ENRICH Forum: Ethical aNd Regulatory Issues in Cancer ResearcH

Ms. Fine, a board certified genetic counselor and former Clinical Associate Professor of Genetics at UNC Chapel Hill, presented on ethical and policy challenges in conducting scalable virtual genetic counseling, and how remote counseling modalities are viewed by patients and oncology providers.

Involving participant advocates at various points within the research lifecycle is intended to ensure that target research populations are duly represented. Significant funding has been allotted to patient engagement activities that promote transparency and representation in research. However, involving advocates may require more than just executing prescribed processes, and even supplying a robust support infrastructure does not guarantee engagement. Instead, meaningful engagement may depend on developing complex human relationships. The speakers described their experience with a multi-year process involving patient advocates in a large multi-site clinical trial of a care-delivery intervention. They highlighted the non-straightforward nature of including advocates in the critique of the study'’'s design and procedures. They also described how advocates enhanced their study in ways not usually articulated in the literature: advocates brought forward critical counterpoints and "slowed" the pace of scholarly conversation, enriched the work with stories and multi-layered perspectives, and imbued the research with a nuanced understanding that could not be achieved without them.

Measurement of environmental biomarkers in biomedia is increasingly used as a method of environmental exposure characterization in human population studies. Reporting the results of biomarker measurements back to study participants has been controversial, including questions of ethics and whether the study participants would want to receive and would understand the results. There is no established guidance for investigators when they encounter an unanticipated finding of a very high level of a chemical or metal in a single study participant. This talk provided some background, then discuss the results of a survey of participants in three exposure studies of persons living in the Ohio River Valley, of whom 60 were parents of children who had been sampled. Some issues raised include: should very high environmental biomarker findings be reported to the research participant’s personal physician or public health officials? Are physicians equipped to answer the participant’s questions? Do they even want to be involved? Do community physicians want to receive that information? Are they prepared to counsel their patients?

Dr. Yvonne Lau spoke about the new consent rules in the Final Rule revisions to the federal regulations protecting human research participants (45 CFR part 46), also known as the “Common Rule.”

Dr. Thomas is the Principal Investigator, with Dr. Sandra Quinn, for the Center of Excellence in Race, Ethnicity and Health Disparities Research, funded by the National Institute for Minority Health and Health Disparities (NIMHD). His current research focuses on understanding how social context shapes attitudes and behaviors of underserved, poorly served, and never-served segments of society towards participation in health promotion and disease prevention activities.

In this webinar, co-sponsored by NCI’s Center to Reduce Cancer Health Disparities, Dr. Thomas spoke about the impact of the Tuskegee Study, and the more recent narrative of Henrietta Lacks, on trust and willingness amongst African Americans to participate in medical research.

Ed Goldman is an attorney/ethicist at the University of Michigan and President of the Michigan BioTrust. He is on faculty at the University of Michigan Medical and Law Schools where he works in the intersection between law and medicine. From 1978-2009 he was Deputy General Counsel at the University of Michigan where he ran the Health System Legal office.

Natasha Bonhomme is the Chief Strategy Officer at Genetic Alliance, an organization dedicated to engaging individuals, families, and communities in their own health and the healthcare system. Part of her role includes directing their maternal and child health initiative, Expecting Health, which develops tools to facilitate informed decision making; positive health communications strategies for healthcare providers, researchers, and organizations; and engages parents and families.

Speakers discussed the ethical challenges surrounding the use of stored tissue in research studies, including how to educate donors about the potential scope of future research involving their biospecimens and data. Ed described the Michigan BioTrust, an honest broker biobank run by the State of Michigan, and Natasha discussed outreach strategies for engaging consumers about donating their biological samples and potential research uses.

In the past decade there has been increasing debate over whether researchers have an ethical obligation to share individual research results with participants. Numerous hypothetical studies have reported high interest in receiving research results, even if the participants knew there was nothing they could do about the results. Still, there remains no consensus on how and which results should be returned. More recently, studies have examined the participant uptake of results, strategies for return, and outcomes of returning results in cancer research. In this talk, Dr. Bradbury gave a brief overview of the return of results debate and discussed her work on this issue, including her NCI-funded projects on return of research results in cancer cohorts and clinical trials, as well as novel models for delivery of genetic education and results.

Ellen T. Matloff, MS is a certified genetic counselor and the President and CEO of a company that has created digital genetic counseling for physicians and consumers. Matloff will present on “A Scalable Model for Returning Continually Updated Genetic Results to Consumers and Clinicians”. Matloff will outline the ethical principles that must be considered in returning understandable, useable and current genetic information. She will also discuss how to make people stewards of their genetic data, provide them with research opportunities, and offer them the ability to provide outcome data and share their genetic data in public databases. She discussed how to make people stewards of their genetic data, provide them with research opportunities, and offer them the ability to provide outcome data and share their genetic data in public databases. She also described how research participants in clinical trials and large-scale genomic studies worldwide, and the 12 million consumers who have had direct-to-consumer testing fit into this equation.

Despite the Congressional directive and NIH policy to include minorities and women in NIH-funded clinical research, biomedical research currently does not have adequate representation of diverse populations. This webinar covered how community-engaged research strategies impacted the successful recruitment of diverse populations in two biomedical research recruitment projects: Project CHURCH – Saliva Sample Collection and The Komen Tissue Bank Event in Houston.

Dr. O’Connor described how new tools for analyzing evolutionary genetics data provide insights into the relationship between population history and health disparities, and how one’s ancestors impact risks and responses to disease. He used the Peruvian Genome Project and variant prioritization in non-Europeans as main examples of the interaction between ancestry, admixture, and genomics.

Patient-centricity is more than a buzz word – it requires being respectful of and responsive to patient preferences, needs, and values in the context of people's social circumstances. That often means integrating considerations beyond clinical outcomes such as a treatment's ability to help patients achieve personal goals. Patient-centricity is created by engaging, informing, and actively listening to people with chronic conditions throughout the research process and beyond. This session explored the recent rise and evolution of patient-centricity, discuss frameworks on when and how to engage patients in research, and presented rubrics on good practices for engagement and representativeness. By collectively embracing the voice of the patient, we will maximize the value and impact of research.

The aim of broad data sharing is to maximize the public benefit derived from genetic and genomic studies. However, tribal leaders have a fiduciary responsibility to assure that uses of tribal data are responsible, particularly in light of past mis-uses of research data. The sovereign status of tribal governments has implications for research agreements and data-sharing negotiations. Recognizing the unique concerns raised by tribal entities, an NIH-funded research center involving a partnership among three tribal organizations and three universities convened a meeting to consider data sharing and related research issues. The speakers discussed the tribal perspectives that arose from the meeting, and from their experience participating in tribal partnerships. While there is strong tribal support for efficient research processes that expedite the benefits from collaborative research, there is also a need for data-sharing procedures that take into account tribal sovereignty and appropriate oversight of research, and move beyond existing models of individual consent and community engagement.

Linking EHRs with biospecimens to conduct systematic, population-based research provides unprecedented opportunities to improve health care. However, this practice poses significant challenges to traditional ethical and regulatory frameworks for data access, use, sharing, and oversight. Further, little research investigates how patients of diverse racial and ethnic backgrounds assess the risks and benefits of volunteering their EHR data and biospecimens for research.

This panel discussed an NIH-funded study of patient preferences and attitudes on the collection and use of EHRs and biospecimens in a large community-based healthcare system that is actively planning to create its own biobank. Study questions included: To what extent do patients perceive benefits of data sharing and analysis? What do they believe are acceptable tradeoffs between risks and benefits? What are the most important features of and preferred processes for governance and oversight? This panel discussed results from 20 focus groups of African American, Chinese, Hispanic, non-Hispanic White, and South Asian patients in a community-based healthcare system. It also discussed lessons learned from the development of novel multilingual videos as methodological tools.

Significant debate has occurred over the acceptability of broad consent approaches for collecting biospecimens to use in future unspecified research. Our speaker discussed his participation in an NCI-funded study eliciting the views of actual broad consent cancer tissue donors at four academic medical centers regarding the use of their biospecimens in future medical research.

Henrietta Lacks, foremother of the rapidly reproducing and scientifically invaluable HeLa cell lines, was a cancer patient at Johns Hopkins in 1951 when her tissue was (in accordance with standard practice at the time) collected and stored for future research without her knowledge or consent. In this presentation, Dr. Debra Matthews explored the ethical issues surrounding compensation for tissue donation as well as continued research uses of HeLa tissue, including the HeLa genome, and discussed the different and sometimes contradictory views of Lacks family members regarding these uses.

Dr. Baquet has been a pioneer in advancing cancer disparities research and bringing national attention to the field of health disparities. Diversity in clinical trial participation and biospecimen donation remain significant barriers to equity in access to emerging prevention and therapeutic modalities. Dr. Baquet described an FDA-funded study in Maryland which examined in rural and urban communities the barriers, challenges, and supportive factors that impact a person's willingness to consider participating in clinical trials, factors associated with promoting biospecimen donation, and suggestions on how to increase public trust and research participation.

While struggling to cope with the loss of her anencephalic 6-day old son, Sarah navigated the complicated but ultimately rewarding path of donating Thomas's biospecimens to medical research. Thomas's retina and corneas were matched with research programs through the National Disease Research Interchange with the help of the Washington Regional Transplant Community. Sarah spoke about her experience as a research donor's parent, including her family's meetings with the PIs who received Thomas' corneas, retina, liver, and cord blood donations.

The Human Genome Project raised researchers, policymakers, and the general public's expectations that genomics would provide a scientific foundation to improve the understanding of diseases, and population and racial differences. Despite the tumultuous history that race and genetics share, research and commercial efforts have been harnessing and increasing the availability and use of genomic and self-inferred "ancestry" information to researchers, clinicians, and the general public. The speaker discussed how a conversation beyond whether genomics is relevant to the salience of racial and cultural realities is needed to better understand how understandings of race are informing genomics, identity, and health disparities science and policy issues.

Dr. Biesecker presented her research data assessing perceived uncertainty in genomic sequencing. She discussed interventions her research team is developing to assess their effectiveness in helping participants navigate responses.

The primary purpose of the ClinOmics protocol is to take advantage of high throughput techniques to discover somatic alterations in cancer to identify novel biomarkers and biologically relevant targets for therapy to allow for the development of new treatment strategies for patients with high-risk malignancies. The ClinOmics investigators will perform genomics, proteomics, metabolomics and other high throughput methods to perform a comprehensive Omics analysis of tumor and normal tissues. Exome and cancer panel sequencing will be performed on tumor and germ line DNA in a Clinical Laboratory Improvement Act (CLIA) setting through the ClinOmics core, a newly established resource established by the CCR. High confidence somatic mutations and germ line mutations with established clinical validity and utility will be reported to CRIS, the NIH's electronic medical records system and reported to the treating physician and the patient.

Genomic technology has the potential to transform the delivery of healthcare while improving the cost and efficacy of medical interventions. Historical population sampling approaches for investigating the genetic variations that influence patients. responses to drug therapy, however, are not representative of the complex ancestral backgrounds of individual patients. In this talk, the speaker discussed the regulatory challenges and opportunities related to addressing the ethnic and racial diversity among patients in the era of precision medicine, lawsuits filed against drug manufacturers for allegedly failing to appropriately disclose knowledge about poor drug response in specific populations, and strategies that ethics committees are implementing in low and middle income countries to advance genomic research in diverse populations.

Dr. Gerson from the Patient-Centered Outcomes Research Institute (PCORI) presented on the significant regulatory and ethical issues PCORI encounters in its mission to fund comparative clinical effectiveness research while engaging patients and other stakeholders throughout the research process. PCORI sponsors research on issues related to human subjects protections, including Institutional Review Board (IRB) review and novel approaches to informed consent. Ethical issues arise in the context of study designs (e.g., cluster randomized trials, pragmatic randomized trials) or the use of particular data sources for comparative effective research (e.g., electronic clinical data).

Dr. Rebecca Pentz, Professor of Research Ethics at the Emory School of Medicine and the Winship Cancer Center, spoke of the misleading nature of media hyperbole about personalized medicine and its potential negative impact on cancer patients and the general public. Television and radio advertisements, newspaper articles, and even science journals tend to exaggerate the progress of targeted therapies and the successful translation of genomic research to clinical oncology. Beyond toning down the rhetoric, better efforts at community engagement in medical research can hopefully counter some of these ill effects.

Mr. John Wilbanks, Chief Commons Office at Sage Bionetworks, and Dr. Dave Wendler, Head of the Section on Research Ethics in the Department of Bioethics at the NIH Clinical Center, presented on operational and ethical aspects of mobile consent technologies. Mr. Wilbanks provided an overview of the rapidly developing field of mobile and connected health technologies, culminating in Apple's recent internationally publicized ResearchKit app. Dr. Wendler highlighted some of the many ethical issues that mobile consent technologies pose, including expansive recruitment opportunities, ability to comprehend and utilize technology, and diversifying participant populations.

The speakers discussed ethical issues and presented case studies of different models for engaging communities to inform the creation and governance of biobanks. Dr. Brothers' presentation, "Different Headaches: The Human Non-Subjects Approach to Biobanking," provided background on governance and discussed the creation of Vanderbilt University's BioVU. Dr. Koenig's presentation, "Using Deliberative Community Engagement to Help Craft Biobanking Policy," focused on a model of engagement grounded in deliberative democracy and used at the Mayo Clinic as well as other biomedical and health research sites.

Dr. Grady's presentation focused on communicating with research participants through the consenting process, with a focus on the recommendations set forth in two Bioethics Commission reports on Privacy and Progress in Whole Genome Sequencing (October 2012) and Ethical Management of Incidental and Secondary Findings (December 2013).

Dr. Rodriguez described the challenge of balancing competing ethical and policy priorities in genomics research, including calculating the risks of identifiability, public tolerance for loss of privacy, and promoting medical advances while ensuring transparency and appropriate stewardship of the public trust.

Drs. Mosavel and Siminoff are primary investigators in a survey study to examine the attitudes of family decision-makers of participants in the Genotype Tissue Expression Project (GTEx). GTEx compares gene expression in multiple types of normal tissue taken from deceased participants and works with multiple community advisory boards (CABs). The presenters described how CABs are used in medical research, including in biobanking and cancer prevention and control studies. CAB activities include recruiting participants, reviewing consent documentation, and assisting with study design and/or implementation.

Although research on de-identified human data currently does not require informed consent from participants, the Advanced Notice of Proposed Rulemaking (ANPRM) for Revision to the Common Rule proposes that consent be required for research using de-identified data/specimens in biobank research. In anticipation of this change, the Electronic Medical Records and Genomics (eMERGE) Network is developing a survey instrument to elicit perspectives from a wide cross-section of patients on broad consent, sample and data sharing for future research, biobank governance, data protection, and return of research results. This talk highlighted key findings from a systematic literature review on individuals' willingness to provide broad consent for biobank research and data sharing, conducted for the eMERGE project.

Ms. Kaneshiro presented on the human subject regulatory implications of using stored tissue for genomic research. She described requirements under the current regulatory scheme at 45 CFR part 46 (the Common Rule), as well as proposed amendments to the current regulations published in the Advanced Notice of Proposed Rulemaking in 2011. Under current rules and Office for Human Research Protections (OHRP) guidance, genomic data is not considered inherently identifiable and research involving only coded data and biospecimens is not considered to be human subject research. Revisions proposed to the Common Rule may alter some of these research guidelines in the future.

Bio-PIN is a novel concept that recently was proposed to address ethical, legal, and social issues related to biobanking, such as privacy, informed consent, autonomy, data security, and public trust. This concept involves the anonymous deposition of samples and associated data into a biobank in which the samples and data are labeled using a code generated from an individual's biological characteristics. This session discussed the bioethical considerations of this system, as well as practical issues and challenges associated with its implementation.

The speakers described two paradigms that enable patients and prospective research participants to learn about and share health information. Mr. Wilbanks spoke about Portable Legal Consent, a web-based consent protocol that enables individuals to understand the implications of broad data sharing, and grants medical researchers unparalleled access to eligible and interested participants. Ms. Terry discussed "Reg4All," a patient-centric registry that offers clinical trial participants the ability to fine-tune how their data are used for research and with whom the data are shared.

The presenters discussed the impact of the U.S. Supreme Court's recent Myriad Genetics patent decision and how, in the wake of that decision, companies may look to the trade secret doctrine to withhold genetic information.

The presenters discussed potential ethical obligations to disclose incidental findings and individual research results to people who participate in genomics studies.