Causality Assessment in Premarketing Drug Clinical Trials: Regulatory Evolution in the USA and Ongoing Concerns

Abstract Since 1993, how to assess the causality of serious adverse events in premarketing drug clinical trials has undergone sustained regulatory evolution in the USA. In that year, an investigational drug study for chronic hepatitis B virus infection was emergently stopped after a patient suddenly exhibited hepatic failure and lactic acidosis, which later developed, along with pancreatitis and peripheral neuropathy, in several others after drug discontinuation. Five patients eventually died, including three despite emergency liver transplantation. The drug ’s multisystem toxicity was not predicted by preclinical animal studies, with grave injury to human mitochondria subsequently implicated. A concerned US Food and Drug Administration (FDA) created a task force whose findings would have a lasting impact on the agency’s thinking. In 1994, the FDA p roposed to amend its investigational new drug reporting requirements largely based on task force recommendations for ways to enhance the likelihood that sponsors and investigators would consider investigational agents as a possible cause of serious adverse events mimicking the underlying disease or concomitant drug toxicity. Then, in its 1997 final rule for expedited safety reporting requirements for drugs and biologics, the FDA advised sponsors that such reporting of serious, unexpected clinical trial cases would be expected when “there is a reasonable suspected causal relationship between the investigational p...
Source: Drug Safety - Category: Drugs & Pharmacology Source Type: research

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Transplant patients and people with lung diseases are among those who have been missed off the list.
Source: BBC News | Health | UK Edition - Category: Consumer Health News Source Type: news
The Fontan procedure is often the only definitive palliative surgical option for patients with a variety of complex CHD sharing in common, a single, dominant ventricle. In recent decades, imaging and therapeutic improvement have played a crucial role in those patients in whom many complications can hamper their life. After 50 years from the first procedure, heart transplantation remains the only definitive treatment for those with a failing Fontan circulation.
Source: Journal of Cardiovascular Medicine - Category: Cardiology Tags: Review Source Type: research
Immunosuppression continues to be a necessary component of transplantation, despite its association with a multitude of adverse effects. Numerous efforts have been made to circumvent the need for immunosuppression by using various techniques to achieve donor hyporesponsiveness. In this issue of the JCI, Morath et al. take this endeavor forward. Prior to transplantation, the researchers infused recipients with donor-modified immune cells and achieved immunologic hyporesponsiveness. This successful phase I trial also provides a possible avenue for achieving transplantation without the requisite immunosuppression.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
CONCLUSION MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.TRIAL REGISTRATION EudraCT number: 2014-002086-30; ClinicalTrials.gov identifier: NCT02560220FUNDING Federal Ministry for Economic Affairs and Technology, Berlin, Germany, and TolerogenixX GmbH, Heidelberg, Germany.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Publication date: Available online 5 April 2020Source: Biochimica et Biophysica Acta (BBA) - BiomembranesAuthor(s): Laurent Mailly, Thomas F. Baumert
Source: Biochimica et Biophysica Acta (BBA) Biomembranes - Category: Biochemistry Source Type: research
We take steps toward causally interpretable meta-analysis by describing methods for transporting causal inferences from a collection of randomized trials to a new target population, one trial at a time and pooling all trials. We discuss identifiability conditions for average treatment effects in the target population and provide identification results. We show that the assumptions that allow inferences to be transported from all trials in the collection to the same target population have implications for the law underlying the observed data. We propose average treatment effect estimators that rely on different working mode...
Source: Epidemiology - Category: Epidemiology Tags: Methods Source Type: research
The aim of this study was to investigate the regulatory function of the non-coding microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS1) in alcoholic hepatitis (AH) and its potential mechanism associated with the mitogen-activated protein kinase (MAPK) signaling pathway. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured in a rat model of AH. The biological prediction website microRNA.org and dual-luciferase reporter gene assay were used to identify whether SOCS1 was a direct t...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 16 March 2020Source: Best Practice &Research Clinical Obstetrics &GynaecologyAuthor(s): Terence T. Lao
Source: Best Practice and Research Clinical Obstetrics and Gynaecology - Category: OBGYN Source Type: research
Purpose of review The available vaccine and therapies against hepatitis B virus (HBV) rarely eliminate chronic infection with the virus. High mortality resulting from complicating cirrhosis and hepatocellular carcinoma makes improving anti-HBV therapy an important priority. Recent advances with using gene therapy to counter HBV have potential and are the focus of this review. Recent findings The stable replication-competent HBV intermediate comprising covalently closed circular DNA (cccDNA) is the template for expression of all viral genes. Inactivating cccDNA has thus been a focus of research aimed at achieving cure ...
Source: Current Opinion in HIV and AIDS - Category: Infectious Diseases Tags: HIV AND HEPATITIS B CURE: Edited by Sharon R. Lewin and Peter A. Revill Source Type: research
Purpose of review The cure for hepatitis C virus infection has raised hope for a potential hepatitis B virus (HBV) cure, but the high price tag has led to serious questions about the affordability, and thus to access for all. This review discusses cost-effectiveness models, affordability, and access to a potential new cure for chronic HBV infection. Recent findings A cure does not yet exist for HBV, but the antiviral treatments that are currently available help slow down the progression of disease. There is limited research in the area of cost-effectiveness and economic analysis comparing a potential cure. Our prelimi...
Source: Current Opinion in HIV and AIDS - Category: Infectious Diseases Tags: HIV AND HEPATITIS B CURE: Edited by Sharon R. Lewin and Peter A. Revill Source Type: research
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