ArticleBritish journal of clinical pharmacology2016
Implications of the BIA-102474-101 study for review of first-into-human clinical trials.
Article in British journal of clinical pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Pooled it
- Safety, Tolerability, and Pharmacokinetics of FAAH Inhibitor BIA 10-2474: A Double-Blind, Randomized, Placebo-Controlled Study in Healthy Volunteers.Clinical pharmacology and therapeutics · 2022Trial
- Enhancing anandamide signalling through fatty acid amide hydrolase inhibition: An update on the pharmacological strategy for treating psychiatric disorders.Translational psychiatry · 2026Review
- Sentinel dosing: A proposed algorithm to guide decision making on which cohorts in early phase clinical pharmacology trials should use this approach.British journal of clinical pharmacology · 2025Article
- Neural organoids as advanced tools for neurotoxicity modeling.Current research in toxicology · 2025Review
- Review
- Adopting human factors in early phase and experimental medicine research: A nested pilot study observing controlled human infection with SARS-CoV-2.British journal of clinical pharmacology · 2024Article
- Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician's Perspective.Brain sciences · 2024Review
- CSL-Tox: an open-source analytical framework for the comparison of short-term and long-term toxicity end points and assessing the need of chronic studies in drug development.Scientific reports · 2023Article
- The role of endocannabinoids in consolidation, retrieval, reconsolidation, and extinction of fear memory.Pharmacological reports : PR · 2021Review
- The endocannabinoid system - current implications for drug development.Journal of internal medicine · 2021Review
- A pharmacological characterization of Cannabis sativa chemovar extracts.Journal of cannabis research · 2020Article
- Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Is it Time to Rethink Our Current Approach?JACC. Basic to translational science · 2019Article
- Adverse immunostimulation caused by impurities: The dark side of biopharmaceuticals.British journal of clinical pharmacology · 2019Review
- Regulatory Affairs 101: Introduction to Investigational New Drug Applications and Clinical Trial Applications.Clinical and translational science · 2019Article
- Practical risk management in early phase clinical trials.European journal of clinical pharmacology · 2019Article
- Recent efforts to elucidate the scientific validity of animal-based drug tests by the pharmaceutical industry, pro-testing lobby groups, and animal welfare organisations.BMC medical ethics · 2019Article
- Global Portrait of Protein Targets of Metabolites of the Neurotoxic Compound BIA 10-2474.ACS chemical biology · 2019Article
- Commentary on the EMA Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products.British journal of clinical pharmacology · 2018Article
- Annotated guidance to the European Medicines Agency (EMA) guidelines and regulatory documents. A new series of the BJCP.British journal of clinical pharmacology · 2018Article
Corrections and comments
- Commented on by
Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Over the past 10 years, thousands of first-into-human (FIH) clinical trials have been performed in Europe, with few severe adverse events (SAEs). Each has received detailed prior safety review at both the local clinical research facility and at national drug regulatory authority level. The recent fatal SAE in the BIA-102474-101 clinical trial shows the limitations of this process. Although criticized for not sequentially dosing subjects both within and between cohorts - as recommended by the European Medicines Agency for high-risk compounds after the TeGenero clinical trial disaster in 2006 - BIA-102474-101 was not considered to be high risk. Indeed, compounds with similar mechanisms of action had previously been taken through phase I and II trials without incident, and higher doses had been safely given for longer durations to nonhuman primates. If the available data are comprehensive and accurate, and further investigation does not reveal unreported warning signs, this study has serious implications for ongoing and future review of FIH clinical trials. All preclinical study documents and clinical data collected during the BIA-102474-101 trial should be made available urgently so that lessons can be learnt. In the meantime, reviewers and clinical researchers should always ask for information on drug and target interactions and full reports of preclinical toxicity studies, and plan sequential dosing with longer delays between patients and cohorts, particularly if late SAEs might be anticipated. The use of individual patient pharmacokinetic and dynamic data should guide sequential dosing. A process for systematic risk assessment, like that currently used in the Netherlands, should be applied routinely to all trials with novel compounds.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.