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The Development of Practice Guidelines

One objective in adopting clinical practice guidelines is to help standardize the application of genomic data in medical care. Workshop participants discussed processes and principles for developing guidelines for the clinical use of next-generation genome sequencing as well as various challenges, such as which principles should guide return of results for pediatric patients, test affordability, and who should order genetic testing and be responsible for discussing the results with patients. While rigorous processes exist for developing clinical guidelines, such as those in oncology, development can be time consuming and may not meet the demands of the field.

GUIDELINE DEVELOPMENT: LESSONS FROM ONCOLOGY

As is the case in many other fields of medicine, the oncology community is trying to come to grips with the rapidly emerging trove of genomic-driven data, said Gary Lyman, a full member in the Cancer Prevention Program, Public Health Sciences Division, at the Fred Hutchinson Cancer Research Center. Lyman addressed the active, rigorous process that the American Society of Clinical Oncology (ASCO) uses for developing clinical guidelines. He noted that the challenges of genomic-driven cancer medicine were summarized in a paper in a special issue of the Journal of Clinical Oncology with the following questions (Garraway, 2013):

• What mutation profiling approaches will enable genomics-driven cancer medicine?
• What interpretive frameworks are necessary to render complex genomic data accessible to oncologists?
• What clinical trial designs will be optimal for evaluating the utility of tumor genomic information?
• How will oncologists and patients handle the return of large-scale genomic information?

In the paper, two conclusions were drawn: “Oncology has served as a unique proving ground for genomic-driven medicine,” while oncology has also highlighted a “well-recognized pitfall—the risk that large-scale genomic data generation can emerge without an evidence-based clinical approach to data analysis and interpretation” (Garraway, 2013).

“We have a great deal of work to do,” Lyman said. As emerging technologies lead to an ever-increasing volume of genomic data, the evidence for clinical utility goes down, he said. Lyman referred to this situation as a “paradox.”

The ASCO approach to developing clinical practice guidelines predates, but is mostly consistent with, the IOM standards for the creation of trustworthy clinical practice guidelines (IOM, 2011), Lyman said. The IOM standards call for a transparent guideline development process; management and disclosure of conflicts of interest; multidisciplinary expert panels; rigorous systematic reviews of existing evidence; grades for strength of evidence and strength of recommendations; standardized and clear recommendations; external review, including public comment; and a plan for revising and updating. The ASCO protocol starts with topic selection for clinical practice guideline development, followed by the appointment of a steering committee to define the relevant questions and facilitate a systematic review of published research with explicit criteria for inclusion and exclusion. A volunteer expert panel of stakeholders (vetted for conflicts of interest) examines the extracted body of evidence and generates recommendations, which undergo multiple levels of internal and external review (but no public comment), feedback, and modification. The recommendations are then disseminated through publication in the Journal of Clinical Oncology, ASCO’s website, and other venues.

This process poses a dilemma, however, Lyman said. While the oncology society strives for an ideal, methodologically rigorous approach that is consistent with the IOM standards, the process is time consuming when dealing with cancer, which encompasses hundreds of distinct diseases involving different subsets or clinical scenarios. As a result, about 60 guidelines have been generated over 20 years, but many more guidelines are actually needed, Lyman said. One challenge is completing guideline development in a reasonable timeframe when the process often depends on volunteer experts. Typically, it requires a “champion” to expedite the process. “While there are other approaches that are more efficient or expedient,” he said, “we are trying to find the right balance right now as we approach next-gen sequencing in the cancer arena.”

Published ASCO clinical practice guidelines to date include several guidelines for testing select genetic mutations or molecular biomarkers to assist with the prevention, screening, or treatment of breast cancer, gastrointestinal cancer, colorectal cancer, and prostate cancer, among others, Lyman said. The selected mutations or biomarkers are evaluated for their clinical validity, or their ability to predict health outcomes, as well as for

their clinical utility. A set of recently developed guidelines focuses on biomarkers that might guide treatment decisions in early-stage breast cancer (Lyman et al., 2014).

The ability to capture how whole-genome sequencing tests are being used and what the outcomes are, perhaps in registries or other types of observational studies that could support guideline development, is extremely important, Lyman said. Several other experts also mentioned the need for more clinical annotation of the genetic data that are available. Lyman noted that ASCO is investing in a national initiative called CancerLinQ (Cancer Learning Intelligence Network for Quality), which is attempting to compile, analyze, and annotate clinical information on patients in real time, including their treatments, side effects, and, where available, tumor genomic or molecular profile information, with the goal of eventually including clinical decision support. With genomic and biomarker information integrated, the project offers the potential for mining this database to formulate hypotheses for improving cancer care that can be tested in randomized clinical trials, Lyman said.

Soliciting feedback on practice guidelines is of critical interest to ASCO. As part of the Quality Oncology Practice Initiative (QOPI), ASCO is integrating guideline recommendations as quality indicators for assessment and certification of cancer specialists. As clinical genomics guidelines are developed, Lyman said, QOPI can provide information about adherence to guideline recommendations. Moreover, ASCO plans to build the QOPI quality indicators into CancerLinQ, so that data on adherence to recommendations and validated clinical outcomes in patients seen in community oncology practices can be routinely accessed by guideline-development panels and other stakeholders. Hopefully, this will happen in the next 2 or 3 years, Lyman said.

MAKING GUIDELINES

The main reason why physicians order genetic testing for patients is to make a diagnosis, said Howard Saal, professor of pediatrics at the University of Cincinnati College of Medicine. Chromosome microarray analysis has increased the ability to determine a diagnosis by about 10 to 15 percent, Saal said, and next-generation sequencing may increase diagnoses by up to 25 percent, according to a recent study (Yang et al., 2013). Because genome sequencing is being used more broadly in clinical practice today and it is predicted that one day all newborns will be

sequenced to inform health care throughout their lives (Collins, 2010), it would be helpful to study how much front-line physicians understand about genome sequencing and its applications and also to develop guidelines for the use of this sequencing in various populations.

To study how genome sequencing is being incorporated into medical practice today and how physicians are responding to it, Green is currently working on a clinical trial, the Medical Sequencing (MedSeq) Research Project, which is part of the CSER consortium.¹ MedSeq is designed to test the hypothesis that primary care physicians will be overwhelmed by genomic information in their practices and find it difficult to negotiate this new kind of medical information, Green said. A one-page whole-genome summary report has been designed to distill results into different groupings—monogenic disease risk, carrier disease risk, pharmacogenomics associations, and blood group antigens—for clinicians to review. In addition, primary care physicians receive training in clinical genomics through a 6-hour orientation course. “In the first 20 or 30 disclosures that we are into right now, we are not finding that these admittedly volunteer, adventurous primary care docs are overwhelmed or frightened or compromised by the data,” Green said.

Individual populations, such as pediatric patients, present unique challenges which require consideration and guidance. In a separate study, BabySeq, Green is examining sequencing in healthy newborns or in those who received care in neonatal intensive care units. Part of the study will examine the perspectives of parents who have this “book of life” genomic reference for their baby’s future medical care from that day forward, Green said. Preliminary data captured from parents before the BabySeq clinical trial started and within 24 hours of giving birth revealed that the majority of those asked were at least “somewhat interested” in exploring genome sequencing for their newborns.²

Saal participated in generating updated guidelines on ethical and policy issues in genetic testing of children which were jointly released by the American Academy of Pediatrics (AAP) and ACMG in 2013 (Committee on Bioethics et al., 2013; Ross et al., 2013). The 2013 AAP/ACMG guidelines do not specifically address the newer genome sequencing technologies, but the rules for those technologies would be essentially the same, Saal said. The same ethical principles that doctors

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¹More information is available at https://cser-consortium.org (accessed July 11, 2014).

²The BabySeq Project, http://www.genomes2people.org/babyseqproject (accessed April 28, 2014).

learn in medical school—a respect for autonomy, beneficence, non-maleficence, justice, and so on—apply to genetic testing.

The first recommendation for genetic testing and screening of children is that decisions about the genetic testing of children should be driven by the best interests of the child. The recommendations advise offer-offering genetic and genomic testing in the context of genetic counseling that informs parents and patients about benefits, risks, and possible outcomes. Under the principle of respect for autonomy, it is important to obtain informed consent and assent for genetic testing, just as would be the case with any other diagnostic test; parents, guardians, and competent children should receive comprehensive pre-test genetic counseling, and Saal pointed out that patients need to receive further genetic counseling to understand the results. In addition, he said, the need to respect patient autonomy dictates that patients can approve or refuse any possible testing of their genomes. “Most patients probably would want that information,” he said, “but on the other hand you need to document that they do or do not.”

The obligation to treat all people equally, fairly, and impartially—that is, to assure justice in treatment—raises additional considerations about the significant issue of the high cost of genetic testing, given that health care has been unaffordable for many Americans and that health insurers often do not cover these tests, Saal said. Generally, genetic testing is not usually covered by third-party payers with the exception of cancer testing, he said. The protocols and policies used by third-party payers to evaluate which genetic conditions are covered may be dated and lack consistency between payers. For some families, an entire deductible could be used on just an exome sequence.

Making a diagnosis is a positive outcome (i.e., beneficence) for patients, not just because it may get them onto treatments, but also because it often ends diagnostic odysseys for families and the costs associated with them. As health care providers strive to do no harm—i.e., to practice non-maleficence—questions arise around whether a knowledge of genetic results may be harmful to patients, as in cases where a diagnosed disease is untreatable or may not develop until later in life (e.g., diagnosis in a minor of a disease that will not develop until adulthood), Lyman said.

Challenges

Several major challenges exist to writing guidelines for using whole-genome sequencing in clinical practice. “First,” Saal said, “next-

generation testing is complex and generates a great deal of data. In addition, interpretation is difficult and challenging.” Saal then asked who should be able to order the testing. Neurologists, developmental pediatricians, and family physicians, for example, may have the credentials to order this testing, but then the issue is who should be responsible for genetic counseling and ensuring that this component is an integral part of the testing.

Informed consent for such testing cannot be obtained without genetic counseling, Saal said, yet there may not be enough genetic counselors to meet future workforce needs. He urged medical schools and residency programs to expand their genetics and genomics curricula to better prepare doctors for the influx of genomic technologies into all realms of medicine.

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