differ in volunteering to join a Research Recruitment Registry when invited to participate via an electronic patient portal without human bias. MATERIALS AND METHODS: Under-representation of women and other demographic groups in clinical research studies could be due either to invitation bias (explicit or implicit) during screening and recruitment or by lower rates of deciding to participate when offered. By making an invitation to participate in a Research Recruitment Registry available to all patients accessing our patient portal, regardless of demographics, we sought to remove implicit bias in offering participation and thus independently assess agreement rates. RESULTS: Women were represented in the Research Recruitment Registry slightly more than their proportion of all portal users (n = 194 775). Controlling for age, race, ethnicity, portal use, chronic disease burden, and other questionnaire use, women were statistically more likely to agree to join the Registry than men (odds ratio 1.17, 95% CI, 1.12-1.21). In contrast, Black males, Hispanics (of both sexes), and particularly Asians (both sexes) had low participation-to-population ratios; this under-representation persisted in the multivariable regression model. DISCUSSION: This supports the view that historical under-representation of women in clinical studies is likely due, at least in part, to implicit bias in offering participation. Distinguishing the mechanism for under-representation could help in designing strategies to improve study representation, leading to more effective evidence-based recommendations. CONCLUSION: Patient portals offer an attractive option for minimizing bias and encouraging broader, more representative participation in clinical research.

Access to Investigational Drugs: FDA Expanded Access Programs or "Right-to-Try" Legislation?

PURPOSE: The Food and Drug Administration Expanded Access (EA) program and "Right-to-Try" legislation aim to provide seriously ill patients who have no other comparable treatment options to gain access to investigational drugs and biological agents. Physicians and institutions need to understand these programs to respond to questions and requests for access. METHODS: FDA EA programs and state and federal legislative efforts to provide investigational products to patients by circumventing FDA regulations were summarized and compared. RESULTS: The FDA EA program includes Single Patient-Investigational New Drug (SP-IND), Emergency SP-IND, Intermediate Sized Population IND, and Treatment IND. Approval rates for all categories exceed 99%. Approval requires FDA and Institutional Review Board (IRB) approval, and cooperation of the pharmaceutical partner is essential. "Right-to-Try" legislation bypasses some of these steps, but provides no regulatory or safety oversight. CONCLUSION: The FDA EA program is a reasonable option for patients for whom all other therapeutic interventions have failed. The SP-IND not only provides patient access to new drugs, but also maintains a balance between immediacy and necessary patient protection. Rather than circumventing existing FDA regulations through proposed legislation, it seems more judicious to provide the knowledge and means to meet the EA requirements.

Intraventricular hemorrhage and vitamin E in the very low-birth-weight infant: evidence for efficacy of early intramuscular vitamin E administration.

To determine whether early intramuscular vitamin E supplementation influences the incidence of intraventricular hemorrhage (IVH) in infants with birth weight less than or equal to 1,500 g, data were analyzed from 134 infants enrolled on a protocol to evaluate the efficacy of intramuscular plus oral vitamin E v oral supplementation alone in the treatment of retrolental fibroplasia. All 134 infants received, via nasogastric tube, 100 mg/kg/d of vitamin E daily (dl-alpha-tocopheryl acetate in MCT [medium-chain triglyceride] oil; 150 mosM) for at least 8 weeks with the first dose administered within the first eight hours of life. Sixty-four patients received, in addition, intramuscular vitamin E on days 1, 2, 4, and 6 of life and 70 patients received placebo injections in a randomized double-blind fashion. In the first week, vitamin E plasma levels were significantly higher in the 64 patients given intramuscular vitamin E. In spite of this difference no change in the incidence of sepsis or necrotizing enterocolitis was observed. Both the incidence and severity of intraventricular hemorrhage were reduced significantly in the patients given intramuscular vitamin E as compared to the patients given placebo (P = .013 and P = .04, respectively). The data suggest that vitamin E, a natural antioxidant, may play an important role in protecting the CNS microcirculation from the effects of hypoxic/ischemic injury.

Retrolental fibroplasia and vitamin E in the preterm infant--comparison of oral versus intramuscular:oral administration.

To evaluate the efficacy of four early intramuscular injections of vitamin E given in addition to continuous minimal oral vitamin E supplementation, 168 very low-birth-weight infants (less than or equal to 1,500 g) have enrolled in a randomized, double-masked, clinical study. All infants received vitamin E orally, 100 mg/kg/d. In addition, on days 1, 2, 4, and 6, seventy-nine infants received vitamin E intramuscularly, 15, 10, 10, and 10 mg/kg, respectively. On the same days, 89 control infants received placebo intramuscular injections. Multivariate analysis of the 135 infants who survived greater than or equal to 10 weeks showed no significant difference in the development of severe retrolental fibroplasia between these two supplementation schedules (P = .86). Plasma vitamin E levels never exceeded a mean of 3.3 mg/100 mL, and no toxicity was observed. Ultrastructural analyses of seven pairs of whole eye donations from infants receiving IM vitamin E demonstrated identical kinetics of gap junction formation between adjacent spindle cells as compared with 13 pairs of whole eye donations from control infants (P greater than .3). Therefore, oral vitamin E supplementation affords retinal protection against the development of severe retrolental fibroplasia when initiated on the first day of life and maintained continuously until retinal vascularization is complete.

Exercise-associated collapse in cyclists is unrelated to endotoxemia.

Endotoxemia occurs when intestinal ischemia allows bacterial lipopolysaccharide to translocate from colonic flora into the bloodstream, which triggers release of cytokines that can cause hypotension, rigors, fever, shock, and even death. Recently, blood endotoxin levels were shown to be higher in athletes needing medical attention (330 pg.ml-1) than in their competitors with similar performances (81 pg.ml-1). Though there were no data showing that these athletes had elevated core temperatures or severe illness, speculation followed that endotoxin may play a causal role in heat stroke. We examined the relationship between endotoxemia and mild post-exertional illness in 39 cyclists after a 100-mile ride. Thirteen cyclists had at least one of the following: orthostatic hypotension, rigors, nausea, vomiting, diarrhea, or syncope. Only 2/26 case-controls had any of these symptoms. Data were collected on vital signs, hemoglobin, sodium, creatine kinase, creatinine, and uric acid. Endotoxin titer was determined by chromogenic assay; tumor necrosis factor alpha (TNF-alpha) titer was determined by ELISA. One ill cyclist had an endotoxin level of 330 pg.ml-1, one control had an endotoxin level of 150 pg.ml-1, but endotoxin level was < or = 64 pg.ml-1 in all others. Comparison of pre- and post-ride data showed that controls increased creatine kinase activity (154 +/- 34 vs 561 +/- 191 IU.dl, P < 0.05), creatinine concentration (1.5 +/- 0.0 vs 1.6 +/- 0.0 mg.dl-1, P < 0.05), and uric acid concentration (5.4 +/- 0.3 vs 6.3 +/- 0.3 mg.dl-1, P < 0.05). Ill cyclists had lower serum sodium than post-ride controls (138 +/- 2 vs 142 +/- 0.6 mEq.l-1, P < 0.05), but there were no differences between groups in CK, creatinine, or uric acid. These findings suggest that endotoxemia may complicate, but does not cause mild post-exertional illness in cyclists.

Recommendations from the Investigational New Drug/Investigational Device Exemption Task Force of the clInical and Translational Science Award Consortium: developing and implementing a sponsor-investigators training program.

OBJECTIVE: The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers. BACKGROUND: A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role. METHODS: The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation. RECOMMENDATIONS: The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration-regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.

Understanding Food and Drug Administration regulatory requirements for an investigational device exemption for sponsor-investigators.

Clinical investigators in academic medical centers often perceive federal regulations as a significant obstacle to conducting clinical research. The regulatory authority of the Food and Drug Administration (FDA) extends to clinical studies of medical devices. Consequently, researchers wishing to conduct device research using FDA-approved as well as nonapproved devices must comply with federal regulations for investigational device exemptions (IDE) as described in Title 21 of the Code of Federal Regulations Part 812. FDA regulatory oversight is structured to match the risk to the subject to the risk of the device. Medical device studies can be categorized as follows: meeting exemption criteria, being a nonsignificant risk device, or being a significant risk device. All IDE studies must meet regulations for the protection of human subjects, but no additional federal filing on the part of the investigator is necessary for those that meet exempt criteria. Nonsignificant risk device studies require meeting abbreviated IDE regulatory requirements for the conduct of the study, but no previous FDA approval is required. Significant risk device studies require that the investigator also function as a sponsor and to file an IDE with the FDA for approval before starting. A sponsor-investigator filing an IDE follows the format and content described in 21 CFR 812.20. The study may begin 30 days after the date of submission receipt unless the FDA notifies the sponsor otherwise. While the IDE is active, the sponsor-investigator must meet the requirements for the conduct of the study and the required monitoring and reporting to the FDA.

Cost-effectiveness of monoclonal antibodies to gram-negative endotoxin in the treatment of gram-negative sepsis in ICU patients.

OBJECTIVE: To evaluate the fiscal impact and the cost-effectiveness of monoclonal antibodies against gram-negative endotoxin (MAbGNE) in the treatment of presumed gram-negative sepsis. DESIGN: A decision analysis model was developed from (1) data from two phase III trials that studied the E5 or HA-1A MAbGNE, and (2) financial data from 1405 septic patients who required intensive care at a large tertiary hospital. SETTING: Intensive care unit (ICU) patients with presumed gram-negative sepsis. PATIENTS: The E5 trial evaluated 468 patients, and the HA-1A study enrolled 543 patients with presumed gram-negative sepsis. INTERVENTIONS: The addition of MAbGNE to standard regimens or standard regimens alone. MAIN OUTCOME MEASURES: Total expected charges and the expected probability of survival were determined for each option. Cost-effectiveness and marginal cost-effectiveness ratios were also derived. Multiple sensitivity and Monte Carlo analyses were performed to test the underlying assumptions. RESULTS: MAbGNE therapy always resulted in higher expected charges; however, these differences were less than its acquisition cost by $870. The cost-effectiveness ratio for MAbGNE, for $2000 and $4000 acquisition costs, was $71,674 and $74,900 per probability of survival, respectively. Sensitivity analysis showed that cost-effectiveness was most affected by diagnostic accuracy, patient selection, and acquisition cost. Monte Carlo analysis showed that MAbGNE was more costly for 71% of simulations, yet the most efficacious option for 79% of simulations. CONCLUSIONS: From the perspective of acute care institutions, MAbGNE is expensive and cannot be justified on a cost-saving basis. However, it may be cost-effective throughout a reasonable range of assumptions.