By Deborah Borfitz  

November 25, 2020 | New models of implementing informed consent will be needed for clinical trials where participants are weighing the benefits and risks of genome editing, most immediately individuals with sickle cell disease (SCD) for whom the technique is potentially curative. Lessons learned in this new area of research will be important for a growing number of disease conditions—including other blood disorders like beta thalassemia as well as muscular dystrophy and certain cancers and retinal diseases—where gene treatments or cures are under active investigation, says Vence Bonham, J.D., an associate investigator in the Social and Behavioral Research Branch at the National Human Genome Research Institute. 

SCD is of particular interest to Bonham, whose research focuses on health disparity populations. The chronic, life-shortening condition disproportionately affects blacks and has historically lacked treatments of any kind. 

Over the past five years, multiple therapies for SCD have been approved by the Food and Drug Administration, Bonham says. SCD is also at the front of the line as a target of CRISPR-mediated somatic genome editing, with several clinical studies getting the regulatory green light only last year. 

The burden of the disease is greatest in Sub-Saharan Africa, India and the Mediterranean, but SCD genome editing trials are currently being conducted in the U.S. and other high-income countries like Canada and the U.K., he continues. The trials are expected to move to middle- and low-income countries at later stages of clinical development. 

Bonham say his research group was particularly interested in the viewpoint of the SCD community on the potential curative therapies. So, a few years ago they engaged patients, parents, and physicians in a series of focus groups to assess their perspectives and information needs when deciding if a gene-editing trial is a good idea. 

Study results published as a trio of papers, the latest on needed improvements to the informed consent process appearing in AJOB Empirical Bioethics (DOI: 10.1080/23294515.2020.1818876). Researchers convened a total of 15 focus groups in the Southern and Mid-Atlantic regions of the country, including six specific to adults living with SCD, six comprised of parents having a child with SCD, and three for hematologists who were regularly caring for at least five SCD patients. 

The conversations touched on issues of trust in the research enterprise, access to clinical studies, and broader issues of equity and justice as it relates to curative genome-editing therapies, says Bonham. But the prevailing theme that emerged was the need for complete and comprehensive information, accessible in various ways, to make an informed decision about trial participation.  

Information Please 

SCD stakeholders in the focus groups collectively voiced a desire for informed consent to include the treatment side effects of CRISPR somatic genome editing and many people also wanted to know how such editing works and its impact on their quality of life. The groups also reflected on the need to flexibly provide information based on an individual’s level of knowledge about biology and genomics. 

“Today, there is real excitement and hope about what is happening in the field,” Bonham says. The big surprise from the study was the expressed level of need for more knowledge and education about the new curative techniques. 

The SCD community was already proactively reaching out to researchers to learn more about genome-editing trials and, as the study confirms, these decision-makers are clearly concerned about the potential risks and if the approach will ultimately be successful, he adds. Trial sponsors and academic researchers have been partnering with patient advocacy organizations to ensure studies are respectful of the needs of the SCD community, but opportunities remain to ensure the voices of individual patients are being heard at the trial design stage. 

One interesting study finding is that physicians tend to underestimate the genetics knowledge literacy level of SCD patients and parents, says Bonham. “It’s important for healthcare professionals to meet patients where they’re at and recognize that individuals who are living with a genetic condition become very knowledgeable about [their disease and genetic concepts].” By miscalculating the literacy of potential participants and parents, researchers may unwittingly create frustration and mistrust that could deter clinical trial participation. 

In recent years, the informed consent process has been better engaging individual study participants to make sure they understand the risks and benefits—by, for example, dividing lengthy consent documents into sections and communicating the same information in different ways, Bonham notes. But continued innovation is needed for genome-editing studies where prospective volunteers are not entirely unfamiliar with foundational concepts, nor resistant to research, but simply want more detailed, trial-specific information.   

A paper that separately published in Genetics in Medicine (DOI: 10.1038/s41436-018-0409-6) discusses how the advent of genome editing has renewed hope in the SCD community but also raised concerns related to the burden of participation, uncertainty of clinical outcomes, and equity in access. The third paper, appearing in The CRISPR Journal (DOI: 10.1089/crispr.2019.0034), highlights the community’s high but conditional degree of support for heritable genome editing (passed on to future generations) and simultaneous concerns about potential implications of the technology.  

Of note in the latter paper is that the overall acceptance level for somatic gene editing was found to be higher than for germline editing, even when no other treatments are available. But relative to the general population—particularly African Americans—SCD stakeholders were significantly more supportive of the future use of heritable genome editing.   

Bonham say it is his hope that biotechnology companies and research institutions will similarly engage patient communities to build new models of consent, understanding, and trust that promote safety and success for patients considering genome-editing clinical trials.