The Regulation Debate

Is government oversight of laboratory-developed tests needed?

By Joseph Guinto featured image

When Liz Mansfield’s doctor orders a test for her, she always asks the same question: Has that test been reviewed by the Food and Drug Administration (FDA)? She asks, even though she already knows what the answer will be. “My doctor can’t tell me if the test has been reviewed by the FDA,” Mansfield says. “As a patient, that concerns me.”

As a government official, it concerns her, too. Mansfield is the deputy office director for personalized medicine at the FDA. That makes her one of the top officials overseeing a newly proposed set of regulations that would govern a plethora of tests — from routine cholesterol screenings to genetic testing for cancer predisposition — that are now unregulated by the federal government.

These tests are known as laboratory-developed tests, or LDTs. They’ve been around for decades. But even though the FDA says a 1976 Congressional law has given it authority to regulate LDTs, the agency has declined to do so until now. That’s because initially, LDTs were simple, low-risk pathology tests used to diagnose rare conditions. The tests were ordered by doctors working in the same facility where the tests had been developed and would be administered. But in the last decade, as personalized medicine has advanced rapidly, LDTs have changed. They’ve become more complex. They’re used to diagnose a broader array of conditions. And they’re not always ordered by doctors who work in the same place where the tests will be administered. All of that has the FDA concerned.

“There has been what I would call an explosion of molecular technology and other new technologies … that were not around in 1976 and that are now very important in medicine,” Mansfield says. “As time has passed, the ability for labs to do higher-risk tests, the larger market penetration that LDTs now have, and the change in the whole business profile — now you can send a sample from New York to Los Angeles overnight, so you can provide results to people who are nowhere near the place where the test is performed — made us believe that the risk profile of these tests in general had changed enough to warrant another look.”

New proposal

The results were the LDT enforcement guidelines the FDA first proposed in September 2014, sparking an ongoing, often-heated debate. Some doctors, pharmaceutical companies, and medical device makers say the regulations will benefit patients because the tests will be held to a higher standard of academic rigor.

As Joshua Sharfstein, the former principal deputy commissioner of the FDA, wrote in an essay in The Journal of the American Medical Association in January, “A patient travels by an ambulance that is regulated, to a hospital that is regulated, for care using medicines that are regulated, administered by nurses and physicians, who are regulated. Yet today, that same patient’s life or death could hinge on whether a single, unregulated diagnostic test result is meaningful.”

The FDA wants the labs that have created certain LDTs to show the tests have “clinical validity.” That means that if a test is being run for high cholesterol, the lab needs to show how well high cholesterol predicts heart disease. Or the labs must show how well fasting glucose numbers indicate diabetes, or how much a person’s genotype may indicate risks of cancer. All of which, Mansfield says, shouldn’t be the job of physicians ordering LDTs.

“I think that many physicians are very, very busy people, and they may not necessarily be able to evaluate whether the tests that labs offer are of good quality or not,” Mansfield says.

I think that many physicians are very, very busy people, and they may not necessarily be able to evaluate whether the tests that labs offer are of good quality or not.

Still, some believe that FDA evaluation of most LDTs is unnecessary because there are few signs that poor-quality LDTs have led to unneeded or dangerous treatments.

In a recent article in Nature, authors Robert C. Green, a geneticist at Brigham and Women’s Hospital in Boston, and Nita Farahany, a Duke University law professor specializing in biosciences, caution against overzealous regulation, saying that the FDA has even left open the possibility of regulating everything from fitness trackers to questionnaires evaluating disease risk.

“Such consumer products could democratize health care by enabling individuals to make choices that maximize their own health,” they write. “They follow the historical trend of patient empowerment that brought informed-consent laws, access to medical records and now direct access to electronic personal health data.” Others argue that LDTs must already meet scientific standards set forth by an array of organizations, including state and federal agencies and guidelines issued under the 1988 Clinical Laboratory Improvement Amendments (CLIA).

“CLIA was developed to make sure labs had the personnel and processes in place to do quality testing,” Mansfield says. “It was not designed to make sure that the tests themselves were safe and effective. That’s what the FDA does.”

Definition Debated

Some in the lab and diagnostics industry object to the FDA’s core belief that LDTs are medical devices. After all, an insulin pump, for instance, is a device that delivers a treatment directly, but a genetic test delivers a result that can be acted on in different ways. But the FDA contends that many LDTs offer more than just raw results. “We agree that laboratory developed tests include laboratory procedures,” Mansfield says. “We don’t agree that that’s all that an LDT is. The tests themselves — the actual instructions for use — are not procedures; they are devices.”

At an FDA workshop held in January, Alan Mertz, president of the American Clinical Laboratory Association, came bearing a white paper written by two leading attorneys in the medical field — Paul Clement and Laurence Tribe. It was a challenge to the FDA’s legal claim that LDTs are medical devices.

That the industry can’t agree with the FDA even on the definition of an LDT has some fretting that a slew of new regulations on LDTs will stifle innovation at a critical moment in genetic research. They argue that LDTs by their very nature are in a state of constant evolution. New methods of testing are developed quickly, sometimes in response to the needs of a single patient — like cancer patients hoping for individualized treatments. The American Medical Association (AMA) is in that camp. Last August, the AMA issued a statement that warned, “The FDA proposal … may result in patients losing access to timely life-saving diagnostic services and hinder advancements in the practice of medicine.”

Mansfield, though, says the FDA took innovation into account in creating its draft regulations. That’s why the agency plans to allow nine years to phase in its LDT oversight, beginning with LDTs that it considers high risk. The FDA will also not, for now, regulate LDTs that test for rare diseases and “unmet needs” — the very kinds of testing where innovation is most important.

“Our objective,” Mansfield says, “is essentially to make sure patients have access to safe and effective tests.” Mansfield says the FDA believes the new regulations, once finalized and adopted, will require labs to meet a high standard for the clinical validity of their tests — something she says they don’t always have to meet under existing regulations and guidelines. She says proving that genetic variants are related to disease risks, as LDTs often promise to do, was one of the key motivations for the FDA.

“We’re in this new era of personalized medicine where diagnostic tests already drive a very large number of medical management decisions,” Mansfield says. “When a doctor orders a test, he has to be sure that somebody knows it is working well and that patients will have the same assurances. Personalized medicine needs these assurances.”