The Havasupai Indians and the Challenge of Informed Consent for Genomic Research

Pulitzer Prize-winning journalist Amy Harmon, of The New York Times, reports that a long-running dispute between Arizona State University (ASU) and the Havasupai Indians over the allegedly improper research use of DNA from members of the tribe has been settled.

The research began two decades ago, ostensibly to search for a genetic variant that might be contributing to the increasing rate of diabetes in the tribe. The diabetes research proved unfruitful, but the blood donated by the Havasupai tribe members, and the DNA extracted from it, led to a number of follow-on research projects, grants and publications. It was that research – including searching tribe members’ DNA for variants linked to schizophrenia, and inferring the likely ancestral origins of the tribe’s founders – that led to lawsuits, millions in legal fees and, ultimately, the settlement.

Implications of the Havasupai Settlement. Harmon’s article provides a concise background to the dispute, and briefly describes the $700,000 settlement between ASU and the tribe to “remedy the wrong that was done.” Harmon and unnamed “legal experts” suggest that the settlement is significant because “it implied that the rights of research subjects can be violated when they are not fully informed about how their DNA might be used.”

In some respects, this is a trivial conclusion. One of the most important and well-known elements of the Common Rule – the regulatory regime that governs federally-funded human subjects research – is that researchers must seek, and participants provide, informed consent. Participants that are uninformed cannot provide valid consent and, thus, their rights as subjects are violated. In that respect, at least, the Havasupai case tells us nothing new. (I have not seen the settlement, but I doubt that it will (a) be made public or (b) contain an express admission of guilt from ASU, both factors that will limit its relevance to future similar scenarios.)

But the Havasupai case and Harmon’s article shine light on an important, and difficult, problem that continues to face scientific researchers, particularly those exploring human genetic variation: what does it really mean to provide “fully informed” consent for genomic research?

Fully Informed Consent? Looking at the text of the Common Rule, there are requirements that the researchers describe the nature and purposes of the research (§ 46.116(a)(1)), as well as both reasonably foreseeable (§ 46.116(a)(2)) and unforeseeable (§ 46.116(b)(1)) risks of participation. But the standard of informed consent that must be achieved is not explicitly spelled out. Is it “reasonably informed,” “substantially informed,” “fully informed” or something else altogether? (Interestingly enough, the language that Harmon uses – “fully informed” – does appear, but only in sections regarding research on pregnant women and fetuses, which is not applicable in this case.) Even if a clearer standard were articulated, how would researchers demonstrate that it had been satisfied?

The requirement of informed consent is part of the bedrock of modern human subjects research in the United States, and it is not going anywhere. In fact, the story of the Havasupai, as well as the tale of Henrietta Lacks (told so remarkably well in Rebecca Skloot’s new book) and other past failures of informed consent, suggest the informed consent requirement is here to stay, as well it should be.

A Difficult Balance. Yet, as we push forward into an era of large-scale, personalized genomic research, it is impossible to ignore the difficulties – legal, ethical and practical – that informed consent requirements impose. For example, truly informed consent for genomic research might require participants to possess a deep – or at least working – understanding of the underlying science. That sets a very high bar, and finding sufficient numbers of participants capable of providing such consent could restrict important research.

Even more daunting, however, is the difficulty of fully informing participants of the benefits and risks of participation in genomic research – particularly where the resultant findings could conceivably be linked back to the individual or, as in the case of the Havasupai, the individual’s community – when the researchers themselves lack this understanding. What genetic information can tell us about disease and other traits, and how this information can be used or misused in the case of individuals, is an area of continuing uncertainty. With the publication of the draft human genome sequence a decade in the rearview mirror, we know more than ever before. But there is still much that we don’t know.

Thankfully, new research models and strategies for seeking informed consent are being developed and tested. For instance, the Personal Genome Project (PGP) – for which I am an advisor, including with respect to the informed consent protocol – employs a model of “open consent.” The PGP focuses on preemptive and extensive risk disclosure, along with rigorous participant pre-screening to ensure that the risks of participation are understood. More broadly, the difficulties of informed consent and genomic research is an issue that the NIH is studying on an ongoing basis, with multiple internal working groups looking at different dimensions of the problem. Nevertheless, informed consent for genomic research poses a considerable challenge for policymakers, funding bodies, researchers and participants, and it is unlikely that any of the existing models represent a perfect approach.

None of this should be taken to mean that informed consent for genomic research is impossible. To admit that would leave us with the unenviable choice of sacrificing either the informed consent of participants or the valuable scientific research they enable. What the case of the Havasupai tribe does underscore, however, is just how difficult a task this is. It is clear that the next generation of personal genomics research will require more than purely scientific breakthroughs. We also need to think creatively about the ethical and legal framework in which such research is conducted, to make sure that it continues to promote scientific progress while protecting the participants – no matter what their background – that make such research possible.