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The Research Ethics Blog by Bernard Lo, MD

Research with Existing Data and Specimens: What if Participants Object?

The Havasupai, a Native American tribe living near the Grand Canyon, have a very high prevalence of diabetes.  Researchers collected blood samples and clinical data from 200 tribal members.  Discussions with the tribe focused on research with diabetes, but the consent form allowed the study “the causes of behavioral/medical disorders.” 

The researchers carried out a number of studies, including three genetic studies that tribe members found objectionable: on schizophrenia, on inbreeding, and on the evolution of populations.  The tribe regarded the first two studies as stigmatizing, and the latter study contradicted the tribe’s beliefs about their ancestry.  The tribe and individual donors of materials brought a lawsuit. 

After protracted legal procedures, in 2010 the university agreed to settle the suit, formally apologized, and agreed to return remaining blood samples to the tribe. Several of the researchers defended these studies as complying with federal research regulations and warned that the settlement could have a chilling effect on research with stored specimens. See article

Although this case involves a well-defined Native American tribe, it raises more general questions about broad consent for future research with biological specimens, which is frequently requested when specimens are obtained and does facilitate future studies. 

Question:

  • How can consent for collection of samples be improved, to take into account that some donors of materials might regard some future studies offensive, while not raising impeding important future research that cannot be anticipated at the time samples are collected? 

Comments

The most important consideration in this scenario is to be aware that this Native American tribe may have very different ways of viewing the world, university research and the consenting process. We already know that many mainstream community participants may have difficulty understanding exactly how research differs from standard medical care and may have problems understanding the jargon of research protocols. These problems may be exacerbated in a Native American population due to linguistic and cultural factors. It may also be the case that the tribe is not concerned with the same issues (i.e. schizophrenia, inbreeding or evolution of populations) the researchers find important. It would, therefore, be important to meet with tribal leaders to know what cultural and linguistic factors are relevant to the group. Additionally, researchers should have a thorough understanding of research questions the tribe deems would improve their quality of living. The tribe may already have culturally sanctioned ways of dealing with particular health issues and these responses to health concerns may or may not be compatible with the proposed research studies. Finally, we know that federal research regulations often do not fully cover ethical concerns. The fact that “several of the researchers defended these studies as complying with federal research regulations” makes me wonder how much knowledge they had of Native American culture broadly, let alone of this individual tribe. The disappointments that Native Americans have had with the actions and rules of the federal government are well documented and it is likely that only research that is well-planned with substantial input from the group will be meaningful.

This scenario highlights the difference between the legal and ethical responsibilities of researchers. While these researchers may have adhered to federal regulations, they did not take into account the potential difference in cultural values of the Native American group. In this specific scenario, the wording of the consent appears vague enough to give too great license to the researchers. Surely, at the time of collection, the researchers could have anticipated that they would examine such a common illness as schizophrenia, or concepts of inbreeding and evolution of populations among a small, isolated group. These issues do not appear to have been specified as best as possible for the informed consent of the Havasupai population. In terms of future use of stored samples, in the case of non de-identified information (that at least contains a cultural identifier), perhaps it would be prudent to review with the donating group any proposed research arising after collection of samples to ensure a re-informed consent is given. One might argue that not apologizing to the affected group and returning the blood samples would have a much more chilling effect on future research among the Native Americans and many other potential communities than would winning a lengthy legal battle to keep donated samples for future study.

I agree with Lawrence, there seems to be a fine line which becomes blurred when legality and ethics come into play. It is often that at risk groups are utilized for research purposes that purport to help that group in the long run.

Although I agree with many of the points of the first two commenters, I think there remains room to disagree. Although I agree that in this situation, the researchers may have overstepped their bounds from an ethical standpoint, I feel that a blanket prohibition on future research using current biobanked specimens without the express consent of the subjects who donated their samples would deal a significant blow to future avenues of research. I think that future research should be allowed to be conducted without express written consent of the subjects unless it deals in strict areas including substance abuse, mental illness, etc that can have a negative, stigmatizing impact on the group being studies even if their individual identities are preserved. It may make more sense to allow research on de-identified, banked specimens to occur without express written consent unless it involves these pre-specified sensitive subject areas including substance abuse, illegal activities (which would incorporate inbreeding as in this example), mental illness, etc. This may not solve all areas of cultural insensitivity that may arise (ie it wouldn't address areas of evolutionary history that the Native American tribe objected to), but it would mark a major step in the right direction.

The case of the Havasupai Indian tribe brings to the forefront the difference between what is legally acceptable and what is ethically acceptable. Because this group is a very specific demographic, one should not assume the same rules of informed consent as with another more general demographic. Indians have a long and complicated history in America and cultural issues play a part in what is considered ethical and appropriate. While it is true that normally an investigator would not need to get re-informed consent to run further studies on banked blood, these rules should have been re-examined by investigators in light of the population in question. The investigators should have considered the possibility that this group of people has a different belief system than the general american public. As mentioned in previous comments, investigators should have tried to be as explicit as possible with the original consent form to explain that blood might be used to study potentially stigmatizing conditions such as mental illness. In fact, even if we were not talking about the Havasupai Indians it would be prudent to explain this in detail in a consent form since for many people in the general community mental illness can be stigmatizing. One possible solution would be to make a good faith effort to track down the original study participants and ask them individually if they would agree to having further studies on schizophrenia and inbreeding done with their blood samples. Perhaps if investigators had asked permission from the community first and explained the goals of their studies, the participants would have been more likely to agree. It is always harder to ask for forgiveness than permission! If the participants or community refuses, then I think it would be appropriate not to do the studies since investigators have a moral responsibility to protect research subjects regardless of what is legal.

Earlier comments made a valuable point that differences in cultural belief systems are important in informed consent. However, I believe that the issues here are not so culturally distinct. I think many members of the more 'mainstream' american culture, even those very educated in the biomedical sciences, could empathize with the position of the members of this tribe. Imagine instead that you are the research subject. You have diabetes or your parent has diabetes, so supporting this research is meaningful for you. You sign a consent sheet that lists immediate risks and benefits, and the possibility of future secondary research on your sample. Now imagine that you pick up the newspaper the next year and find the researchers, having examined your sample from the diabetes study, have announced that your family has a (hypothetical) gene that shows a very high propensity to alcohol abuse and that your father is not actually your father. Whether you find this information distressing is highly personal, and it is quite possible you do not want such information being discussed by a larger community without your permission. I think the relevant issues here are not differing cultural cosmologies regarding blood and identity, but rather a legitimate sense of losing power over information about yourself and the people to whom you are connected. As mentioned by another commenter, the information about this tribe was not anonymous-for each individual yes, but not of the group as a whole. It identified who they were and dissected out their collective histories and identities for a bunch of strangers. I think the lack of anonymity is what is so unique about this particular case. In light of these concerns, an informed consent process should itemize the components, so that open ended secondary studies can be consented to independently of the primary study. This allows greater power to the subject and encourages further discussion between researcher and subject. A second suggestion is that in the case when groups are studied, efforts should be made to thoroughly anonymize the source of the samples, as you would with individual patients. The issue of the banked specimen here are that findings were identified with a distinct group of people, in a way that is more fundamental than, say banked neonatal blood of all californians. In the type of studies where such anonymity cannot be assured (e.g. when studying migration or evolution of a group) additional permission should be sought.

Researchers should explicitly state that “future studies have not yet been determined and may examine topics/diseases you could potentially find offensive.” The consent forms should include options such as “I wish that my blood be used by ASU researchers only,” or “I wish that my blood be used for the current study on diabetes only.” The informed consent discussion should also reinforce that the participant can withdraw from the study at any time and can request that his/her sample be destroyed at any time. Furthermore, because influential community leaders granted researchers access to the group, researchers should ensure that individual participants do not feel obligated to participate or fear consequences for declining to participate. The risk to confidentiality must also be discussed—although the individuals of the Havasupai remain unidentified, they have legitimate concerns about being stigmatized as a group.

There are two aspect of this problem 1. Individual autonomy: From the Michelle M. Mello et al article. Which focus on type of informed consent. It seem more specific purpose of using describe, more offensive but more burden for researchers. They recommended “Tiered consent” which combined specific consent and general permission. However, one of it’s disadvantage - sophisticated form. This problem may be amplified for people with cognitive or communication difficulty. It may raise doubt and burden for researcher to explain each items ( eg. What are other heath problems?) 2. Community perception: From this case study, it seem individual inform consents may not guarantee conflict with community belief. It need critical judgment whether that community’s belief need or no need to be changed. For example, in case of myth about HIV infection – definitely need correction for their well being. However, some historical or culture related issue are too sensitive to be manipulated ,or it should be address the community opinion before publish the result. I would like to share perspective as a person come from different culture. In some country, community and family in is very influence to personal expectation. People may feel comfort if they follow social norms or somewhat patronage. This may produce point of view differ from highly value identity and liberty society. In such case, I may choose to use general permission but more emphasize in community engage and understanding. In conclusion. I think it is good to aware autonomy in both level of individual and community. Thanks for nice blog!

Although there are challenges associated with obtaining informed consent for research involving blood samples, one should not forget that a subject has every right to be informed of what will be done or how their blood sample will be used for (future) research. It would be good to see a copy of the informed consent that they signed for this particular study. Hypothetically, Title 45 Part 46: Protection of Human Subjects was violated in this case, though there was no harm done to the involved human subjects. It is very clear that the tribe people gave blood samples and consented for research involving diabetes, but was taken advantage of their vulnerable situation and their consent was misused for research which they were not aware of. My thinking is what was IRB doing at that time? My impression is IRB, whose primary responsibility is protecting the safety, rights and welfare of research subjects, is equally accountable. Some of the points to reminisce when dealing with informed consent - relevant new information must be provided to the subject before and after the Study, when handling an ethnic or minority community, it is always best to have an advocate or a community leader to explain or translate to their people about the specific use of the specimens that were collected for research. Furthermore, other options must be explored like using a short form of the informed consent document stating that the elements of Informed Consent have been presented orally to the subject or subject’s legal representative and giving a copy of the signed and dated ICF. Blanket consent is another alternative, but no matter what, all investigators must be extensively educated on the informed consent process, GCP, CFR (US Code of Federal Regulations)and IRB.

The Havasupai Indians concerns regarding public perception and potential stigmatization of their tribe when their community is being scrutinized by researchers looking for a genetic basis for schizophrenia or the incidence of inbreeding are not unreasonable nor are they unexpected. Prior to the recent ethical issues raised by usage of banked specimens, informed consent was a necessary step in human research whenever there was the potential for physical harm (i.e. invasive procedure, receiving/not receiving a study drug). Now that samples are stored and housed in specimen-libraries for countless future studies, informed consent seeks to identify study subjects who will not be offended by how their samples are used. Preparing a consent form for a project that has not yet been identified is challenging. Although most study subjects have few objections on how their samples are used as long as their individual privacy is maintained, not all people feel the same way. However, we can predict which research areas are likely to raise the most debate. Therefore, I propose a modified tiered consent form for future research involving stored specimens. The consent form would specify a list of pre-determined research topics that are recognized by most reasonable people, as controversial or stigmatizing (human stem cell research, mental health disorders). Prior to specimen collection, subjects will be asked permission to use their samples in these pre-specified areas of future research. I do not favor a blanket or general consent for all genetics research involving stored specimens. In the Havasupai case against ASU, the researchers obtained written consent from all study subjects using a blanket consent form; the complaint raised by the Havasupai Indians against the ASU researchers was that they failed to inform the tribe the research questions their samples will be used for.

Informed consent should explain thoroughly the use that researchers are going to give to the samples. I recognize it is difficult to predict clearly secondary studies in which those samples are going to be used. However, participants should be warned about that possibility in the consent form they are signing in the first place. Although in the article states that a minority of people perceive donating samples to research could make them not want to participate in that kind of research, researchers and the regulatory agencies have to respect that and consider every single case as a possible person who could feel threatened or simply don’t want to give consent to participate. De-identification provides a respectable way to manage confidentiality issues. But I think potential participants need to be explained that there is a possibility that the samples they are providing could be use in future studies.

1. The reason why many of us feel discomfort with the use of these previously collected samples for purposes of research on inbreeding, evolution of populations and schizophrenia is because we intrinsically feel the moral obligation of the first principle of ethics: beneficence (do no wrong). While the researchers may have not violated any federal regulations, the results of their research have harming implications to these tribes. Native Americans have for the past two centuries been subjugated to oppression and stigmatized by the dominant society not only in the United States but in Latin America. The results of the research that suggest high levels of inbreeding and schizophrenia is a new version of stigmatization and yet another burden placed on this group to genetically diversify (aka assimilate to mainstream) and potentially loose their way of life. The results of the research contradicting the tribe’s beliefs about their ancestry may be interesting and compelling research to mainstream culture but to the tribes, it can affect their claims to land rights again, further subjugating these groups and potentially leaving them destitute. The question about how to improve sample collection to take into account future studies that participants may find offensive is best answered by spelling out all the research that these samples will be used for or potentially be used for. Anything short of that is violating the notion of informed consent, especially when the samples are used for “objectionable” research (objectionable to the participants). I agree with the overall outcome in this case which involved returning of samples to the objecting parties, despite the fact that the reports were published and the damage had already been done. Since spelling out every single possible study the sample can be used for is not a feasible goal, the second best option is to train researchers on ethical principles that should guide their research. If a study was to determine the high prevalence of disease in an isolated group in order to provide solutions to the problem and overall provide some beneficence, we would not feel so compelled against the use of the samples for secondary studies. It is obvious that in this case, the first principle of beneficence was violated because the results of the additional research had more risk of adverse downstream effects for the Native American group. If we do not heed these ethical principles while doing research, more ethical concerns may be raised and researchers run the risk of having other institutions put in place more stringent regulations on stored sample research, therefore interfering with research that may be beneficial.

I find this particular case to be of vital importance to issues regarding informed consent and global health research. The goal of obtaining informed consent is to guarantee that the subject understands the risks, the benefits and the alternatives to treatment, entry into a study, etc. A signed informed consent form is reassuring (to both researchers, study subjects and patients), but it does not assure an accurate understanding of the risks, benefits and alternatives in actuality. As researchers and as clinicians we need to be aware of and careful of this discrepancy. The law aside “doing right” or “justly serving study subjects and patients” should be at the core of all efforts. I appreciate the comments of anonymous and agree a tiered consent form (or a modified tiered consent) form improves the communication between researcher and study subject. Additionally, I find that there is an important incompatibility between deeming blood specimens as de-identified while studying and publicly publishing research that demonstrates how those anonymous specimens relate to the behavioral and biological history of a specific tribe. If the blood specimens are truly de-identified how can they be linked to a tribal community in Arizona. It is pivotal (and not surprising) that the community felt a powerful connection to the supposedly de-identified data and felt violated when they believed their blood specimens were used for objectionable and potentially incriminating topics. For example, in an article published in AOL online news, the Havasupai, were described as being most concerned about providing a proper burial to relatives who have died since their blood was collected and studied. Carletta Tilousi, a member of the Havasupai tribal council was quoted as having informed the The Associated Press, "Their spirits will no longer be locked in a cooler...and We are going to take them back down to Supai Canyon so they can rest in peace." Global health research usually refers to investigations performed outside of the United States. However, this case, which occurs in Arizona, exemplifies issues that are at the core of research performed with resource poor and culturally distinct populations. Namely, it is a mistake and may lead to detrimental problems if the following questions are not addressed: Does the research question address a health priority of the population being studied, will the investigation provide any benefits to the population being studied, and are their any community leaders or community scientists involved in the study? Therese Markow, one the the Arizona State University (ASU) researchers who used Havasupai blood samples at ASU, for studies outside the verbally consented for diabetes research defended her research explaining, "I was doing good science," as quoted in the AOL online new report. The community leaders, however, retorted, we are not against scientific research...."I just want it to be done right...They used our blood for all these studies, people got degrees and grants, and they never asked our permission." Clearly T. Markow and the ASU IRB believed the required consent was established. Nonetheless, had the above listed questions been evaluated prior to embarking on the studies on schizophrenia, inbreeding, and ancestry (as it was done for questions concerning diabetes), this law suit and ethical predicament could have been avoided. (http://www.aolnews.com/nation/article/arizona-state-settles-dna-dispute-...).

In this case the Havasupai tribe were clearly not consented for the study properly. Informed consent can be one of the most difficult and time consuming parts of a study, however it should always be done with great diligence. In this case, I do not believe that the subjects were given complete disclosure in regards to what their blood samples would be used for. Specifically, it does not seem that "inbreeding" falls into either of the categories listed on the consent form as a behavioral or medical disorder. It can be very detrimental to a person's self worth and sense of family to become aware of inbreeding within one's own family. It is extremely important when conducting research to not only think of the greater good of people who suffer from a disease and those who may benefit from more research on that disease, but to also think about any community which may be negatively affected by research results. Especially in Native American tribes who have throughout history gone through much strife and do face a lot of stigma in regards to their health, the outcomes of such a study can be harsh. I think in the future researchers may need to re-consent patients that they have decided to use additional samples on. Consent for sample collections should list all possible uses and may also need additional consent as different tests come up that may be performed on a sample. It is impossible to anticipate all the research that may be done on a sample at the time of collection, so an option that additional consent be obtained from donors should be provided at the time of the initial consent.

The use of existing data and specimens in this case is important because it is from a small, identifiable, ethnic group. Sensitive topics such as mental health, substance abuse, and sexual history need additional consideration for the researcher. Many people, not just this small group of Native Americans, may have issue if their data are being used for such research topics without their explicit consent- particularly if they could be identified to a degree- such as belonging to a particular ethnic/racial group. If one applies the “Common Rule” algorithm to this case, the research deals with data and specimens that are not individually identifiable, so it would not be considered human subjects research and, therefore, informed consent would not be required. However, as with any algorithm, clinical, or in this case, research judgment should have led to some kind of “Common Sense” realization that this might not fly. In particular, sensitive topic + data from a small tribe with a history of being discriminated against and possible low health literacy=some red flags. In their literature review preceding the study, these researchers should have been familiar with other studies that dealt with thesesensitive topic areas and familiar with subject recruitment and methods. Perhaps they did consider this and still had precedence that it had not been a problem in prior studies. While the primary researchers did include “behavioral/medical disorders” in their consent- this is too vague and the second group of researchers should have realized the sensitive nature of the research warranted more consent. However, the primary researchers also bear responsibility in permitting use of the data and perhaps not obtaining more detailed consent for future studies at that time of initial procurement (ie, may be used for other topics unrelated to diabetes and could have a negative impact on how their tribe is viewed) with not only the tribal elder who offered the sample, but with the individuals.

The specimen incident with the Havasupai does not seem like an ethical dilemma to me, rather it seems clearly unethical. The donor is entitled to determine what is allowed with his or her sample, and just as you couldn’t spend a car loan on a jet ski, you cannot expand or change what you decide to with a solicited sample. This ethical limitation could potentially have extremely restrictive effects upon biomedical science, slowing down progress in a mire of tape and consent forms. The question posed in this forum seeks to determine how ethics can be upheld without arresting progress in such an important realm of research. One solution could be to universally assume that samples are eligible for whatever tests they might possibly be used for, and allow donors to accept or reject those terms at face value. The deal could be made more amenable by altering it with caveats such as “I authorize my sample to be used for ‘x’ purpose only” or “I do not authorize the following tests,” as another commented above. Patients would need to be openly notified of the potential uses of their sample before being allowed to restrict its use or donate in the first place. This is perhaps the most difficult part, in ensuring that patients are made aware. Conversely, any sample donated without restriction should be fair game. If this system were carried out uncorrupted, ethics would be preserved while helping to avail previously collected samples to future testing. Submitted by Joseph Eliason

First off, I’d like to just comment on how insightful and interesting previous comments have been on this subject. It really has been a pleasure to read these comments, and I will definitely stay tuned to what others have to say. A few of my opinions and comments…I agree with many of the statements that have been made about this stark disconnect between what is ethical and what is legal. A previous blogger pointed out the lack of anonymity that accompanies using a very small study group, such as a very specific ethnic population. I absolutely agree. Any sense of anonymity either within or outside the community was lost when a group of only 41 individuals within this small community had their blood samples analyzed for mental illnesses. But ultimately, what it comes down to is that “In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.” This statement, made in 1975 by the Declaration of Helsinki, the document on which human research ethics is based, in my opinion, drives home the heart of the matter: research should always be in the best interest of those involved. As physicians and health care professionals, we have subscribed to the idea that we protect our patients from harm; and as academics, we must subscribe to this same ethic—we promote the interests of our study participants over those of science. Perhaps we have lost sight of this fundamental principle in our “publish or perish” culture. Perhaps investigators should start taking the time to explain their research and its potential benefits to their subject population. Nowadays, more often than not, informed consent becomes a piece of paper that needs to be signed, not a communicative process that exemplifies the spirit of informed consent. Maybe if we begin to revert back to the values that made scientific research more human in the first place, we can avoid disrespecting people and communities while maintaining the validity and prestige of the scientific process.

The question of how to obtain informed consent for future, unspecified uses of specimens is a challenging dilemma. Respecting participants’ rights and providing opportunities for scientific progress must be balanced. This case study illustrates the challenges of obtaining informed consent for future uses of obtained biospecimens for purposes not related to the original studies, while still respecting the interests of research participants. In my opinion, tiered consent and general permission (“broad consent”) -- which is a level of consent in-between strictly specified and unconditional "blanket consent" --might be a good choice for this. It is the responsibility of the investigator, and a best practice, to provide information up front and ask the donors for consent for future use prior to collecting samples -- even in cases where the specifics of the future research projects are still unknown. This kind of informed consent would allow participants to narrow their permission for future uses of their donated specimens, if they wish, and still provide opportunities of using specimens for future study. This would also reduce burdensome and possibly inappropriate time and cost to re-contact all participants. However, personal information related to research would be handled safely, and the donors of biomedical samples would be allowed the right to withdraw consent at any time. New research studies of those specimens should be first assessed for the risk-benefit in relation the donors, and then approved by an ethics-review board. If the research involves a specific community, such as this Havasupai Indian tribe, consideration only about the potential risks to individual contributors might not be enough. De-identified information of the donor samples would not have eliminated the tribe’s concern regarding public perception and potential overall stigmatization of their community, and also interference of their cultural beliefs. Researchers should always carefully search for sensitive issues in the communities related to their research topics. They should remember to "always put yourself into the other's shoes. If you feel that something would hurt you, it probably hurts the person too."

This is a challenging issue. Though it is important not to create insurmountable obstacles to conducting research with biologic specimens, the informed consent process cannot be compromised soley for this sake - as it seemed to be in this case. In seems to me that adding a line so vague as "the causes of behavioral/medical disorders" is in itself a contradiction to an "informed consent." Though the researchers may have felt they were complying with federal regulations, were study subjects really informed about the nature of the studies in which they were ultimately participating? How could they if the studies that they were later included in were not even described to them when they signed the consent form? Especially given that there were potential risks secondary to the cultural/stigma issues raised by the additional studies. It should not be allowed to include such lines in informed consents that essentially give permission to researchers to include specimens in all future research studies. Prior to each new study, a new informed consent should be conducted with each participant prior to each study. This is the only way to preserve the integrity of the informed consent process for this kind of research.

It is clear that the researchers who defended the study by citing compliance with federal regulations failed to understand the difference between what is legal and what is ethical. One can certainly understand the tribe members' objections on the studies mentioned, as the loosely worded terms of "causes of behavioral/medical disorders" on the original consent form appeared misleading and open to interpretation. Clearly, the researchers picked a specific high-risk group -- a Native American tribe with high DM prevalence -- to study, so one would have expected them to do more research on the actual beliefs and value systems of this particular population and to perhaps seek input from within the tribe (i.e. community leaders) while designing the study and informed consent procedures. If the challenged studies were conceived after the initial informed consent and specimen collection had been completed, due to the potential stigmatizing or sensitive nature of study topics, perhaps a new informed consent should be obtained from subjects who had previously given their blood for storage, in order to not risk ethical and legal ramifications.

Informed consent can be pretty tricky especially if there are certain issues that aren’t clearly stated to the subjects involved in the study. In this case, there are existing data and specimens which were used for studies that the subjects clearly didn’t consent to. I think that was a mistake on the part of the researchers to “assume” that since the subjects have already consented to the previous research that it gave them the freedom to use the available samples for their research. I was reading Mello and Wolf’s article on the Havasupai Indian Tribe Case and they suggested using the tiered consent where research participants are presented with a menu of options from which to choose. This can be an option for future researchers dealing with existing data and samples.

As have been pointed out by several of the previous commentators, this case is a perfect illustration that compliance with federal research regulations does not equal ethical research conduct. The particular genetics studies in question here should have caused researchers special ethical considerations for several reasons. First, genetic studies, even on de-identified specimens, always have the potential of discovery of information which could have important implications for the individual or the cohort who may not have wished to have such knowledge in the first place. Especially when the cohort is small enough, even though the specimens are themselves de-identified, the individuals within the cohort may still feel their confidentiality violated when information discovered applies to the whole group. Second, mental health disorders, even in mainstream culture, are highly stigmatized conditions. Studies of these conditions should always take special caution to obtain informed consent specifying the particular disorders under study. Simply stating “the causes of behavioral/medical disorders” is far from being adequate. Especially when such conditions are to be studied in an ethnic minority, there is even more reason for researchers to obtain specific informed consent as the value system of the ethnic minority may differ substantially from the researcher themselves and therefore nothing should have been taken for granted. Although researchers may not always be able to anticipate the specific conditions to be studied on stored biological samples in the future, the initial informed consent should state as many disorders as researchers can possibly anticipate. More importantly, when using previously stored biological samples to study any potentially stigmatized conditions in any minority groups, it is necessary to have consultations with ethicists, representatives from the initial cohort, or other experts in this area, to decide whether informed re-consent is necessary. In certain conditions, maybe informed re-consent of available individuals is the most ethical approach and will be time worth spending.

During applying for the IRB approval of a human subject related research, the purpose of using collected samples and the method to deal with the leftover of samples after doing research should be will described. In term of the donors, no new research should be done if the research is beyond the field stated on the informed consent, otherwise, a new consent should be got from the donors. In term of the investigators, they should describe all the possible research fields before collecting the samples. If there is any important research but not approved by IRB, a new consent should be applied for IRB approval.

This scenario brings up multiple interesting issues around the informed consent process. While I understand that time is limited for many investigators, participants should not be put at a disadvantage because of it. I am curious about how the initial conversations about informed consent transpired with tribe members. Though we know that the investigators focused mainly on research about diabetes in the population, I wonder if they allowed time for questions and time for the tribe members to review the form completely on their own. It would be best if the investigators used common language and circumstances familiar to the tribe members. This would have helped to improve comprehension of participants. Language issues manifest in both the direct conversation as well as the form itself. Vulnerable populations can easily become confused or lost in medical jargon. Participants may feel ashamed that they do not understand what is being said and decide not to voice their concerns. Investigators must create an environment to facilitate an open discussion and invite questions. One method to do this is to simplify the language on the consent form, shorten the length, and direct the conversation from the perspective of the participant. Clearly, the participants felt they were not properly informed of the potentially damaging ramifications of the genetic studies centering on schizophrenia and inbreeding. Overall, I am happy that the tribe members took a stand on these issues. Investigators need to be reminded of the impact that research can cause to the participants. By reserving adequate time for a discussion regarding consent with each participant, those that did not wish to be involved in future studies could have declined. This situation could have been avoided. Perhaps new consent forms can provide an option to select if participants do not mind being involved in future (currently undeclared) studies. Those interested in only involving themselves with specified topics could be protected and those that are open to any subject matter could still contribute to the research community.

"sensitive topic + data from a small tribe with a history of being discriminated against and possible low health literacy=some red flags"...what a great quote from a prevous post. As physician investigators, we always have obligations to our Hippocratic oaths...namely, to "first, do no harm". There is a legal standard known as "prudent man" which asks what a hypothetical reasonable person with average intellect and care would have done in a similar situation. What would the "prudent man" have done in a circumstance where eventual data would have reported mental health outcomes and "inbreeding" data on a small, easily recognizable population? I think that question answers itself. Ultimately, researchers are responsible not only for doing "good science" but for protecting those participating in the "good science". A tiered consent form is certainly one way to improve the future use of data which is collected. No amount of forethought can predict every possible future study which may arise. However, there could be some part of the consent opting in/out of potentially offensive areas such as mental health, sexual practices, etc. Finally, if a researcher finds himself in a position where he hopes to use previously collected samples for a study where there might be questionable agreement from participants, he has two options. First, to contact the participants and obtain explicit consent, or start from scratch and collect new samples specifically for the study. That is what the "prudent man" would do.

The incident and resulting law suit raises the following concerns. The original sample collection was to study diabetes. However, the fact that the consent the tribe members signed was generalized so broadly as "the causes of behavioral and medical disorders" suggests that there was a clear intention to use the samples for other than diabetes related studies. This was already unethical, as study subjects have the right to know in what specific studies they as individuals and their samples will be involved in. It is not known, that when the consent signing happened, how well informed it was verbally by the study coordinators. When later using the samples for non diabetes related studies, in my opinion they should have re-consented the subjects, or in case a subject deceased, their relatives, with the specific objectives of the new studies, for the following reasons. The ethnic and cultural issues were raised in many previous comments, which is valid argument, by adding stigma to a group of people and undermining their dignity. Sample use where subjects are not identifiable doesn't require consent as per current regulations, however this is a very small and well defined small ethnic group where their being unidentifiable is questionable. Confidentiality is an absolute must in case of sensitive research questions (mental, sexual, illegal) so again it is against human dignity and ethics to carry out such study without properly informed consent and agreement of the subjects. Even when the interest of a large group requires such studies on small group, human dignity can never be overlooked. Unfortunately, this is not the fist time this happened. Consent forms, if want to generalize research questions or additional research questions in the future, in my opinion should specifically mention and exclude sensitive research topics. There should be more emphasis on the process and documentation of verbal explanation of the consent and should be heavily scrutinized by IRBs. Evelin Szakal, PhD Sent via BlackBerry by AT&T

The first basic element of Informed Consent is ‘Statement that research is involved, its purpose, duration and procedures.’ The article clearly stated that ‘The consent form described the project as studying “the causes of behavioral/medical disorders,” but prestudy communications with tribal leaders apparently focused on diabetes.’ Using such a broad term as purpose of the study and using different explanation to the leaders of the tribe, is against the principals of the informed consent. On the other hand, if the researcher’s intention was to use the samples just for studying diabetes, they could have mentioned the purpose of the research as ‘studying the causes of diabetes’. Since they have used such a broad term which also include behavioral disorders, it is highly suspicious that even in the beginning of the study they knew that they will use the samples for many other purposes. This, is totally unethical and against the ‘principals of informed consent’ and ‘Protection of Human Subjects’. To improve the consent for collection of these samples, the researchers should have either discussed this issue with the leaders of the tribe from the beginning of the study that they might use the samples for other purposes as well unless they express deny permission, or come up with the list of topics that they might use the samples and have agreement for some of them with the leaders, or recontact the individuals or the leaders for each new use of their specimen. Studying sensitive topics such as schizophrenia, examining inbreeding and evolutionary-genetics studies among a known tribe members is unethical.

The idea of a tiered consent for the collection and banking of de-identified biological specimens has been mentioned by several bloggers. Sensitive areas of research such as substance abuse, mental health and sexual health would be listed. Study participants may opt in or out of their biological specimens being used for research in these areas. I think this would be preferable to a blanket consent or lack of consent for all other secondary research studies. However, does this really protect study participants or simply lengthen consent forms further? There will be future research in aspects of non-sensitive subject areas that some study participants may find objectionable but have consented to participate “unknowingly”. How could this be informed consent? Every individual is important but surely it would be impossible to ensure that everyone’s current and future views are taken into account. One could argue that surely achieving benefit for the majority should triumph over upsetting the minority. Will this simply disempower the minority who object to certain uses of their biological specimens for secondary studies and only find out when the study has been completed and published? This may be a substantial minority especially if the research findings are controversial or touch on emotive subjects. Despite this, would tiered consent forms still make research participants feel that they have greater control over the biological specimens that they have donated to research?

I would like to add an additional section in the informed consent.Let the participants choose: " (YES or NO) If necessary, do you agree with utilizatin and examination of your de-identified specimen in this study such as blood samples for future investigational and non-profit purposes? (studies involving stem cell research are NOT included) "

The guiding principle regarding this particular situation is the complete definition of informed consent. In this particular case, while the tribal members were informed of the broad potential purpose of the study, by using the vague language of “the causes of behavioral/medical disorders” they did not fully disclose the possible aims of their study. Informed consent requires disclosure of what “research is involved, its purpose, duration and procedures”. By not detailing what the future potential aims of the study, the researchers failed this definition of informing the subjects with their purposes and their procedures. It appears that the use of encompassing and vague language when informing subjects of study aims is commonplace and allows researchers to expand on their studies. However, even when using umbrella type language, subjects must still be informed of the aims of the study and what the overall purpose of their participation entails. It is clear that the focus of the consent discussions revolved around the study of diabetes and subjects were not expressly informed of the potential studies of schizophrenia, inbreeding, and population evolution. From their later objections and controversial implications of these studies, it is clear that they would have not agreed to participation had they truly been fully informed. The use of the samples for these further studies while well intended were unethical. One potential solution to obtaining informed consent while protecting potential future aims and important studies would be to elucidate what studies subjects would object to. In addition to full disclosure of all known possible aims of the study and all known potential uses of the samples, subjects might also be given an area to submit all uses they may find objectionable. This could be a checklist of potential uses that they would object to or an open area to provide questionable research aims. Overall, we need to improve communication and disclosure of possible research uses and allow subjects the ability and option to opt out of the study should they disagree with its uses.

The language that was written in the consent form took into consideration the desire to do future research on a wide range of medical topics but unfortunately this written language was not adequately understood by the participants consenting for the study. This is often the case that participants don't know what they are consenting for and if they did, they might chose not to participate in a research project. This is one of the many hurtles that exist in clinical research. In this case participants were ok consenting to certain subject matters pertaining to the study but uncomfortable with the more taboo medical topics that researchers wanted to pursue later. This is complicated for many reasons. From the researchers perspective this is very important research that could have a positive impact on the population. Finding sensitive ways to ask for consent to study this information could be helpful in diminishing the existing taboos. It is not fair to try and study this topics without the participants knowing. On the other hand if the researchers told participants that they were going to study Diabetes as well as more taboo topics many participants may have not consented to the study which would have been non-productive for the researchers and the study population. Consent is tricky, but it is important to be forthcoming with participants even if it means losing some people who would have consented if they didn't know what they were consenting to.

It is understandable that one may not be able to conceive all the research questions prior to data collection. However, the 2 areas that the research team looked at, schizophrenia and inbreeding, are very sensitive topics. I wonder whether the research team had to go back to their IRB to look at those additional questions. Anyway, to prevent similar incident from happeninging in the future, researchers should resubmit for IRB approval for research questions that are not clearly stated in the original proposal. If the new questions posted risk to violate the trust with the subjects (e.g. questions on mental health or other issues that may stigmitize the population), new consent should be obtained.

I agree with many of the previous comments about the original informed consent being too broadly defined. However, that is exactly how many of the genetic research being conducted currently operates. It's also how many large-scale health providers like Kaiser operate as well. I understand that it is difficult to go back later for informed consent, however, I do think that the original consent should stay within certain parameters. If the study was intended for diabetes, then it should stay within diabetes. However, if the study was more broadly defined as "chronic health problems within the Havasupai people" and participants were explained that this included a large umbrella of different types of diseases, then I think it would be ethical to study schizophrenia and other types of disorders. However, I think that in order for this type of work to be conducted, it needs to be based within a community participatory framework with a liaison to the community that is culturally accepted. I wonder if asking the Havasupai Council if there were any diseases, outcomes or issues that were important for them to look at, if the researchers could have done some compromise. It's when communities feel taken advantage of that problems arise, and I think even with sensitive questions, there are sensitive ways to partner, discuss and broach the topics.

This story brings up several issues and teaches us several lessons about forming a trusting relationship between researcher and subject. For one, it highlights the importance of effective communication and the necessity of setting expectations between researchers and subjects prior to the beginning of the study. Although it is impossible to know the true intentions of the researchers and it may very well be that the researchers were well-intentioned, I find it questionable that discussions with the tribesmen focused on diabetes yet the informed consent document allowed the study of "the causes of behavioral/medical disorders." It is possible that the researchers focused their discussion on diabetes and avoided discussing more controversial medical issues included in the consent form in order to increase the chances that subjects choose to participate. Also on the issue of communication, as with any subject population, it is very important for the researchers to keep in mind that the subjects do not possess the same level of understanding of science and research regulations as do the subjects. For this reason, it is crucial that the researchers spend a significant amount of time explaining the study to the subjects and adequately addressing any of their concerns. Another question this brings up is how culturally sensitive the researchers were. As with any participant population, the researcher should take care to truly understand the subject's cultural norms and go so far as to be proactive in asking the subjects if an intended purpose for the specimens might go against a known or obvious value to that people. In this instance, the researchers perhaps should have realized beforehand that this tribe has a firmly held belief about the origins of their tribe and that a study that attempts to explain the origin of their tribe through evolution might be offensive to the tribe, and this issue should have been brought up. By taking proactive measures such as this early in the study, greater trust can be formed between researchers and subjects, and the study will be more fruitful. Furthermore, the informed consent form statement is extremely vague. The use of the phrase "medical disorders" grants the researchers freedom to study virtually any type of disease. Consent forms should be much more specific than this in order to allow the subjects a better understanding of what the biological specimens may potentially be used for in the future, even if it means limiting the use of biological specimens or requiring new specimens to be obtained.

Before collecting blood samples and clinical data, the consent form should well define the range of the study. If the researchers hope to use the blood sample beyond the previously defined studying field. The study protocol including the consent form should be renewed and get the approval of the donors again.

The issue of further study of stored biological specimens of human participants is indeed an ethical dilemma that is gaining increasing importance as our research technologies evolve. This particular example is even more compelling as it deals with a study population that has been exploited in history. While de-identification of specimens is important, it seems that the even bigger issue is that of inferring consent. As mentioned by some other bloggers, mental health, evolution, and inbreeding are some particularly sensitive topics that many may object to on cultural and religious grounds. Ergo, consent should not simply be inferred in these cases. While making a consent form more explicit may indeed be a bit more challenging from the researchers' perspective, it is worth incorporating questions from a tiered approach in order to "cover the bases" so to speak. Perhaps including a line consenting for mental health research would also be prudent in this situation, and regardless, patients should be counseled on examples of what kinds of research may be conducted. We need to ensure not only that the privacy of patients is maintained, but also that the informed consent process is truly "informed."

I agree with many of the previous comments suggesting that special attention be paid to sensitive topics such as mental health disorders and inbreeding, especially in this case which studied a specific small tribe, and the results were reported as specific to this tribe (and therefore the results were essentially de-identified). I agree that in these cases, repeat IRB approval and informed consent should be obtained. I think in this case it is fairly clear (certainly in retrospect at least) that repeat IRB approval and informed consent should have been obtained. Other cases may be less clear -- but when in doubt, I would err on the side of caution. It is of paramount importance for us as researchers to respect our participants and ensure their trust.

The first basic element of Informed Consent is ‘Statement that research is involved, its purpose, duration and procedures.’ The article clearly stated that ‘The consent form described the project as studying “the causes of behavioral/medical disorders,” but prestudy communications with tribal leaders apparently focused on diabetes.’ Using such a broad term as purpose of the study and using different explanation to the leaders of the tribe, is against the principals of the informed consent. On the other hand, if the researcher’s intention was to use the samples just for studying diabetes, they could have mentioned the purpose of the research as ‘studying the causes of diabetes’. Since they have used such a broad term which also include behavioral disorders, it is highly suspicious that even in the beginning of the study they knew that they will use the samples for many other purposes. This, is totally unethical and against the ‘principals of informed consent’ and ‘Protection of Human Subjects’. To improve the consent for collection of these samples, the researchers should have either discussed this issue with the leaders of the tribe from the beginning of the study that they might use the samples for other purposes as well unless they express deny permission, or come up with the list of topics that they might use the samples and have agreement for some of them with the leaders, or recontact the individuals or the leaders for each new use of their specimen. Studying sensitive topics such as schizophrenia, examining inbreeding and evolutionary-genetics studies among a known tribe members is unethical.

I agree to a certain extent with the study investigators in that they legally may have done no wrong. However, I agree with a recent commenter that the authors likely planned future studies at the time of obtaining consent, and likely used an all-encompassing consent form to allow this, consenting to study of “the causes of behavioral/medical disorders.” One could easily argue in this case that informed consent was not obtained. I suspect that this tribe consented to the overall study concept because they wanted to help investigators determine why they have diabetes. Presumably they fully understood this, and the use of their data for this purpose would be considered fully informed consent. However, I strongly suspect that participants were not informed of the other potential uses, and in particular the de-identified (at least at a tribe level) reporting of inbreeding and behavioral problems. This later study would result in stigmatization of an entire population, which is in my mind different than studying a less-well-defined group of patients that share a disease, but otherwise lack identifying features.

I agree with the point that studying population origin is very different than studying disease especially when the study population is so small and well defined. Perhaps a distinction could be made between studies that intend to make claims about the population versus studies where the aim is to understand a condition as if affects a much broader population.

I think that informed consent needs to be handled seriously and carefully by study investigators. If the study is collecting biologic samples and there is an option to have unused samples banked, this needs to be discussed with the study participant (giving them the option to opt-in or out). They need to understand the risks involved in agreeing to have their specimens banked. If the study participant agrees to have their biologic specimens banked, then the study investigator needs to see if the study participant wants to impose any limitations on how their specimen can be used (mental health, alcoholism, genetics, etc). If, after all of this is done and the study participant agrees, then the study participant and the researcher are protected. In the case described above, it sounds like the risks and the potential research questions were possibly glossed over and the study participants did not know what they were agreeing too.

There is an issue of cultural sensitivity in this case that is not typically spelled out by a standard informed consent document. I currently am the PI in a study in which we are collecting biospecimens, and our consent includes standard wording that allows for the specimens to be stored and used for future research approved by a Tissue Utilization Review Committee and by the institutional IRB. It seems to me that this case is a failure of this secondary review processes to consider the cultural issues associated with testing biospecimens for associations with conditions associated with such stigma. This is particularly relevant when a study is testing these associations within a particular ethnic group rather than in the population at large. I disagree to some extent with the comment posted on 5/5 at 9:17 PM about the level at which this review should have occurred. I don't think that researchers necessarily need to have an individualized conversation with every participant about all hypothetical future research possibilities at the time a specimen is collected for another purpose. Quite frankly, this does not seem like a feasible solution. As an alternative solution I would propose to include a representative member of the community as a lay representative on Tissue Utilization Review Committee for any discussion about future uses of the specimens.

Research, involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects can be used. However, if the participants object the information should not be used for research purposes anymore. To avoid this delicate situation one could ask the participants if their information could be used for future studies as long as it is non-identifiable.