MaryAnn Labant

Social, Legal, and Ethical Issues Need to Be Addressed Before Genomics Can Be Widely Adopted in the Clinic

Genetic information is already being applied clinically, with genomic testing on tumors providing insights into treatment routes, and the knowledge base will continue to grow. But before this technology can be widely adopted and implemented into clinical care, major social, legal, and ethical issues need to be addressed. Thought leaders convened late June at the first Festival of Genomics in Boston to discuss crucial elements of the genomic revolution.

Essentially at some point in the future, individuals will have their complete genome sequenced; the data will be securely stored; and clinicians will reference the information throughout a patient’s lifetime. Doctors will be charged with ordering the tests and will need accessible and easily interpretable reports in order to apply the results in the clinical setting.

The education and training gap is a significant difficulty facing healthcare professionals. Less than 15 years ago the human genome was sequenced and not even 10 years have passed since researchers began to identify patterns of variation across populations. More recent still is the discovery of significant associations between genetics and health conditions and drug responses. The majority of practicing clinicians were likely out of school when these breakthroughs were achieved, or otherwise received limited instruction in these areas.

“We are now in a position, and have an imperative, to teach the next generation of medical students about the values of genome-informed medicine. I see this as a larger discussion involving genetic counselors and pharmacists, who will be able to communicate the genetic effects on complex disease risk and adverse drug reactions,” commented Michael Christman, Ph.D., President and CEO, Coriell Institute for Medical Research.

“We are moving in the direction of more cost-effective, widely available genetic testing. I believe doctors will assimilate the information into their practice through the use of decision-support tools, by which point the entire process will have become routine.

“Newborns, for instance, will be sequenced at birth, with clinicians regularly referencing genetic information in order to make the most precise health decisions and improve chances of early detection.”

Ensuring data security is a matter of public concern, while also a massive logistical, and theoretical, challenge. Legal protections are in place to protect against cybercrime; offenders are firmly prosecuted, yet more laws may be needed to protect individuals from genomic data breaches. In fact, the White House recently announced proposed privacy and trust principles for the Precision Medicine Initiative (PMI). The principles can be read here.


In the future, a patient will have his or her complete genome sequenced, and clinicians will reference the information throughout the patient’s lifetime. [iStockphoto/Mark Bowden]

Regulatory Hurdles

An appropriate regulatory framework and legal structure is not currently in place to regulate, and not impede, technology that is safe. The existing one-and-done model of regulatory approval is not equipped to deal with a field impacted by a flow of new knowledge; how genetic tests, including whole exome or whole genome sequencing fit within the regulatory structure is uncertain.

Although the FDA tries to show flexibility, they are governed, and constrained, by their statute, which was set up decades ago for much simpler tests. There is movement in Congress to adopt a new statute that would significantly affect the FDA’s regulatory authority, and both the legal and regulatory worlds are trying to determine the rules.

“For example, in November 2014, the American Clinical Laboratory Association announced that it had retained former Solicitor General Paul Clement, and Laurence Tribe, the Carl. M. Loeb University Professor and Professor of Constitutional Law at Harvard University, for representation on matters relating to the FDA’s recently issued draft guidance to regulate laboratory developed tests (LDTs) as medical devices. This is clear indication that a lawsuit is planned if the FDA goes ahead with this plan,” explained Gary Marchant, Ph.D., M.P.P., J.D., professor, Arizona State University.

“It is early and despite a lot of activity much needs to be accomplished. Incidental findings are another hotly debated issue. The American College of Medical Genetics (ACMG) put out a guideline on 56 actionable genes that recommended the testing laboratories examine and return incidental findings within these genes to the clinician. The guidance caused such a controversy that the ACMG backed off mandatory disclosure.” 


Developing Policies

The public must also be considered. Ensuring that individuals do not have a deterministic view of their genetic information is an ongoing challenge as is managing all variants of known significance, communicating this information to patients, using the data in clinical-decision making, and dealing with changing information over time.

In sequencing, multiple variants may pop up with minimal indicative-risk evidence but as research advances new evidence could become available. The current healthcare system is not set up to manage a vast amount of uncertain information for potential future use.

The challenge is dealing with evidence-based information that changes over time without over burdening the patient-doctor relationship and the healthcare system. Other medical fields, such as radiology, have had to deal with incidental or unknown findings, and could provide insight into a pathway forward.

Policies also reflect the ethical, legal, and social implications (ELSI) of human genomics.

For example, the National Human Genome Research Institute (NHGRI) is funding the Center for Transdisciplinary ELSI Research in Translational Genomics (CT2G), a collaboration between Kaiser Permanente, UCSF, and UC Hastings College of Law. CT2G intends to be a hub of interdisciplinary scholarship for development of consensus statements and scholarly publications, and to serve as a training center across the pipeline.

“Genomics lives at the boundary between research and clinical care. CT2G develops new research to facilitate ethical, useful, and appropriate adoption of this technology. We are very interested in working with people who are on the front lines to have discussion about the ethical issues that emerge in clinical research as well as clinical genomics use,” discussed Julie Harris, Ph.D., M.P.H., Staff Scientist, Kaiser Permanente, Associate Director, Center for Transdisciplinary ELSI Research in Translational Genomics.

CT2G has several working groups that look at larger issues, such as how various genomic-screening tools will be adopted and used across a lifespan, and how to move these tools forward in clinical care. Other research topics include development of a policy brief determining the role of ethnicity and gender in defining large biorepository research, and definition of a research project involving Kaiser Permanente members who have participated in a biorepository to evaluate their expectations about how research impacts clinical care, and how their clinical care may also be used for research.

Up until this point there has been little stakeholder involvement and new models of governing genomics are under discussion. Many organizations are interested in getting stakeholders more involved in developing policies and guidance for clinical care, research, and other technologies. 


Open Questions

New legislation allows patients to acquire medical results directly from the laboratory. The rule states that patients should have access to all data personally linked to them and thus could include raw genome variant files. The ability to share genome variant files with other clinicians and researchers could have benefit to patients for whom a genetic diagnosis has not been identified.

Ethical concerns involve privacy, data security, and potential misinterpretation. Individuals can directly upload raw data into web-based interpretation engines for a fee. These services are not intended to be diagnostic or medical, and the quality of results varies. Misinterpretation could lead to harm if unneeded products are purchased or if medical care is erroneously altered.

In contrast, the interpretation of variants performed within clinical genetic laboratories is generally intended to provide clinically relevant information within the limits of current medical genetics knowledge. Laboratories often focus on genes known to be associated with the patient’s symptoms or utilize a conservative approach requiring variants to meet high thresholds of evidence.

If sequencing is done within a diagnostic context, the phenotype is used in the interpretation. Variants whose clinical significance is uncertain (VUS) are often not reported; they give no benefit but could cause harm if misunderstood.

Many labs only include VUS results in the test report when they involve genes within the diagnostic spectrum or specific-testing indication; though often the full list of variants findings can be requested. This means a small fraction of real results may not be returned simply because there is no current evidence to indicate pathogenicity.

“Another debated issue is the relevance of incidental adult-onset findings in minors. Learning of predictive genetic results in this manner is quite different from a situation in which the sole purpose of the test is to learn whether or not the child has inherited a known, adult-onset disorder that is in the family. When it is learned incidentally through sequencing, this information could benefit more than just the child,” concluded Julianne M. O’Daniel, M.S., C.G.C., Assistant Professor, Genetics, University of North Carolina at Chapel Hill.

“It may have a more immediate beneficial impact on the parents, and could ensure that they get screening or evaluation which in turn may enable them to continue to be healthy caregivers. The counter argument is that since it is not relevant to the child until adulthood, it violates the child’s future ability to decide whether to learn it and could create a type of sick-child syndrome or patient-in-waiting, putting the child at risk for differential treatment and, potentially, genetic discrimination.” 







































This article was originally published in the August 2015 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.

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