The UK’s Medical Research Council (MRC) has defended its role in a cancer trial sponsored by the Council in which a patient died last year after receiving an accidental overdose of the chemotherapy drug bleomycin.

In particular the MRC has stressed that the incident occurred as a result of an error in the computer prescribing system at University College London Hospital (UCLH), where Gary Foster was taking part in the trial. This error was a departure from the trial protocol (which is the sponsor’s responsibility) and “does not call into question the safety of the treatment regimens” used, it said. Both the MRC and UCHL have since reviewed and amended their trial procedures.

The issue has come to light after an inquest into Foster’s death in October 2007. Media coverage predictably drew parallels with the disastrous first-in-human trial of TeGenero’s monoclonal antibody TGN1412 at London’s Northwick Park Hospital in March 2006, even though – accepting the common questions raised about the safety of clinical research – the circumstances were very different.

The Northwick Park trial involved an unexpected – if perhaps not entirely unforeseeable – and violent adverse reaction to a novel and previously untried therapy in healthy volunteers. In the MRC trial there was a fatal dosing error with a well-established drug – albeit one associated with pulmonary toxicity in around 10% of treated patients – used as part of a chemotherapy combination.

None of this will be much comfort to Foster’s family and fiancée, who were hoping the trial would boost his chances of survival from what UCLH described as “very widespread” testicular cancer.

TE23 trial

The circumstances were that Foster was referred to University College London Hospitals NHS Trust (UCLH) in June 2007, joining the TE23 trial sponsored by the MRC and funded by Cancer Research UK.

The TE23 trial, which was immediately suspended at UCLH but continues to run at other sites (a total of 20 hospitals in the UK), is a randomised Phase II study in metastatic testicular cancer patients comparing two chemotherapy regimens: the standard treatment consisting of four cycles of BEP (bleomycin etoposide, cisplatin) and a new regimen of the existing chemotherapy drugs carboplatin, bleomycin, vincristine, and cisplatin (CBOP), followed by BEP.

In this new treatment regimen, six weeks of CBOP are followed by three cycles of BEP. All drugs are given as per standard except for bleomycin, which is administered at the lower dose of 15,000 IU (International Units) as opposed to 30,000 IU in the standard BEP. In all three cases of dosing error associated with the TE23 trial, patients due to receive 15,000 IU of bleomycin in the second part of their treatment received 30,000 IU instead, the MRC reported.

The CBOP/BEP regimen has been evaluated in two previous non-randomised trials, although in these it was not compared with existing treatments, the Council pointed out. The TE23 trial has been open to patients since June 2005 and 56 have been recruited to date.

Before starting, TE23 was reviewed and approved by Cancer Research UK, the MRC, a central national ethics committee and the Medicines and Healthcare products Regulatory Agency (MHRA), the Council noted. The MRC had also received all of the necessary documentation (evidence of local research ethics committee approval, etc) from UCLH.

Set-up error

UCLH was sketchy about what exactly happened next in its arm of the trial, stating only that Foster was “treated intensively and, despite an initial improvement in his condition, died as a result of drug toxicity”.

According to the MRC, though, there was an “error in the set-up of the chemotherapy protocol at UCLH which led to Mr Foster receiving an incorrect dose of bleomycin, potentially contributing to his death”. This error “related to a hospital computer prescribing system”, the Council said, adding that systems of this kind are widely used for routine chemotherapy in many hospitals.

As the MRC pointed out, a second patient at UCLH was inadvertently given a double dose of bleomycin during the trial but did not suffer any adverse effects. Moreover, a patient taking part in TE23 at another hospital received the wrong dose of 30,000 IU bleomycin but “in this instance the patient did not experience lung toxicity associated with this”.

The circumstances relating to the third patient, who died from recurrent testicular cancer, “have been reviewed and the review found that his death was not a consequence of the wrong dosage”, the Council stated.

UCLH offered no further insights into the trial itself, other than to say that it had “thoroughly investigated the circumstances leading to [Foster’s] death” and “there was a full review by the coroner” at the inquest. “We are awaiting the coroner’s written report and therefore it would be inappropriate to comment in further detail on these events,” the Trust stated.

In his summing up, the coroner “did commend the Trust on the openness and thoroughness of its investigation and on its action plan to improve systems and processes”, UCLH added. “He did not criticise any of the clinical staff involved. He concluded that UCLH had already made all appropriate changes to improve patient safety in response to this accident.”

Checks and prompts

These measures include a second and separate check by senior pharmacy staff, in collaboration with the supervising consultants, of all protocols on the Trust’s electronic chemotherapy prescribing system; and additional checks by nurses on chemotherapy toxicity for every patient before repeat doses are given.

For its part, the MRC said its Clinical Trials Unit had reviewed all the relevant trial procedures as a result of Foster’s death and “a number of additional prompts and reminders” had been implemented and approved by the independent trial oversight committees.

Previously the Clinical Trials Unit only issued queries based on forms it had received after treatment had been given, the Council noted, adding that “this might be too late to prevent complications arising”. The Unit has now introduced a new process whereby a copy of each trial patient’s drug prescription is requested as soon as it is available. These are then checked by two members of staff specifically with respect to the bleomycin dose, so that any apparent errors can be queried immediately.

One question raised in media reports on Foster’s death has been why the MRC, having detected a possible dosing error with bleomycin, then informed UCLH of its concerns by letter instead of telephoning the Trust immediately. According to The Sunday Times, this letter was not opened until two days after Foster’s death.

The MRC explained that, during the processing of case report forms for UCLH patients in the TE23 trial, “a possible dosing error for two patients was detected, Gary Foster and one other patient”. A query form was then returned to the hospital “following the usual procedure of sending postal queries”, the Council said, adding: “These practices are standard for our clinical trials”.

The MRC was also at pains to dismiss any suggestion of laxity in its oversight of the trial. “For all trial participants, case report forms are filled out at the clinical site and returned to the MRC Clinical Trials Unit detailing their treatment,” it stated. “Our standard practice is to enter forms on to our database as they come in, and to raise queries regularly, in batches, so that hospitals will receive queries on all their patients at the same time.”

Based on many years of working with UCLH on trials in testicular cancer, and having confirmation that the first patient to receive the CBOP/BEP treatment in the trial was treated correctly, “the MRC had no reason to believe there was any misunderstanding of the trial protocol”, it added.

“It is important to stress that as sponsor the MRC is responsible for the overall conduct of the trial,” the Council commented. “The clinical management of an individual patient always remains the responsibility of the clinical team at the hospital.”

The emergence of further concerns about the adequacy of safeguards for patients taking part in clinical trials comes at an awkward time for the UK government. Only in June, UK Health Secretary Alan Johnson announced plans to give as many patients as possible the opportunity to take part in clinical trials conducted in the National Health Service.