Diagnostic Testing Is a Wild West of Unknowns, Perils

The problem with FDA involvement in the regulation of molecular diagnostics testing is not only the esoteric scientific behind them but also the rapid-fire developments in the field that can make slow moving FDA determinations irrelevant by the time they become official.

Scott Gottlieb, MD

The problem with FDA involvement in the regulation of molecular diagnostics testing is not only the esoteric scientific behind them but also the rapid-fire developments in the field that can make slow moving FDA determinations irrelevant by the time they become official, a group of expert panelists stated in the opening salvos of the 4th Annual Patient Centered Oncology Care conference in Baltimore, hosted by AJMC, last Thursday.

“The FDA does not have a good way to solve for these challenges right now,” said Scott Gottlieb, MD, former FDA deputy commissioner for medical and scientific affairs. Gottlieb recalled that during one period of HIV resistance testing the FDA was looking at genomic tests and eventually would give an approval, but they’d be obsolete before anybody could come in for testing. “Doctors realized that these tests changed all the time. Genomics changed as the viruses mutated,” Gottlieb recalled.

The panel discussion was extremely timely, as last week the FDA released a report on why it feels that stiffer regulatory oversight of laboratory testing is necessary, basing its conclusions on 20 case studies of problematic outcomes. “Laboratory developed tests (LDTs) serve an increasingly important role in health care today. They also have become significantly more complex and higher risk, with several notable examples of inaccurate tests placing patients at otherwise avoidable risk,” the report stated in its executive summary.

With a plethora of testing companies and academics involved in the development of these tests, physicians and patients need clear guidance about what they are getting when they order these tests, but it still needs to be determined what type of a general role the FDA will play as a review body—whether to weigh in on clinical validity or clinical utility, the panelists said.

“The customers need to be confident that the product they’re getting and buying is something they can use to make an intelligent decision,” said Michael A. Kolodziej, MD, Aetna’s national medical director for oncology strategy. “A lot of people do not believe that is occurring. When an oncologist orders the test, they have no idea where it’s going and whether it’s being done well. Patients would be horrified by that statement. Payers do not have the expertise to look at all of these very complicated molecular tests. We need some kind of proficiency testing. Is the test being done right? That’s clinical validity.”

Nevertheless, genomic testing is well established by now. There are 155 biomarkers listed on FDA drug labels, according to session moderator Dennis P. Scanlon, PhD, a professor of health policy and administration at Penn State University. “Fifty percent of all cancer treatments in early clinical development rely on biomarker data,” he noted, and despite the problems associated with genomic testing, the value is indisputable. Women with breast cancer who receive a genetic test of tumor prior to treatment enjoy a 34% reduction in chemotherapy, he said.

Numerous other issues are associated with this form of diagnostics, among them problems that complicate the job of establishing utility for patients, the panelists said. Numerous tissue samples are found to be inadequate and a large percentage, upward of 30%, are returned as unacceptable by laboratories; but also, matching tests with patients is a tricky business, and large numbers of tests are performed without true merit, panelists said.

“A key question comes back to what is the test designed to do, and are we selecting the right test?” said panelist Joy Larsen Haidle, MS, CGC, president of the National Society of Genetic Counselors. “We may be getting an accurate result, but test may not have been designed for that particular patient,” she said. “From the patient’s perspective, they have to be able to count on that result. It impacts not just them but their families, too.”

Another side of this problem is that biomarker testing is very prejudicial to large segments of the patient population, meaning that especially when recruiting for clinical trials, it’s hard to assemble a patient cohort that meets the specifications on a particular molecular level. “A drumbeat of trials that are failing is predicted because they haven’t been able to accumulate enough patients,” Scanlon said. “This incidence rate is really the elephant in the room. Various trials have already run into this issue.”

The US genomics testing market was estimated at $5.9 billion in 2011 by research firm Booz Allen Hamilton, with nearly 2900 different tests available in that year. Subsequent research released in June by Grand View Research predicted that the genomics testing market just in the United States would hit $27.87 billion by 2022.

With this scale of growth and marketing in mind, the FDA has been working to develop a set of standards and processes to ensure that the tests are reliable. The agency is also working to develop clinical databases that will help physicians to make better decisions about what to do based on the information they get from these tests.

“There are a lot of ways to make errors in sequencing, and our concept is to develop a set of process and material standards that will, we hope, allow us to essentially be confident that a lab that develops a test will do it in a manner that generates a test that is accurate and reliable,” Elizabeth Mansfield, PhD, director of personalized medicine for the FDA, told OncLive in an interview earlier this year.

In its report issued last week, the FDA stated that it examined events involving 20 laboratory developed tests (LDT) “that illustrate, in the absence of compliance with FDA requirements, that these products may have caused or have caused actual harm to patients. In some cases, due to false-positive tests, patients were told they have conditions they do not really have, causing unnecessary distress and resulting in unneeded treatment. In other cases, the LDTs were prone to false-negative results, in which patients’ life-threatening diseases went undetected. As a result, patients failed to receive effective treatments.

“Other LDTs provided information with no proven relevance to the disease or condition for which they are intended for use, while still others are linked to treatments based on disproven scientific concepts. In addition to patient harm, inaccurate or unreliable tests can be costly to society,” the report stated.

While the FDA has taken a relatively passive role in oversight of LDT, the Clinical Laboratory Improvement Amendments (CLIA) from the Centers for Medicare & Medicaid Services do provide standards, and yet all of the problem tests discussed in the FDA report did follow CLIA recommendations, which contributes to the conclusion that CLIA may not be strong enough, the FDA said. It said CLIA fails to ensure safety and effectiveness of tests prior to marketing and that it makes no assessment of the quality and design of testing devices. “Greater FDA oversight is needed to promote access to LDTs that provide benefits to patients and the health care system, while helping to ensure patients are not unduly exposed to harm,” the report concluded.

Still, the federal government may be overreaching if it takes on too big of a role as a watchdog when it comes to genomics testing, Gottlieb said. “There’s a lot of tools. Some are used appropriately and some are not. Some information is used appropriately and not. But it’s very risky to put a government arbiter in the position of making a determination.”

If the government is reluctant or hamstrung in its ability to step in and provide the necessary oversight and guidance, the burden must fall to the professional societies who care deeply about the results and who can be relied upon to develop standardized procedures, said Kolodziej. “There’s an opportunity now, if the government won’t do it, for the professional societies to do it. Payers actually pay attention to what the professional societies say. The NCCN has tremendous influence.”

His thought was seconded by panelist Bruce Quinn, MD, PhD, MBA, senior director of FaegreBD Consulting in Washington, DC, who specializes in Medicare policy and health reform in innovation. “Professional societies are extremely important in determining where the cut points should be,” he said.

Whereas confusion appears to reign in this rapidly growing field of medical diagnostics, there is a rapidly growing presence of certified genetic counselors (CGS) who function as in-betweens to directly guide patients toward informed use of genetic testing and to supplement the expertise of doctors for whom these diagnostics may outstrip their zone of competence, said Larsen Haidle. There has been an 88% increase in CGS since 2006, she said.

Their skills are brought to bear in a variety of forums, Larsen Haidle said, among them face to face consulting, telephone and computer interaction, and rural settings. Genetic counselors can reduce costs to the health care system by reducing inappropriate testing, she said, adding that through their expertise and particular focus they can detect genetic risk factors in patients that referring providers may fail to detect.

Office of Public Health Strategy and Analysis, FDA. The public health evidence for FDA oversight of laboratory developed tests: 20 case studies. 2015. http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM472777.pdf. Accessed November 20, 2015.