Opinion: Seeking justice in the age of genomics and a call for higher ethical standards for research involving human populations
Current regulations do not require on-site ethical oversight of research involving human-derived data with the potential to harm marginalized populations. This needs to change.
Ed. note: The Broad Institute notes that the study "Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior" by Ganna et al. raises important social, ethical, and scientific issues that are worth considering and discussing. Because we believe it is important to represent a range of perspectives about this work, we invited members of the Broad community to provide their thoughts on the study, the process, the implications, and lessons we might learn. We hope these perspectives will inform a needed discussion.
I first learned of the genome-wide association study carried out by Ganna et al. in January this year. When I heard that Broad researchers had conducted a study seeking to understand the genetic basis of “same-sex sexual behavior," as the authors put it, I was immediately alarmed. As a proud Broad Institute member and an out gay man passionate about developing new therapeutics for treating psychiatric disorders, I was and continue to be concerned about the goals of this study, the way it was conducted, and the impact its findings will have on the LGBTQIA+ community worldwide. Specifically, I was keen to understand the ethical oversight process of this study and studies like it and whether this process adequately protects the LGBTQIA+ community and other marginalized populations from the potential harms of genomics research. Shockingly, I learned that the current legal regulations and ethical norms often fail to adequately protect historically marginalized populations from the negative impacts of genomics research. As a result of the gaps in these regulations, the Broad’s Office of Research Subject Protection (ORSP), which oversees ethical compliance for Broad research activities, and the Partner’s Institutional Review Board (IRB) did not need to be informed of this research and were not even aware of this investigation until after a public presentation of its findings in the fall of 2018. Given the sensitivity of this investigation and its potential to impact the social well-being of a population that continues to be at risk of harm, this article seeks to break down the inherent legal, ethical, and moral complexities involved in research like this. Specifically, I hope to answer four questions:
- What federal regulations are in place in the US regulating research involving human populations?
- What vulnerabilities in ethical oversight does the application of these standards create at federal funding agencies, large international research consortia, and local research institutes?
- Why is this a problem worth solving?
- What initial steps can be taken to improve ethical oversight?
First, what type of oversight is required for genetics research with the potential to impact the well-being of vulnerable populations according to US federal regulations? The federal government has a set of standards in place known as the Common Rule, a set of federal regulations agreed upon by numerous government agencies, designed to protect human subjects from potential harms resulting from the research process. According to these regulations, IRB review is required for any research deemed “human subjects research” and includes special protections for specific populations, namely pregnant women, fetuses, and neonates, prisoners, and children. Of note, there are no specific protections for minority groups in the US, such as the LGBTQIA+ community. Under these regulations, many types of research can be deemed “not human subjects research," but nevertheless, can impact human populations deeply. For example, data from humans that has been de-identified and does not require researchers to be in contact with subjects does not meet the federal definition of “human subjects research," and thus does not require IRB review. As scientists start to sequence and analyze genomes from hundreds of thousands of individuals, this standard is antiquated and does not consider protections for the populations that could be affected by this research. Consequently, these federal regulations can generate ethical gaps for federal funding agencies, large research consortia, and local research institutes. Let us consider the Ganna et al. study as an example of how the application of these standards at each of these levels can be followed fully, yet can still leave vulnerable populations at risk of harm.
We could consider, first, how these standards are applied during the federal funding process. During the process of an NIH grant application and annual reporting, investigators are required to identify whether the research funded constitutes “human subjects research." Once it has been determined that an institution and its affiliated researchers are engaged in “human subjects research," review by an IRB is required. Because the data used in the Ganna et al. study was de-identified and did not require contact with human subjects, this study did not qualify as “human subjects research” and therefore, did not require IRB review. The current regulations fail to consider that while research that only involves the use of de-identified data and secondary datasets and that does not require contact with subjects may not pose a meaningful risk to the personal health information or identity of research subjects, some studies may have serious potential to harm entire vulnerable populations. If the potential for harm is great enough, review should be required to ensure that these impacts are minimized sufficiently and that researchers consider the benefits and costs of their research throughout the entire research process, rather than as a post hoc consideration.
The next level at which one would expect ethical oversight to occur is at the level of the data repository. In order to access the data stored in the repositories, such as UK Biobank and 23andMe, the investigators needed to file an access request and Data Transfer Agreement to the Data Access Committees (DACs), which are tasked with determining whether the data requested, the analysis, and type of research meet their established ethical standards. Typically, institutions accessing these repositories consider the DACs that are overseeing them as the most qualified body to review requests, as they are the most familiar with the consent process involved in sample collection, the structure of the data, and the restrictions placed around access to the data. Nevertheless, consolidating the review process for data access through these DACs may result in insufficient protections. First, given the importance of protecting the autonomy of research subjects, it’s important to consider how exactly the research subjects were consented. In 2012, 23andMe implemented a “secondary consent” that specifically describes that research like the Ganna et al. study is a possibility, and thus obtained informed consent. In the case of UK Biobank, research subjects submitting samples are “broadly consented." This means subjects consent to having their samples used “to improve the prevention, diagnosis and treatment of illness and the promotion of health throughout society." In the case of the Ganna et al. study, it is debatable as to whether LGBTQIA+-identifying subjects who submitted samples and data to the UK Biobank would have consented if they had been specifically informed that their genetic information would be used for a study like this.
Regardless of the situation, it’s important to ask whether the consent process for major research datasets is overly broad and in turn, does it adequately protect the autonomy of research subjects? Furthermore, large research consortia consist of many scientists, many institutions, and individuals of many different sociocultural backgrounds who vary in their sensitivity to the history and trauma of marginalized populations. Currently, the onus falls on these consortia to carry out the review process for access to data. By depending entirely on these DACs that may or may not recognize the LGBTQIA+ community and other marginalized groups as being worthy of protection, the data access review process currently in place puts these populations at risk of harm.
The third level at which one would expect oversight to occur is at the local institution. Ethical review at any institution in the US, including the Broad Institute, requires the cooperation between federal regulators and institute officials. Through this cooperative relationship, the US Department of Health and Human Services sets the regulations and the institution is responsible for drafting policies enforcing those regulations. Thus, any vulnerabilities that exist in federal regulations will necessarily flow into the local institution. In the case of the Broad, there are two main areas where federal regulations lead to ethical gaps on the local level for research like the Ganna et al. study: determining whether or not contact with the ORSP is required, and obtaining sign-off on a Data Transfer Agreement being filed to a controlled access data repository. The Broad’s policy that regulates review of “data derived from humans” does not require ORSP to be notified regarding the use of de-identified data obtained from a repository with its own DAC. For the Ganna et al. study, this led to the ORSP and the Partner’s IRB becoming aware of this research only after its public presentation at the American Society of Human Genetics (ASHG) meeting in October 2018, when the study was nearly complete. Furthermore, when a Data Transfer Agreement obtains sign-off from a Broad official, all that is required for its approval is whether investigators have completed institute-required bioethics trainings, at best. While these requirements are compliant with federal regulations, we should not view this as sufficient oversight for such a sensitive investigation. The current federal regulations and the local institute policies that reflect these regulations do not currently require investigators using de-identified information to be sensitive to how their research affects vulnerable populations like the LGBTQIA+ community, nor do they require the regulatory office of the institution at which this research is being conducted to be aware from the start of the investigation that this research is occurring. Instead, a large degree of any on-site ethical oversight is left to self-regulation by the researchers themselves.
In sum, the ability for research that poses a risk of significant harm to marginalized populations to proceed despite existing federal regulations, oversight by international research consortia, and the policies of local institutions compel us to ask: should research qualifying as non-human subjects research with implications for marginalized populations require additional ethical oversight? As it stands now, according to federal regulations, the answer is no. But is this right?
The Broad Institute is a leader in genomics and the study of human disease. Minimally, we should strive for this status to be reflected in the ethical and moral standards to which we hold ourselves and each other. The genomic era will introduce new moral and ethical dilemmas and the Broad can be a leader in this process of ensuring stronger oversight of the use of human-derived data, but only if it chooses to be. Studies whose findings have the potential to impact marginalized populations should have on-site institutional oversight from the very beginning, given the sensitivity of the research and its potential to cause real harm. As it stands now, this research can be conducted without the researchers being required to be cognizant of or be held accountable for the potential impacts their findings could have. This is irresponsible. We are better than this and should be held to a higher moral standard.
What we are called to grapple with here goes beyond how we conduct science. At its core, this issue of ethical oversight is about a larger societal question. Who do we value? Whose existence and humanity do we acknowledge and view as valid? Who do we deem worthy of protection from harm? According to GLAAD’s 2019 Accelerating Acceptance Index, acceptance of LGBTQIA+ people among Americans aged 18-34 has declined for the second year in a row. In 2018, at least 26 transgender people in the US died due to fatal violence, according to the Human Rights Campaign. So far in 2019, 16 have died due to violence and this number continues to rise. Recently, the Trump administration announced a plan to roll back protections in the Affordable Care Act (ACA) that protect transgender people from discrimination in healthcare and insurance coverage. On October 8th, the United States Supreme Court will hear arguments as to whether LGBTQIA+ Americans should be protected from workplace discrimination. We cannot pretend that our science is divorced from the society it is conducted in and right now, we’re living in a time when people in power seek to perpetuate harm against LGBTQIA+ people. As a community, we must fight for a system of laws and regulations on both the local and federal level that protect LGBTQIA+ individuals and other marginalized communities from harm, including during the research process.
The seriousness of this issue requires the attention and input of all members of senior leadership at the Broad as well as scientists from diverse disciplines. I call on them to join this debate and push for increased protections for marginalized communities in the research process. In order to provide a foundation for constructive debate aimed at enacting institutional oversight reform, several proposals are listed below. My hope is that they can serve as a starting point for further action and debate, but more can be done beyond what is proposed here. It will be important to balance any proposals or changes made with the need for academic freedom and reducing prohibitive redundancies that could drastically slow the efficiency of impactful research. While these proposals exceed current federal standards, the Broad has already moved ahead of federal regulations in other ways, such as the implementation of a BL2+ biosafety level. Federal regulation does not mean that we cannot hold ourselves to higher ethical and moral standards. I invite all members of the Broad community to use these proposals as the start of a vital debate.
Proposal 1: Convene a committee charged with institutional oversight reform. By establishing a body with a defined mandate, sustained, productive institutional debate and action can be facilitated. This committee should be tasked with leading the institutional debate about the need for increased oversight protections for research involving historically marginalized populations. This committee should consist of institute leadership, including the Chief Compliance Officer, Broad scientists, and institute staff of diverse cultural, racial, sexual, and gender identities in order to establish a body that reflects the diversity of views needed to examine the complex social and ethical issues at hand. Given the Broad’s collaboration with other local institutions, this committee’s task also extends to engaging other institutions at the local, federal, and international level.
Proposal 2: Establish a more rigorous local review process for research impacting humans. Currently, researchers can request data derived from humans without registering with the ORSP if the data is being obtained from an external organization with its own Data Access Committee, such as dbGaP or UK Biobank. If a team of investigators is submitting a data access request and a Data Transfer Agreement (DTA) to a data repository, an ORSP review should be required for the completion of these documents. By requiring all access requests and DTAs to include an ORSP number, this creates a simple mechanism that will allow the ORSP to not only be aware of active research, but also review these projects before sign-off is completed. Second, institute leadership should implement a more thorough screen for sensitive non-human subject research in the ORSP registration system in order to flag sensitive investigations for further oversight. Thirdly, institute leadership should advocate for more thorough screens of research sensitivity to be incorporated into data access requests and DTAs used by external data repositories.
Proposal 3: Integrate the Broad Data Usage Oversight System (DUOS) into the review of all institute research involving data stored in internal or external data repositories. DUOS is a semi-automated data management service recently established as a means of ensuring that restrictions on secondary data and specific forms of analysis are respected by researchers. This system allows for the screening of research projects requesting access to deposited data to be done in a semi-automated way, while also allowing for manual review by an oversight entity when necessary. This system represents a model by which more robust ethical oversight can be carried out by ORSP without unreasonably burdening the system and office and consequently slowing the efficiency of institute-affiliated research.
Proposal 4: Empower current ethics staff, hire more Broad-wide staff bioethicists, and establish a mechanism of connecting researchers with ethics resources. Currently, some Broad staff have a background in bioethics, but these resources will not be sufficient going forward. Hiring more bioethics experts to work alongside current staff would provide more adequate resources for both the ORSP and investigators to utilize throughout the research process. These experts should be tasked with the following:
1. Overseeing and updating policies around ethical and moral considerations for human genetics research, independent of the research’s designation as human subjects research or not.
2. Assist ORSP staff to provide additional expertise for making complex ethical and moral considerations.
3. Serve as a resource for investigators throughout the research process. One way to direct researchers to this resource is when they register with the ORSP.
4. Plan programming and workshops to increase awareness and sensitivity towards research involving marginalized populations, as well as other ethical dilemmas faced by Broad scientists.
Bryan Ferguson is a research associate at the Broad Institute.
Perspectives from the Broad community
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Unintended, but not unanticipated: the consequences of human behavioral genetics
A Broadminded blog opinion piece by Broad Institute bioinformatics analyst Carino Gurjao
Discovery or discrimination? Starting the conversation about the potential outcomes of a LGBTQIA+ targeted study
A Broadminded blog opinion piece by Broad Institute operations specialist Meagan Olive
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A Broadminded blog opinion piece by Broad Institute postdoctoral fellow Steven Reilly
Weighing the positive and negative impacts of studies regarding sexual minorities
A Broadminded blog opinion piece by Broad community members Liam Spurr, Julian Avila-Pacheco, Meagan Olive, and Denisse Rotem
Big data scientists must be ethicists too
A Broadminded blog opinion piece by Broad Institute postdoctoral fellow Joseph Vitti
What Genetics Is Teaching Us About Sexuality
A New York Times opinion piece by Broad Institute and Harvard University postdoctoral fellow and study co-author Robbee Wedow and UT Austin integrative biologist Steven Phelps
Same-sex sexual behavior and genes: like love, the answer is complicated
A STAT opinion piece by 23andMe vice president of business development Emily Drabant Conley