Defining the Responsibility to Recontact Research Participants

Posted By: Staff

This week, ASHG and eight partner organizations issued a position statement outlining whether, and to what extent, there is a responsibility to recontact genetics and genomics research participants when new findings emerge that suggest their genetic information should be interpreted differently.

Today, ASHG and partner organizations issues a statement in AJHG addressing the responsibility to recontact research participants.

Variants of uncertain significance get reclassified at a relatively high rate – up to half of such variants have been reclassified in the past decade. One paper found that 12% of these reclassifications had the potential to alter clinical management.

We sat down with Yvonne Bombard, PhD; and Howard Levy, MD, PhD, lead authors on the statement, to get their take on the issue.

ASHG: Why did the Social Issues Committee tackle this topic?

Yvonne: Genetics and genomics researchers are at the forefront in collecting and analyzing data related to sequence variant interpretations, which is continuously evolving. This means that a variant’s clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis.

While clinical recommendations on the responsibility to recontact research participants with such reinterpretations have begun to emerge, the Social Issues Committee decided to tackle this topic because there is a lack of guidance on the responsibility for researchers. We were fortunate to have collaborative partners on our Workgroup from clinical, research, and laboratory settings across various countries and jurisdictions. The statement reflects their synergistic efforts and the care these members took to carefully craft a comprehensive set of recommendations.

Howard: Perhaps the most obvious but most important concept in this position statement is the recognition that recontacting individuals to keep them abreast of new knowledge is a desirable and laudable goal. The problem is that we live in a world of limited resources, and the cost of achieving this goal can be onerous.

As Yvonne points out, there is only limited guidance on recontact in the clinical arena, and none in the research arena. ASHG and our partner organizations are fortunate to count among our memberships expert clinicians, researchers, laboratorians, educators, counselors, social scientists, bioethicists, lawyers, and patient advocates from around the world. We are uniquely suited to address this topic with the broadest possible representation and perspective.

There is a long history of thinking about clinical care and research as independent, non-overlapping contexts. But in recent years we’ve been recognizing and grappling with the reality that the lines between the two are blurry and sometimes not well-defined. In genetics, many of us serve in both roles concurrently, which can create real or perceived conflicts of interest. It is incumbent on all of us to work as hard as we can to be aware of these potential conflicts and respond appropriately. Having principled and evidence-based guidelines upon which to rely is an invaluable resource in helping us to evaluate these situations and determine the right course of action.

ASHG: What are the key differences between the research and clinical contexts?

Howard: While the intent of biomedical research is ultimately to improve or maintain health and avoid, treat, or cure disease, the proximal goal is to generate knowledge that forms the foundation of that ultimate benefit to society. Direct benefit to individual research participants is wonderful when it occurs, but is not the primary purpose of the research. Conversely, clinical care puts the benefit of the patient front and center as the primary goal.

Thus, in the clinical context, recontact can be argued as furthering the goal of maintaining information and informed consent, so that individual benefits can be maximized and individual harms minimized. But in the research context, the ethical desirability of recontact is not as strong, because the main goal is generation of new knowledge, not individual benefit. In fact, recontact in the research context can be argued as ethically undesirable if the recontact consumes so much resource that the research itself can’t be completed. In addition, while there are mechanisms available to seek at least partial financial compensation for clinical recontact on a case-by-case basis, there is no such funding mechanism in the research context.

Yvonne: The workgroup carefully considered differences between the research and clinical contexts to determine a reasonable set of floor/ceiling recommendations, balancing these imperatives across research and laboratory settings. We also developed a decision tree, which walks a researcher through whether and how to implement these recommendations within their particular research context.

ASHG: What factors affect the strength of the responsibility to recontact?

Yvonne: The workgroup considered a variety of factors that would affect the strength of the responsibility to recontact, and recommended that this responsibility is stronger when:

  • The research is active, ongoing, has funding, and participant contact details are up-to-date
  • The informed consent process set an expectation of potential contact or recontact
  • There is high certainty about the new interpretation of the genetic variant
  • The reinterpretation would be relevant to the condition being investigated

If the interpretation of a given variant is related to the condition under study or reasonably expected to affect participants’ medical management, the Workgroup recommended that there is a strong responsibility for researchers to attempt to recontact participants to offer updated results. If the reinterpretation is not expected to affect medical management, recontact is advised rather than strongly recommended.

Conversely, the statement recommends that there is no responsibility for researchers to hunt or scan the genomic literature for changes in variant interpretation, and that any responsibility to recontact should be limited to the duration of research funding. Additional recommendations address the practicalities of informed consent, involvement of institutional review boards, timeliness and protocol of recontact, and structuring of future research studies.

Howard: Clinical utility to the participant is prioritized higher than personal utility or benefit to family members. And issues of practicality have to be considered, too. Some of these judgments may be subject to bias, and we therefore encourage consultation with and input from IRBs, ethics boards, and clinical consultants.

ASHG: How might advances in IT address practical challenges in fulfilling this responsibility?

Yvonne: Advances in IT will likely reduce the opportunity costs of recontact and open up new avenues of keeping patients and research participants informed. Most electronic medical record systems and many clinical laboratories now offer portals through which patients might see their data, interact with clinical, laboratory, and support staff, and access educational material. As our IT resources and our databases continue to evolve, it is plausible that much of the effort of recontact could become automated. When a variant is reclassified, an automated notification could be sent to all patients and research participants known to harbor that variant, alerting them of the revised interpretation and prompting them to log into the portal to view the new information and associated material.

Howard:  As the volume of identified and re-interpreted variants continues to increase, IT solutions will be critical to handling these immensely large numbers at scale, at much lower cost, and more rapidly than doing so manually.

IT solutions can also reduce the risk of biased or uneven approaches to attempting recontact. Humans may consciously or subconsciously vary their method of communicating information, and sometimes make mistakes in adhering to informed consent, research protocols, and other policies governing the recontact process. An automated, algorithmic approach is still subject to human bias and error in creating and implementing the rules that drive the process, and is obviously not as personal as direct human communication, but is by definition consistent from case to case.

ASHG: What infrastructure would be needed to maximize the impact of such IT advances?

Yvonne: This future vision depends upon well-developed and interoperable databases, including both the interpretations of the variants and the lists of who has each variant. Potentially difficult questions about identity and privacy will need to be answered. There are also significant concerns about the “digital divide” and economic disparities; increasing reliance on IT solutions has the potential to create disparities among people who are unable to or choose not to utilize such resources. There will always be situations that require more nuance and explanation than an automated algorithm can achieve. But there is hope that IT enhancements can significantly lower the costs and barriers to recontacting research participants when it is considered desirable to do so.

Howard: Perhaps more challenging than creating the infrastructure of standardized and interoperable databases will be establishing societal and cultural expectations surrounding privacy, security and sharing of the data, and developing the necessary IT tools to collect, maintain, revise, and respect individuals’ preferences regarding such data sharing. With all of that in place, patient-facing portals built into IT systems and yet-to-be-developed apps can deliver timely and relevant information to consumers who choose to receive it, and pair that information with additional education and support modules to help them make the most of that information.

Yvonne Bombard, PhD, is an Assistant Professor at the University of Toronto Institute of Health Policy, Management and Evaluation; Director of the St. Michael’s Hospital Genomics Health Services Research Program; and Scientist at the St. Michael’s Li Ka Shing Knowledge Institute. Howard P. Levy, MD, PhD, is an Associate Professor in the Division of General Internal Medicine & McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University. 

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