Possible violation of the Helsinki Declaration on Scientific Research with Humans
Case text (Anonymised)
A manuscript underwent peer review and the resulting reviewer comments raised grave concerns about the ethical legitimacy of the study.
- questioned the authors’ impartiality, suggesting that there was an undeclared conflict of interest;
- raised serious concerns about the extent to which participants gave informed consent;
- strongly doubted that the study would have gained ethics committee approval; and
- suggested that the study violates the World Medical Association’s 1964 Helsinki Declaration on Scientific Research with Humans, which states that the welfare of the research subject takes precedence over the interests of science and society.
The manuscript described a randomised controlled trial conducted on patients undergoing brain surgery. Participants were recruited between January 2010 and February 2012 in a single hospital.
The stated aim of the study was to establish the effect of varying the time for which blood flow to the brain is substantially reduced during surgery on postoperative function and disability. It is already well established that reducing the blood flow in this manner for a prolonged period of time is likely to lead to poorer postoperative outcomes due to reduced oxygen supply to the brain.
In order to avoid negative outcomes and improve patient safety, there already exists a warning criterion used in surgery of this type, which alerts the surgeon to the extent of oxygen starvation and indicates when blood supply should be restored.
In the manuscript, the authors outline their knowledge of the risks involved with the procedure itself and report that many surgeons feel that this procedure should only be used as a last resort due to the increased risks outlined above. However, if the procedure is deemed necessary, the risks can be reduced by employing the pre-established warning criterion.
The authors outline perceived flaws of the pre-existing criterion and go on to describe a novel warning mechanism —conceived by them—that they intend to test during the study. Testing this new criterion entailed increasing the time that blood supply in the brain is reduced—to the extent that, in some cases, the current recommended threshold was significantly exceeded. Additionally, while the procedure was underway, the authors ensured that the surgeon was blinded to the patient’s status with respect to the established risk threshold, making is impossible for them to gauge the level of danger the patient was being exposed to. This, as is noted within the manuscript itself, poses serious risk to the patients.
Participants were divided into three groups. In the control group risk was assessed using the normal criterion and blood supply was reinstated once this threshold was crossed. In the second group, blood supply was reduced for a longer period of time. In the third group, blood supply was reduced or completely cut-off for significantly longer.
In the results section, the authors state that in the control group one patient became severely disabled, and that all patients in the third group experienced negative outcomes. Of the patients in the third group, three were severely disabled as a result of the procedure and all of the others suffered some neurological deficit. As the reviewer points out, the pattern of outcomes raises serious ethical concerns about the study. The reviewer questions whether this was (and even should have been) tested on animals first, as this would have provided an upper limit and ‘red flag’ for testing.
The reviewer believes that this study violates the Helsinki Declaration on Scientific Research with Humans in that it appears that subjects randomly included in the third experimental group were subjected to an experimental condition that caused three of them to be severely disabled, and nine of them to be moderately disabled by the experimental manipulation. Because patients were assigned to intervention and control groups randomly and the outcomes between the groups differed significantly, it is highly unlikely that the negative outcomes among group 3 patients are attributable to technical surgical problems in one group only.
It appears that the negative outcomes found in group 3 patients were due to the blood supply being reduced or occluded for long periods of time. The reviewer also suggests that for the control group, there was an omission of a standard of care practiced by most modern medical centres that perform this procedure. The reviewer suggests these findings cannot be generalised to other procedures of this type and he wonders why the original warning criterion was not utilised in this study to further protect these patients.
Furthermore, the study raises serious concerns about the extent to which patient consent (for which consent forms were obtained from the patients) was properly informed. There is no indication that the risks to the participants inherent in an experiment such as this were properly conveyed to the individuals before participation was agreed.
Finally, the Declaration of Helsinki also states that “Physicians must immediately stop a study when the risks are found to outweigh the potential benefits…”; the authors did not stop this study for over a year. And, an unproven intervention should only ever be carried out if “it offers hope of saving life, re-establishing health or alleviating suffering” and that in the nature of research it is “designed to evaluate its safety and efficacy” not to establish a benchmark
The Forum were in agreement that this was very dangerous and very unethical research and that the editor should act quickly. The advice was for the editor to contact the authors informing them that there are substantial concerns with the content of the paper. The editor should copy in all of the authors, giving them a specific and short deadline in which to respond. The editor should tell the authors that he will contact the authors’ institution if no response or an unsatisfactory response is received.
The editor can ask to see proof of the ethics approval of the study, as well as the patient consent forms. Was the trial registered? If no response is received, the editor should contact the institution, copying in all of the authors. If there is no response from the institution, the editor should contact the general medical council or equivalent, or the funding body. For this form of potential misconduct, it is the editor’s responsibility to bring it to the attention of the institution or authority body that can investigate the case.