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IOM Report Recommends Evaluation and Validation Process to Prevent Problems Associated With Turning 'Omics' Research Into Clinical Tests

Many branches of molecular bioscience offer the prospect of greater precision in medical care, but some clinical tests based on "omics" research have proved invalid and highlighted the challenges of dealing with complex data.

by The National Academies
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WASHINGTON — Genomics, proteomics, and other branches of molecular bioscience offer the prospect of greater precision in medical care, but some clinical tests based on "omics" research have proved invalid and highlighted the challenges of dealing with complex data. To enhance the translation of omics-based discoveries to clinical use, a new report by the Institute of Medicine recommends a detailed process to evaluate whether the data and computational steps underlying such tests are sound and the tests are ready to be used in clinical trials. The proposed process defines responsibilities and best practices for the investigators, research institutions, funders, regulators, and journals involved in development and dissemination of clinical omics-based technologies.

The request for the IOM report stemmed in part from a series of events at Duke University in which researchers claimed that their genomics-based tests were reliable predictors of which chemotherapy would be most effective for specific cancer patients. Failure by many parties to detect or act on problems with key data and computational methods underlying the tests led to the inappropriate enrollment of patients in clinical trials, premature launch of companies, and retraction of dozens of research papers. Five years after they were first made public, the tests were acknowledged to be invalid.

Lack of clearly defined development and evaluation processes has caused several problems, noted the committee that wrote the report. Omics-based tests involve large data sets and complex algorithms, and investigators do not routinely make their data and computational procedures accessible to others who could independently verify them. The regulatory steps that investigators and research institutions should follow may be ignored or misunderstood. As a result, flaws and missteps can go unchecked.

Investigators should be required to make the data, computer codes, and computational procedures used to develop their tests publicly accessible for independent review and ensure that their data and steps are presented comprehensibly, the report says. Agencies and companies that fund omics research should require this disclosure and support the cost of independently managed databases to hold the information. Journals also should require researchers to disclose their data and codes at the time of a paper's submission. The computational procedures of candidate tests should be recorded and "locked down" before the start of analytical validation studies designed to assess their accuracy, the report adds.

It is not always clear when researchers and institutions are legally required to consult with the U.S. Food and Drug Administration about new tests developed in clinical laboratories, such as omics-based tests. The committee therefore urged researchers and institutional officials to discuss newly created tests and their intended uses with the agency as a matter of course prior to the start of validation studies. In turn, FDA should issue either guidance or a regulation that specifies when developers need to submit omics-based tests to the agency for review, the report says. Tests should not be changed during clinical trials without a protocol amendment and further discussion with FDA.

Lack of clarity about the regulatory framework for laboratory-developed tests means academic medical centers can choose to move new omics-based tests from discovery to clinical use without external review. This places new, mostly unrecognized responsibilities on these institutions to provide proper oversight of the process.

Given the lessons from the Duke cases and the complexity of these new technologies, institutional leaders should pay greater attention to promoting a culture of scientific integrity and transparency, the committee said. Institutions should establish means to prevent, report, and investigate lapses in scientific integrity. They should designate institutional officials to assess and manage potential conflicts of interest among individuals and the institution, and should supervise procedures for responding to scientific questions or criticisms. They also should ensure that the many scientific disciplines involved in omics research are represented on oversight bodies.

Funders and journals share responsibility for identifying potential problems and responding to questions about the integrity of omics research and development, the committee said. Federal funders, such as the National Institutes of Health, should have the authority to investigate the work of researchers they are supporting even if the study or clinical trial is funded by others. Journal editors should make a greater effort to resolve alleged errors or data corruption in published papers.

"We hope that this report will help all members of the investigative team understand the entire pathway of translating omics discoveries into clinical tests and recognize and avoid the potential pitfalls at each stage," said committee chair Gilbert Omenn, professor of internal medicine, human genetics, and public health, and director, Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor. "We believe that past problems, such as the Duke case, could have been prevented had a clearly defined process been available and been utilized. Scientific and clinical progress in omics test development will be accelerated if these recommendations are broadly adopted."

The report was sponsored by the National Cancer Institute, U.S. Food and Drug Administration, U.S. Department of Veterans Affairs, Centers for Disease Control and Prevention, American Society for Clinical Pathology, and College of American Pathologists. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides objective, evidence-based advice to policymakers, health professionals, the private sector, and the public. The Institute of Medicine, National Academy of Sciences, National Academy of Engineering, and National Research Council together make up the independent, nonprofit National Academies. For more information, visit or