Palo Alto, CA – As genetic testing and molecular biomarkers open new avenues for medical care, researchers are more reliant on samples from human subjects than ever. Participants sometimes want to know research study results, which is driving the scientific community to consider when, what, and how they should be shared. Best practices for sharing study results have not yet been established.
Vinit Mahajan M.D. Ph.D., vice chair of ophthalmology research and Director of the Stanford Molecular Surgery Program, said, “As research focuses on human tissues, there is a need for transparency, collaboration, and the return of individual results reflecting the needs and preferences of each research participant.”
Cutting edge translational research and precision healthcare depend on patients who consent to be research subjects. An initiative such as Stanford’s Biorepository of Eye & Surgical Tissue involves studying ocular tissue obtained from research subjects through surgical biopsies to better understand the molecular biology of ophthalmic and blood biomarkers.
Returning results when feasible with a strong rationale behind the decision could motivate more patients to participate in research studies. New molecular diagnostic methods could personalize diagnoses and therapies.
Unlike results from a clinical lab test ordered for patients, a consenting research subject participating in the biorepository initiative typically does not receive any report because of a difference in certification between results obtained by a clinical lab versus a research lab.
Testing on human specimens to generate patient-specific results is generally certified under the provisions of the Clinical Laboratory Improvement Amendments of 1998 (CLIA). In general, lab results from a clinical test ordered by a physician to assist in making a diagnosis are reported by a CLIA-certified lab. These labs are performing well-established tests under regulatory agencies.
Non-CLIA laboratory and research tests are usually not meant to be diagnostic since many tests are considered experimental or provide no clear course of recommended treatment. The instruments, controls, and reagents do not require rigorous quality control and validation – as in a CLIA-certified lab. Therefore, any results from non-CLIA testing performed on donated specimens are generally not reported since some results may be of unknown value and providing results may lead to misunderstanding, worry, and/or unnecessary treatment. Thus, reporting patient-specific research results presents a challenge as there is the possibility of false positives and false negatives resulting in a potential misdiagnosis.
Mahajan said, “In some instances, however, using lack of CLIA certification as a rationale for preventing return of results is ethically problematic. If the results are of high clinical relevance, time urgent and impossible to replicate in a CLIA-certified laboratory, withholding results could arguably result in unacceptable harm to the participant, especially if that participant suffers from a rare disease.”
There may be situations where ethical considerations require some use of non-CLIA certified results or reporting of non-CLIA certified results to a patient and/or the patient’s physicians. In such cases, it may be prudent to share research results after an informed acknowledgement of the unproven nature of the tests is completed by all parties, the uncertified status of any participating laboratories is detailed, and cautions against the use of research results for diagnosis, prevention, or treatment of any disease or impairment, or the assessment of health of individual patients are given.
CLIA makes an exception for “research laboratories that test human specimens but do not report patient specific results for the diagnosis, prevention or treatment of any disease or impairment of, or the assessment of, the health of individual patients” (42 CFR 493.3(b)(2)).
Best practices for returning patient research results are being studied by many groups, including the National Academies of Sciences, Engineering, and Medicine in a Consensus Study Report.
The report said, “We are recommending that the current absolute standard—that all disclosed results must be generated in a CLIA-certified laboratory—should be replaced with a process-oriented standard, meaning that a peer-review process can be used in some circumstances to weigh competing considerations regarding the return of individual results.”
They state that the decision to return results should be made on a “case-by-case basis” and that the “values of the participants, the risks and benefits of the return of particular results, the quality of the research laboratory and test performance, and the feasibility for investigators to pursue this course” should all be considered in the decision-making process.
Mahajan said, “The easiest situation is when a non-CLIA research test result can be confirmed afterwards by a CLIA-certified lab test. The subsequent validation, say for a genetic variant or elevated protein, can be reported to the patient with confidence.”
He added, “When the research test is cutting-edge, a CLIA-certified validation test may not be available.”
A number of obstacles to returning research results to patients exist. Strict CLIA requirements preventing the sharing of data from non-CLIA labs is sometimes contradicted by Health Insurance Portability and Accountability Act of 1996 (HIPPA) requirements for a patient’s right to results. Sometimes research findings contradict ongoing clinical treatment plans.
Mahajan added, “Research labs also face funding shortages because of the cost of delivering findings to physicians and patients. Lab result delivery costs are factored into an insurance paid clinical visit, but they are not considered in grants and other research funding sources. So, labs performing large studies can find it costly and time consuming to deliver results to participants that can’t be applied on an individual level.”
“Even when there is data for an individual patient, the data can be very complex, and reporting it in a form that patients and their physicians can understand is challenging.”
However, in smaller studies, there are cases where a participant has a rare disease with few therapy options, and research results could help direct a novel treatment plan.
Mahajan said, “There is the potential for medical actionability that makes the return of results important. In several of our proteomics studies, we could see why a particular drug was not working, and this could potentially save a pateint from unnecessary risks. I think academic centers must start tackling this problem. My team is exploring how to report proteomics data we obtain from patient samples – particularly those patients with rare blinding disease where there are seemingly no therapeutic options.”
“We need to involve all the stake holders,” Mahajan said. “A formal written request and acknowledgement of risks by the research subject and their medical care team, clear guidelines on results that are appropriate and inappropriate to return, and attention to laboratory quality is essential.”
“These same issues had to be addressed by medical geneticists when next generation sequencing returned large datasets and there were no best practices for how to interpret and report findings. Proteomics is at that early stage.”
Increased funding to offset additional study costs and collaborations between researchers, physicians, and research participants is crucial to moving the field of personalized medicine forward. The current interest in these issues by a range of researchers, physicians, and patients is sure to lead to protocols for standards and models of return that will benefit all parties involved.