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The news that a participant in a phase I clinical study had been declared brain dead, and others were critically ill, was a pretty ghastly start to the year (http://www.nature.com/news/scientists-in-the-dark-after-french-clinical-trial-proves-fatal-1.19189). The drug involved was an inhibitor of FAAH (fatty acid amide hydrolase) - an enzyme which inactivates a series of naturally-occurring compounds in the body, notably anandamide. So, inhibition of FAAH will permit accumulation of a number of compounds, including anandamide. Anandamide acts at cannabinoid receptors, like the agonist Delta9-tetrahydrocannabinol or THC in the brain. So, it is pretty close to home.
Many of us do healthy volunteer studies with licensed compounds, where the risks have been tested by many thousands of prescriptions. This compound was in early clinical development, so the risk was necessarily higher that this could happen. But nothing in the development of the drug will have prepared the sponsor for this, and had I been drafting the information sheet for young people offering to take the drug, I would have felt reassured by the completion of studies with comparable compounds. It is a reminder that declaring risk does not avoid risk.
It will be interesting to see what emerges from the post hoc enquiry into how this accident happened. It would be good if a root cause is identified so that we can all learn something that will generalise beyond the individual case. However enquiries that do not or cannot identify a root cause can be the opposite of constructive. My personal experience of this dates from when the UK’s NHS used to insist on elaborate enquiries into suicide or, especially, homicide. The ‘cause’ of these cases was almost always a mental illness but the focus of enquiry was always on the actions of staff who were deemed to have failed to prevent the preventable. Such scrutiny will almost always throw up details where a procedure or protocol was not followed to the letter. It was not uncommon for enquiries of this kind to conclude that these omissions explained the outcome. While this was nonsense, and the facts never compared with similar cases in which suicide or murder did not occur, it was deeply damaging to the staff who were implicated in the management of the case. It fuelled an obsession with completing forms and ‘assessing risk’. The actual risk, which is always present in patients with major psychiatric disorder, remained exactly the same of course. Staff had no option but to run the risk.
The same kind of thing could occur in the present case. Regulation could be further tightened on the testing of new drugs: more forms, more approvals required from bodies for whom managing risk means avoiding risk. In fact, we have no guarantee that rare fatal events of this kind can ever be avoided completely, except by stopping drug development in its entirety. The truth is that, as a Principal Investigator, we have to run the risk that something horrible will happen. Translational research involves giving drugs to people to find out what will happen. It's the human condition.
Guy Goodwin
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