Re: Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
In my view, this publication has significant implications for research ethics. Whether or not a clinical trial is considered ethical hinges on a number of factors, including risk to participants, the merit and integrity of the research, potential benefits such as producing important knowledge, whether or not individuals are respected and offered an informed choice regarding participation in the study, and whether the research meets justice requirements.1 The merit and integrity of the research are linked to the potential benefits: high quality research produces valid and reliable results that can usefully inform the care of future patients.
This ethical rationale for clinical research was turned on its head by the original study 329. Restoring Study 329 demonstrates with forensic detail just how the general justifying principles were ignored or subverted. The research was not conducted with integrity (the protocol was not followed, adverse events were not comprehensively reported), therefore the results were not reliable in guiding the care of future patients, leading to unquantified harms. Patients were not respected but rather their data were used to make a case for marketing commercial products. It is unknowable how many would have agreed to participate if this aim had been explicit in the patient information provided prior to seeking informed consent. Rather than serving the greater good, the original study met the economic interests of the pharmaceutical company.
Restoring Study 329 is both encouraging and deeply dismaying. It is encouraging because it shows that it is possible for a small number of extremely motivated people to identify research misconduct, and make comprehensive suggestions for avoiding future problems of this nature. It is dismaying because the ground has shifted in terms of undermining, perhaps terminally, the profession’s and the community’s confidence in the published findings of existing clinical research. And overcoming this seems unsurmountable given the resources required to do this kind of reanalysis, even if investigators (both commercially and publicly funded) open up their data.
However, a phoenix might rise from these ashes. The restoration of study 329 could be a trigger to demand that open access to protocols and data become the new norm. Human research ethics committees (institutional review boards) could demand open access as a requirement for ethics approval. Such a proposal might restore confidence in the clinical research enterprise, and thereby ensure that when patients enrol in research for the greater good, there is some chance of that good coming to pass.
1. National Health and Medical Research Council. (2007; updates May 2015) National Statement on Ethical Conduct in Human Research. Available from: https://www.nhmrc.gov.au/guidelines-publications/e72
Competing interests: I have previously published with Jon Jureidini and Melissa Raven and have an ongoing project with them. I am on the Advisory Board of the Critical and Ethical Mental Health research cluster in the Robinson Institute at the University of Adelaide, where Prof Jureidini and Dr Raven are based.