Medical research with 'legacy samples' raises ethical questions.

In the July 18, 2008 issue of Science, I noticed a news item, "Old Samples Trip Up Tokyo Team":

A University of Tokyo team has retracted a published research paper because it apparently failed to obtain informed consent from tissue donors or approval from an institutional review board (IRB). Other papers by the same group are under investigation by the university. Observers believe problems stem in part from guidelines that don't sufficiently explain how to handle samples collected before Japan established informed consent procedures.

The samples in question were "legacy samples", samples that had been previously collected for other research projects. The fact that these samples were collected before the institution of the rules for research with human subjects to which Japanese researchers are now bound complicates the ethical considerations for the researchers.

A bit more from the story:

The withdrawn paper was published online on 21 May and in the 1 July issue of Haematologica. A statement on the journal's Web site says a paper on acute myeloid leukemia by Seiichiro Kobayashi et al. was retracted on 27 June by Tojo, the corresponding author, who had informed the editors that an investigation found that the "study had not been approved by the IRB."

[Motoharu] Seiki [dean of the University of Tokyo Institute of Medical Science (IMS)] says tissue samples used for the retracted paper were collected before Japan's Ministry of Health issued guidelines for IRBs and informed consent in 2003. IMS's policies call for an IRB review of the use of old samples. "But [the researchers] did not follow that process," says Seiki. Tohru Masui, a bioresources policy specialist at the National Institute of Biomedical Innovation in Osaka, says few researchers are aware of the ethical issues surrounding old samples because the ministry guidelines "do not have [anything] about legacy samples."

The first thing to note is that, according to this story, the paper in question was withdrawn solely due to the ethical issues around the use of the already collected samples. To all appearances, the results reported in the withdrawn paper are scientifically sound and potentially useful to other scientists in the field. Since the paper falls in the realm of biomedical research, the knowledge contained in the withdrawn paper could also lead to benefits for patients and the physicians treating them.

The problem here is that the blood and bone marrow samples used in the present study were collected prior to 2003, when Japan's Ministry of Health put forth its guidelines on ethical research with human subjects -- guidelines that govern, among other things, the workings of the Institutional Review Boards (IRBs) that review experimental protocols. These guidelines also specify what sorts of protections human subjects are owed by researchers, and what counts as informed consent.

In some ways, the use of already collected tissue samples would seem like a good move from the point of view of minimizing harms to human subjects. Since the tissues have already been collected, getting the most knowledge out of them means less risk to additional human subjects to whom one might otherwise turn for new tissue samples.

The problem is that there is no clear way to establish that "legacy samples" collected in Japan prior to 2003 were collected from subjects who gave their informed consent for the tissue's collection and use in scientific research. It is possible that the tissue samples were collected without patient consent, or that their consent only extended to the use of their tissue samples in the specific research projects for which they were originally collected.

Once the bone marrow is out of the donor, you might think he no longer has a compelling interest in what you do with it, but the presumption is for the rights of the subject to control his body and the tissues extracted from it. At least, that's the presumption in the Japanese biomedical research world since the introduction of the Ministry of Health guidelines. That means that if researchers want to get more scientific use out of those tissue samples, they have to double back to get proper consent from the original donors, or at least make the case to their IRB that their research respects the rights of the human subjects from whom these "legacy samples" were collected (e.g., by not compromising the confidentiality of their personal information).

2003 is pretty recent, which means that there are likely plenty of "legacy samples" still on hand that predate the current ethical guidelines. It seems clear that the Ministry of Health could head off further incidents of this sort by working out clear guidelines for the ethical use of legacy samples.

Update: As I finished writing this, I noticed a follow-up article in the July 25, 2008 issue of Science. Part of the article discusses whether journals ought to trust authors for assurance that their research conformed to the prevailing ethical regulations, or whether manuscripts ought to be submitted with copies of approval letters from IRBs.

Until the rules on the use of archived tissue samples are made clear, I doubt that author assurances or IRB approval letters will be enough to ensure that the reported research meets the ethical guidelines.