NEW YORK (GenomeWeb News) – The Institute of Medicine today provided a broad set of guidelines for the development of 'omics-based tests, a little more than one year after alleged scientific fraud by a former Duke University researcher was uncovered and shed light on the need for greater oversight.
The nearly 300-page report details recommendations for the many parties involved in developing 'omics-based tests, which are often technologically complex, but which have been much subjected to comparatively looser oversight than other medical technologies, such as drugs, IOM said.
In crafting its guidelines, the institute is aiming to establish best practices for taking an 'omics-based test into clinical trials and evaluating it for clinical utility and use. The recommendations being made are not for taking a test from the clinical trial setting into clinical practice, the report noted.
IOM formed a 20-person committee consisting of experts in 'omics research and charged them with devising steps to improve the scientific standards of tests based on genomics, proteomics, metabolomics, and other similar fields. Additionally, the report addresses conflict-of-interest issues, funding, and regulatory components of the test development process.
The report lays out recommendations for three overarching areas in the development process: discovery, test validation, and evaluation for clinical utility and use.
In the discovery stage, the use of statistics, bioinformatics, and data management for analyzing large datasets are essential, IOM said, and its guidelines call for the use of independent sample sets "not used in [the] generation of the computational model" and blinded to any outcome or other phenotypic data until after the computational methods have been recorded and "locked down."
The data and metadata should also be publicly available in an independently managed database in standard format with molecular measurements, computational procedures, and intended clinical use clearly defined, IOM added. The result from this work would be a candidate 'omics-based test that would be transitioned into a validation phase "to assess analytical and clinical/biological validation," it said.
IOM said that there is a "wealth of existing work" that describes best practices for developing clinical laboratory tests, much of which can be applied to 'omics-based tests. Discussions with the US Food and Drug Administration about intended use should be held prior to starting a validation study, the institute suggested, and test validation should be done in a CLIA laboratory, which should design, optimize, and implement the test under current clinical laboratory standards.
If more than one CLIA lab will be used to conduct the clinical trial, analytical validation and CLIA requirements should be met by each laboratory, IOM added.
If a test passes this stage, it would then be evaluated for clinical use. The institute said that ideally a prospective randomized clinical trial would be conducted for such an assessment, but it recognized that this is not always possible.
Whatever strategy is pursued, however, IOM said, early correspondence with FDA "regarding the investigational device exemption process and validation requirements," should be performed. This is already required in instances in which patient management will be influenced by the findings of the test.
But even when it is not required, IOM said that consultation with the agency can benefit the test developer. If the test will be subject to FDA clearance, for example, meeting with the FDA can aid both parties on the appropriate FDA review pathway.
Shared Responsibility on Oversight
The report also pays attention to the role of the institution where the research is done and noted that while individual researchers bear the greatest responsibility for ensuring the integrity and accountability of the research, academic institutions, non-profit organizations, and for-profit entities that support the development of 'omics tests also have a responsibility for ensuring proper oversight.
Among the steps IOM recommends is the designation of a specific institutional review board member who would be responsible for "considering investigational device exemption (IDE) and investigational new drug requirements as a component of ensuring the proper conduct of 'omics-based clinical research," and an institutional official to comprehensively document, disclose, and manage financial and non-financial conflicts-of-interest, both individual and institutional.
IOM also called for the designation of officials who would be responsible for preventing, reporting, and adjudicating "lapses in scientific integrity," and establishing procedures for responding to accusations or questions about research being done at the institution.
The IOM committee tried to "emphasize and enhance institutional awareness of existing responsibilities to ensure the integrity of the scientific progress," in order to avoid creating additional barriers to innovation in 'omics-based test development. They acknowledge that the guidelines may create oversight burdens for some institutions, but the potential additional costs would be offset "by the added safeguards for the integrity of this research."
If an institution is unable to take on the added responsibilities of the recommendations, "the committee believes that institution should consider not engaging in the translation of 'omics-based discoveries into validated tests intended for clinical use," the report said.
Because the guidelines set forth by the report do not have the power of law, there is no way to mandate compliance with them. Nonetheless, Gilbert Omenn, the chair of the committee, said on a conference call today that "this kind of careful, and rigorous, transparent process was to everyone's benefit, so we expect voluntary compliance."
Omenn is a professor of internal medicine, human genetics and public health, and director of the Center for Computational Medicine and Bioinformatics at the University of Michigan Medical School.
Debra Leonard, a committee member and a professor and vice chair of laboratory medicine, and director of clinical laboratories at Weill Medical College of Cornell University, added on the conference call that in light of the problems at Duke that prompted the report, academia and other institutions where 'omics-based research is being done realize they are not experts at translating research discoveries to clinical tools.
The report provides them with a roadmap to that pathway and a framework to follow best practices — and "institutions do tend to follow best practices," she said.
The scandal at Duke pointed to potential flaws within the field of 'omics research and test development. Anil Potti, a former researcher at the university, and colleagues had published several papers in which they claimed they could predict lung cancer progression based on gene expression levels using microarrays. The research and the results were almost immediately questioned and eventually Potti was accused of manipulating the data.
After Duke suspended him, suspended clinical trials based on his research, and retracted his published data, Potti resigned from Duke in late 2010. In response to that incident, the National Cancer Institute asked IOM to create a committee to develop guidelines for the development of 'omics-based tests.
In its report, IOM noted the complexity of 'omics research and the resulting data, as well as a regulatory framework that may not be properly set up to prevent missteps, such as those made by Potti. Unlike its approach to drugs, FDA has not actively regulated many 'omics tests, though the agency has the power to do so. Instead, as most of them are laboratory developed tests, they fall under the purview of CLIA regulations.
"It is precisely this LDT pathway that allows academic medical centers to move 'omics-based tests from discovery to clinical use without external regulatory review of the new test, and places a new and mostly unrecognized demand on academic institutions to provide proper oversight for 'omics-based test development, validation, and clinical implementation," the IOM report said.
It also said that the lack of a "widely agreed-upon process" for translating 'omics research into clinical tools may be one reason that the development of such tools has been slower than expected.
On the conference call, Omenn said that the guidelines could help to accelerate 'omics-based tests through the development pipeline as well as improve their clinical utility.
"The ultimate goals are to avoid future problems in translation and to speed the development of revolutionary new 'omics-based tools that can improve patient care," he said.
In addition to Omenn and Leonard, the committee that created the report includes Catherine DeAngelis of Johns Hopkins School of Medicine; David DeMets of the University of Wisconsin, Madison; Thomas Fleming of the University of Washington; Gail Geller of Johns Hopkins University; Joe Gray of Oregon Health & Science University Knight Cancer Institute; Daniel Hayes of the University of Michigan Comprehensive Cancer Center; Craig Henderson of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center; Larry Kessler of the University of Washington School of Public Health; and Stanley Lapidus of SynapDx.
It also includes Harold Moses, Vanderbilt-Ingram Cancer Center; William Pao, Vanderbilt University School of Medicine; Rebecca Pentz, Emory School of Medicine; Nathan Price, Institute for Systems Biology; John Quackenbush, Dana-Farber Cancer Institute; Elda Railey, Research Advocacy Network; David Ransohoff, University of North Carolina School of Medicine and Gillings School of Global Public Health; Albert Reece, University of Maryland School of Medicine; and Daniela Witten, University of Washington.