Dutch probiotics study is criticised for its “design, approval, and conduct”

A joint investigation by three Dutch authorities has criticised the preparation and execution of a study of the use of probiotics in patients with acute pancreatitis.

Their two year investigation was launched (BMJ 2008;336:296-7, doi:10.1136/bmj.39482.327350.C2) after it emerged that the mortality rate among the trial participants who had received the probiotics preparation was higher (24 of 152 participants died) than that among those who had received a placebo (nine of 144).

The Dutch Healthcare Inspectorate, the Central Commission on Research involving Human Participants, and the Food and Consumer Product Safety Authority now conclude that the study’s design, approval, and conduct had “major shortcomings.” Their investigation did not, however, establish any “direct causal link” between these and the unexpectedly higher mortality in the treatment group (www.igz.nl).

The three groups argue that the trial participants could have been better protected if “a more critical approach to the assessment and reporting of the adverse events had been applied.”

The multicentre, double blind, randomised controlled trial, carried out in 15 hospitals between 2003 and 2007, was designed to see whether probiotics could reduce the incidence of infectious complications in patients with severe acute pancreatitis (Lancet 2008;371:651-9, doi:10.1016/S0140-6736(08)60207-X). Previous small scale studies had indicated that probiotic treatment might be effective (British Journal of Surgery 2002;89:1103-7, doi:10.1046/j.1365-2168.2002.02189.x).

The inspectorate’s report criticises the executive board of the Utrecht University Medical Centre, saying that as the study’s sponsor it failed to meet all its responsibilities for the design and conduct of the study, laid down in Dutch law. It also concludes that the medical ethics committee should have taken a more critical approach before approving the research. The information for patients was too optimistic, given that the research product had not been tested on humans before, it said. In addition, the procedures for reporting serious adverse events did not conform to existing best practice.

Serious adverse events should have been reported promptly to the centre’s data and safety monitoring committee, which should have had “clear instructions and procedures at its disposal,” said the report.

But 31 of the 33 deaths were not reported directly to the data and ethics committees and were reported only later, for example in the annual progress report to the ethics committee. Therefore “the evaluation of these incidents could not take place satisfactorily during the conduct of the study,” it said.

The inspectorate’s inspector general, Gerrit van der Wal, said on Dutch television: “Let there be no misunderstanding: the medical ethics committee should have been more critical.”

The inspectorate emphasised that the study’s shortcomings carried lessons for all medical research in the Netherlands. Its recommendations include introducing “a clear legal obligation to report promptly serious adverse events to the responsible ethics committee” and that study sponsors “establish an appropriate research structure for clinical studies, whereby its own tasks and responsibilities, as well as those of all research staff, are clearly defined.”

The Utrecht University Medical Centre said that most of the recommendations had already been adopted since 2002, when the study was designed. It said that there is no relation between the procedural mistakes and the deaths.