In the Reasoner: Phase one trials

The Reasoner is a monthly digest highlighting exciting new research on reasoning, inference and method broadly construed. It is interdisciplinary, covering research in, e.g., philosophy, logic, AI, statistics, cognitive science, law, psychology, mathematics and the sciences. Each month, there is a column on Evidence-Based Medicine. Here is this month’s column:

About ten years ago there was a trial of a drug that made the news. The study was a phase one trial, which is a trial conducted with a small group of people, intended to determine any side effects and to evaluate the safety of the drug. In this trial, six participants were hospitalized, and four of these suffered multi-organ failure. Following the trial, an expert scientific group was set up to provide recommendations in order to help prevent something like happening again.

Among other things, the expert scientific group recommended that ‘new agents in first-in-man trials should be administered sequentially to human subjects with an appropriate interval between dosing of subjects to limit the number of people that may be affected by a severe adverse reaction’. They also recommended that:

The calculation of starting dose should utilise all relevant information. Factors to be taken into account include the novelty of the agent, its biological potency and its mechanism of action, the degree of species-specificity of the agent, the dose-response curves of biological effects in human and animal cells, dose-response data from in vivo animal studies, pharmacokinetic and pharmacodynamic modelling, the calculation of target occupancy versus concentration and the calculated exposure of targets or target cells in humans in vivo.

These recommendations look to require gathering a range of different types of evidence including evidence of mechanisms. But a major focus of the recommendations was in making more accessible evidence that had already been gathered. In particular, the expert scientific group were presented with a phase one trial of a similar drug with a similar adverse outcome that had gone unpublished. Therefore, the group recommended also that ‘[d]evelopers of medicine, research funding bodies and regulatory authorities should expedite the collection of information from unpublished pre-clinical studies relevant to the safety of human exposure’.

More recently, last month a phase one first-in-man drug trial left one man brain-dead and another five hospitalized. It was reported shortly after that the man left brain-dead had later died, and four of the five other people hospitalized had neurological problems. Once again there has been a call to improve the access to evidence from unpublished trials. For instance, the British Pharmacological Society released a statement. In about ten years, it looks like not much has changed.

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