Mr Maurice Macdonnell · Prevention of Future Deaths report

On 23rd August 2015, I opened an inquest into the death of Mr Maurice Macdonnell who died on 16.08.16 in Kings College Hospital; ████████

It was concluded on 24th May 2017. The medical cause of death was:
1a Giant cell and lymphohistiocytic myocarditis and myositis
1b Rare immune related adverse reaction of an immune checkpoint inhibitor in a clinical trail for treatment of hepatocellular carcinoma.
The conclusion as to the death was: Unintended consequence of consented pharmaceutical treatment in a drug trial for advanced cancer..

Mr Macdonnell was diagnosed with advanced liver cancer in May 2016 and chose to participate in an international randomized clinical trial (Study CA209-040) of Nivolumab v the standard relatively ineffective treatment with Sorafenib. 10 days after the first dose of the trial drug, he developed a ptosis and became progressively fatigued. At review at 14/7 on 8th August he was administered a second dose of the drug before a diagnosis of the cause of the ptosis had been made. This was not a breach of trial protocol (although 2/7 later the pharmaceutical company advised withholding the drug) and there is insufficient evidence to conclude that the decision contributed to the death. He did not report muscle pain or breathlessness. Clinical examination, blood tests and CT scan excluded non drug causes of ptosis and he went home. Neurological advice suggested an urgent MRI scan was done. However he became progressively weaker at home, his GP attending on 15th. He became unsteady and incontinent in the night and arrested on the way to King's College Hospital the next morning, due to progressive myositis and myocarditis, without further investigation.

The decision to administer the second dose after fatigue and ptosis had developed was taken by the doctor who was also the investigator in the research study. There would appear to be a conflict of interest between the benefits of keeping the patient in the trial in the interests of research and the potential risks to health of the patient from receiving the second dose, if that decision is taken by the same doctor.

████████ Director BMS R&D advised that the research had received UK Ethics Committee Approval, but this approval was not received as evidence by the court. He advised in his experience in international drug trials, there was no such arrangement of different doctors to deal with this conflict of interest. He pointed out that the severity of reaction was not enough to require stopping the drug, according to the protocol, but he would want the drug stopped if it was likely the changes were related to drug administration. He encouraged clinical exploration of alternative diagnoses. The letter of response to the enquiry made of BMS by the research nurse advised “hold any further study drug administration”.

After the inquest the R&D director wrote to the coroner explained the extensive training of investigators and they have access to a medical monitor, who attends a committee to see if any modifications are required in the trial for safety reasons. He also informs the court that introducing an independent adjudicator could pose a risk of bias and a burden of bureaucracy.