Prevention of Future Deaths reports · 2017
Regulation 28 report to prevent future deaths, reference 2017-0188, written 14 Jun 2017. A coroner writes one of these when an inquest reveals a risk that could cause further deaths unless something changes.
| Date of report | 14 Jun 2017 |
|---|---|
| Reference | 2017-0188 |
| Deceased | Maurice Macdonnell |
| Coroner | Andrew Harris |
| Coroner area | London Inner (South) |
| Category | Product related deaths |
| Source | judiciary.uk record · original PDF |
| Responses published | 1 |
Text recovered by OCR from a scanned PDF. OCR is imperfect: check anything you rely on against the source PDF. Reproduced verbatim, including the scan's own layout.
REGULATION 28 REPORT TO PREVENT FUTURE DEATHS THIS REPORT IS BEING SENT TO: FY Head of Enforcement, MHRA Medicines and Healthcare Products Regulatory Agency, 151 Buckingham Palace Road, London SW1W 9SZ CORONER lam Andrew Hartis, Senior Coroner, London Inner South jurisdiction CORONER’S LEGAL POWERS I make this report under paragraph 7, Schedule 5, Coroners and Justice Act 2009 and regulations 28 and 29 of the Coroners (Investigations) Regulations 2013. INQUEST On 23rd August 2015, I opened an inquest into the death of Mr Mautice Macdonnell who died on 16.08.16 in Kings College Hospital; It was concluded on 24th May 2017. The medical cause of death was: ta Giant cell and lymphohistiocytic myocarditis and myositis ib 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.. CIRCUMSTANCES OF THE DEATH 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. CORONER’S CONCERNS During the course of the inquest, the evidence revealed a matter giving rise to concern that in my opinion means that there is still a risk that future deaths will occur unless action is taken. In the circumstances it is my statutory duty to report to you. The MATTER OF CONCERN is as follows. - 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. HEE (icector 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 nutse 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 tisk of bias and a burden of bureaucracy, ACTION SHOULD BE TAKEN The court has not had the benefit of independent opinion as to whether the arrangements in this or indeed other trials, adequately protects patients when the conflict of interest identified above arises. It would seem prima facie to create a potential risk to lives, but the MHRA would seem to be the appropriate body to make a judgment on this matter. It is understood that the adverse reaction has already been reported to the MHRA and that new drug guidance has been issued. If any action is required the MHRA may choose to communicate that to the hospital, pharmaceutical company and/or investigator, who are copied into this report, as they may be in positions to take further actions to prevent future deaths. H i YOUR RESPONSE You are under a duty to respond to this report within 56 days of the date of this report, namely by 9 August 2017. I, the coroner, may extend the period. Your response must contain details of action taken ot proposed to be taken, setting out the timetable for action. Otherwise you must explain why no action is proposed. If you require any further information or assistance about the case, pl act COPIES and PUBLICATION I have sent a copy of my report to the following Interested Persons: At King’s College Hospital: The Research Ethics Committee Consultant oncologist) (study investigator) PY Bristol Myers Squibb (R&D Director) Tam also under a duty to send the Chief Coroner a copy of your response. The Chief Coroner may publish either or both in a complete or redacted ot summary form. He may send a copy of this report to any person who he believes may find it useful or of interest. You may make representations to me, the coroner, at the time of your response, about the release or the publication of your response by the Chief Coroner. [DATE] [SIGNED BY CORONER] [G- 6-17 § i i i
1 response published against this report on judiciary.uk. A response is a body's written reply to the coroner's concerns; publication is at the discretion of the Chief Coroner's office, so an absent response does not mean nobody replied.
Regulating Medicines and Mi MHRA 151 Buckingham Palace Road London SW1W 9SZ United Kingdom mhra.gov.uk Dr Andrew Harris Coroner for Inner South District Greater London th < and of fo the Southwark Coroner's Court 1 Tennis Street a 1% Southwark London SE1 1YD 24t July 2017 Dear Dr Harris, Coroners and Justice Act 2009 — Regulation 28 Report following the inquest in to the death of Mr Macdonnell PFD report touching the death of Maurice Macdonnell Date of death 16.08.2016 / Thank you for your letter of 20" June 2017, received on 26" June 2017, enclosing your Report under Regulation 28 following the inquest into the death of Mr Maurice Macdnnell and the concern raised that there is still a risk that future deaths will occur unless action is taken. Notification of the death was reported to MHRA as a fatal suspected unexpected serious adverse reaction (SUSAR) within statutory timelines i.e. within 7 days of the trial sponsor becoming aware of the event, in line with Directive 2001/20/EC. The SUSAR report has been reviewed and the trial sponsor has done due diligence in investigating the cause of death and the potential risk to other patients being treated with nivolumab. The symptoms shown by Mr Macdonell prior to his death are in line with the known safety profile for nivolumab and he was managed in line with the protocol. Other similar events have been noted in the annual safety report reviewed by MHRA and this new information does not alter the safety profile or require any further action for participants in nivolumab clinical trials. With regard to the possible conflict of interest in reporting the death of Mr Macdonnell and the balance between the risk to the patient from receiving further doses and the benefit from staying in the trial in the interests of research, MHRA has received an opinion from the Health Research Authority (HRA) as conflict of interest lies outside the remit of MHRA for clinical trials. The HRA confirmed that it is common practice for the Principal Investigator in a clinical trial to also be the patient's physician. The duty of care owed by a physician should always be the primary role, above the interests of the trial, and this is generally accepted by physicians participating in clinical trials. These aspects are considered by the Ethics Committee at the time of the initial application of the clinical trial to them, in accordance with the Declaration of Helsinki. We are not aware any concerns were raised for this trial regarding conflict of interest. The HRA have also issued guidance for Ethics Committees on managing potential or perceived competing interests in a clinical trial, and this would have been followed at the time of the initial review and provision of a positive opinion. Medicines and Healthcare Products Regulatory Agency Bee Regulating Medicines and Medicaf Devices The conflict of interest concern for Mr Macdonnell was also reviewed by an Expert Good Clinical Practice Inspector who raised no concerns from the perspective of MHRA inspectorate. MHRA does not consider that any further action is warranted at this time given that the fatal event is not considered a new safety signal and ail appropriate mitigation steps are considered to be in place for nivolumab clinical trials. MHRA will continue to monitor all fatal events in the UK for patients participating in clinical triais and who are being treated with nivolumab. Conflict of interest will continue to be reviewed by the Ethics Committee for all clinical trials in tine with the HRA guidance. Yours sincerely Senior Medical Assessor / Deputy Unit Manager CTU 020 3080 6859 Medicines and Healthcare Products Regulatory Agency See
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