Regulatory Considerations

This project (Utah NeoSeq) was approved by the University of Utah Institutional Review Board (IRB). The development of rapid WGS was a collaboration between the University of Utah Department of Pediatrics, the Utah Center for Genetic Discovery, and ARUP Laboratories, a large reference laboratory (Fig. 1).

Fig. 1. Regulation considerations during research rapid WGS (NeoSeq).

The NeoSeq consent contains language indicating HIPAA Right to Access and the parents’ request to receive research results. The patient has a clinical blood draw and sequencing is done under a research protocol at ARUP Laboratories which is a CLIA certified lab. Analysis is done at a separate non-CLIA facility by the Utah Center for Genetic Discovery. All results are returned to the family by the study and clinical teams and the benefits and risks of a change in management are discussed. This testing is done in parallel with normal standard of care testing. Abbreviations: CLIA, Clinical Laboratory Improvement Amendments; EMR, electronic medical records; FDA, Food and Drug Administration; HIPAA, Health Insurance Portability and Accountability Act of 1996; IDE, Investigational Device Examination; IRB, institutional review board; UCGD, Utah Center for Genetic Discovery.

Patient access to genomic research results is governed by a complex set of regulatory bodies and associated laws and standards [10–13]. Initial discussions were in person between the study team and IRB committee. When the complex situation was recognized, we formed an expert panel of legal and ethical counsel, including members of the University of Utah IRB, University Office of General Counsel, bioethicists, genetic laboratory directors, and clinician researchers, with the goal of reviewing and evaluating applicable laws and weighing them with ethical considerations. We had a large in-person meeting then continued discussion by email. Here, we summarize the reviewed laws (Table 1) as they pertain to return of genomic research results and discuss the application of these laws to our study protocols in the subsequent sections.

Table 1. Federal regulatory laws governing return of Genomic research results

Abbreviations: CLIA, Clinical Laboratory Improvement Amendments; FDA, Food and Drug Administration; HIPAA, Health Insurance Portability and Accountability Act of 1996; IRB, institutional review board; SACHRP, Secretary’s Advisory Committee on Human Research Protections.

Bioethical Principles and Return of Results

Ethical considerations for implementing WGS in the NICU [Reference Lantos14, Reference Bell15] were a further consideration, given that as a research protocol there were competing interests of research result validity evaluation, and intervening in clinical care as quickly as possible. Although both interests strive to adhere to principles of benefice, nonmaleficence, and autonomy, they can be at practical and regulatory odds. For example, if there is a gene variant (pyridoxine-dependent epilepsy) that causes on-going seizures, for which there is a low-risk treatment, a research result may allow clinicians to discuss possible treatment with parents, allowing them to adhere to all three of the above principles. However, acting on an “uncertified” result could be countered to those same principles. Withholding possible treatment would also be unethical if doing so harmed the patient. If research WGS identified a relevant gene variant, it would be difficult to obscure the result from the family because of the need for confirmatory testing. This would also create the potential for distrust, as the healthcare team would be aware of the research finding but would be precluded from sharing this with the family. We balanced these competing interests by developing a plan to return results centered around shared-decision making [Reference Soltys, Philpott-Streiff, Fuzzell and Politi16].

CLIA Regulations

The Clinical Laboratory Improvement Amendments (CLIA) are federal regulatory standards that guide clinical laboratory testing of human specimens. CLIA standards do not apply to research testing if results are not reported for diagnosis, prevention, treatment, or other health assessment purposes [12]. Prior to use in clinical patient care, an expectation is that a laboratory research and validate any new test, such as rapid WGS.

Recognition of the Health Insurance Portability and Accountability Act (HIPAA) Right to Results

The norm for our institution’s informed consent process outlines a patient’s right to obtain their protected health information (PHI) including genetic test results from a designated record set (DRS) under the HIPAA privacy rule. As the rapid WGS is performed under a research protocol, we recognized that returning results prior to a CLIA-certified confirmation is in tension with CLIA regulations. In an effort to resolve the tension between HIPAA and CLIA on this point, some academic research institutions have developed policies to exclude research results from the DRS.

The National Academies of Sciences evaluated these conflicting and ambiguous regulatory laws governing the return of individual results [10]. Their recommendations included better defining the DRS and requiring all HIPAA-covered entities completing human biospecimen research to have an IRB-approved plan for the return of results when requested under HIPAA. However, these issues and recommendations remain unresolved by regulatory agencies.

We therefore included in the informed consent the discussion of the benefits and risks of using research results for clinical care, and that there might be an in-depth discussion on this topic at the time of return of results. For the study child, we report variants related to their clinical presentation. We also will report variants of uncertain significance if associated with their medical issues. We do not report variants of unknown significance (VUS) that are not related to the clinical presentation. For the family members, we will report the presence or absence of variants that are detected in the study child. Optional results for the study child and family members include the American College of Medical Genetics 59 medically actionable incidental findings, which we report if the family opts in. (see our informed consent in the Supplementary Information ). The results are returned to the family in person during a care conference by the study neonatologist, study medical geneticist, the attending neonatologist, and the attending medical geneticist. A research letter is also uploaded to the electronic medical record under the research tab. This allowed the research and clinical teams to utilize shared-decision making, whereby parents are engaged in NICU care decisions resulting in less decisional regret [Reference Soltys, Philpott-Streiff, Fuzzell and Politi16], with the goal to support parental autonomy and care provider obligation for beneficial care. The IRB would be contacted if there was a risk of harm to the patient from potential next steps guided by the research results.

Determination as a Nonsignificant Risk Device Study

Another important consideration was the determination that the proposed investigation would be considered a nonsignificant risk (NSR) device study. This requires approval of the protocol and compliance with NSR regulatory standards [17] but does not require submitting an Investigational Device Exemption (IDE) to the United States Food and Drug Administration (FDA).

This determination was based on a 2014 FDA decision regarding a comparable WGS study and the inclusion of appropriate risk-mitigating measures. In the 2014 precedent, the FDA had determined that the use of rapid WGS for critically ill neonates was a NSR study based on the following rationale: “1) Although you (the study) may return investigational test results to the treating physician that may influence important treatment decisions prior to their confirmation, this risk is lessened because the study population is critically ill, unlikely to be diagnosed quickly by other mechanisms, and suffers from a high mortality rate, 2) the treating physician can apply clinical judgment on whether treatment based on a preliminary, investigational result is warranted for a given patient, including considering the potential risk(s) the patient may incur given the nature/severity of the treatment, and 3) all returned investigational test results will ultimately be confirmed [Reference Litwack18].”

There were two other factors in the NSR determination. First, the research rapid WGS used existing certified personnel and processes; including the hospital, laboratory, and staff involved. Second, the return of results and any clinical care decisions were managed by a joint team of specialists, including medical geneticists and neonatologists.

The high accuracy of WGS technology was also taken into consideration. WGS has a well-demonstrated record of clinically appropriate sensitivity and specificity [Reference Shevchenko and Bale19], and the technology of Sanger sequencing used for CLIA confirmation is at a similar risk of errors as to WGS [Reference Strom, Lee and Das20–Reference Mu, Lu, Chen, Li and Elliott22]. Therefore, rapid WGS technology itself was not a separate risk to consider for the study.