An old high school friend of mine—call him Craig—recently took a test for cancer, after which he and his doctor had to decide whether he should undergo radical surgery. The evidence for the test’s reliability might have been stronger, and the decision clearer, had the federal Food and Drug Administration known more about this diagnostic tool. But that isn’t likely to happen anytime soon.
The tool in question belongs to a category known as laboratory developed tests, or LDTs. These are used to diagnose and guide treatment for a range of conditions, from Lyme disease, fetal chromosomal defects, and autism spectrum disorder, to ovarian, cervical, breast, and prostate cancers. The FDA, which since its creation in 1906 has been largely responsible for pulling medical remedies out of the snake-oil era, has tried for decades to establish oversight for LDTs in order to verify claims about their safety and effectiveness.
At one time, these tests were a minor part of medical practice; today, thanks to recent advances in genomics and other molecular techniques, thousands of LDTs are available, with more coming on the market each day. But the FDA, after identifying problems with the claims made about these tests, has taken a giant step back from imposing stricter regulations.
In November, shortly after the election of Donald Trump, the agency announced that it was delaying action on new regulatory guidelines for LDTs, which had been in the works for several years. It said it might take some other action, some other time.
“FDA believes that patients and health-care providers need accurate, reliable, and clinically valid tests to make good health care decisions—inaccurate or false test results can harm individual patients,” agency press officer Tara Goodin said in November. “We have been working to develop a new oversight policy for laboratory developed tests, one that balances patient protection with continued access and innovation, and realize just how important it is that we continue to work with stakeholders, our new Administration, and Congress to get our approach right.”
LDTs hold great promise. But without independent, careful validation of their safety and effectiveness—ideally by folks who don’t have a financial stake in their use—neither doctors nor patients can distinguish marketing hype from real evidence.
You might think scrutinizing such tests is the province of scientists free of political pressure and conflicts of interest. You’d be wrong. Billions of dollars in Big Pharma revenue hang in the balance, and “stakeholder processes” can substitute for science at times. “It’s a very politicized issue and there are a lot of players,” Dr. Elizabeth Mansfield, the FDA’s director for personalized medicine and molecular genetics, told me not long before the agency’s stand-down.
In support of its proposal to impose new regulations, the FDA identified twenty examples of LDTs on the market that “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,” the agency’s November 2015 report states, “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.” But proposed regulations were met with intense lobbying and sometimes hostile Congressional hearings. And the new President has openly derided the FDA, citing it as an example of an excessively meddling government agency.
Industry groups, including the American Clinical Laboratory Association (ACLA), cheered the agency’s postponement of regulatory action. “The FDA’s decision not to issue final guidance to regulate LDTs is a victory for diagnostic innovation and most importantly, patients,” said Alan Mertz, ACLA president.
But the FDA’s retreat from regulation is bad news for some people.
Among the problems with LDTs cited in the agency’s 2015 report were: lack of evidence supporting the clinical validity of tests, deficient adverse event reporting, unsupported manufacturer claims, and inadequate product labeling. The report also raised concerns about “threats to the scientific integrity of clinical trials,” because clinical investigators studying LDTs often rely on these tests to pick patients for participation: “If the tests are inaccurate, the scientific conclusions derived from these trials may also be inaccurate.”
The most serious findings alleged that LDTs can lead to harmful effects. For instance, patients who receive a false positive from a test meant to diagnose Lyme disease may be prescribed a regimen of antibiotics that increase “the risk of creating infectious organisms resistant to the antibiotics used to treat Lyme disease, and delay in the diagnosis of a patient’s true underlying condition.”
“The rules for new lab tests aren’t as rigorous as the rules for new drugs,” Dr. David F. Penson, chairman of urologic surgery at Vanderbilt University Medical Center, told The New York Times in 2015. “A lot of companies are developing tests that may be promising, but they push them out the door into clinical practice without really doing all their homework.”
As it happens, Penson was talking about tests involving prostate cancer. Unfortunately, this all-too-common disease underscores the dangers of inadequate proof of test effectiveness.
The prostate-specific antigen test—the PSA, it’s called—has been widely used as a screen to detect early cancer since the 1990s. But its originator, Dr. Richard Ablin, recently told me that “the test doesn’t work” as a screen. He’s even written a book about it, published in 2014. It’s one of those books whose title gives the game away: The Great Prostate Hoax: How Big Medicine Hijacked the PSA Test and Caused a Public Health Disaster.
Ablin is not going out on a limb. The test’s high rate of false-positive results—bad scores even though there is no cancer or it is not a threat—has led the U.S. Preventive Services Task Force, a government advisory panel, to recommend against its use for routine screening, saying “many men are being subjected to the harms of treatment for prostate cancer that will never become symptomatic.” The task force’s recommendations are under review. In recent years, the PSA test’s use has been slowly declining.
This corrective action comes too late for many. As Dr. Otis Brawley, chief medical officer for the American Cancer Society, has said: “Our aggressive approach to screening and treating has resulted in more than a million American men getting needless treatment.” Typically, that treatment involves surgery or radiation with harrowing side-effects.
Still, the PSA test can have benefits, in cases where it directs people to treatment who need it. Dr. Saurabh Jha, a radiologist in Pennsylvania, parsed this issue in a recent column: “Screening is an information problem—some benefit, some are harmed, but we don’t know who will benefit or who will be harmed.”
Jha also noted that the prostate “doesn’t have the prettiest real estate.” It occupies a kind of lower-torso Grand Central of plumbing and electrical systems, wrapped around a close-packed gore of intestines, kidneys, sex organs, and waste disposal routes, so treatment can readily lead to complications.
Prostate cancer is no small hazard. It is the second most frequently diagnosed cancer among American men, after skin cancer, and is the most common cause of cancer death after lung cancer and colorectal cancer, according to the American Cancer Society. In 2016 alone, the group estimates, there were about 180,890 new cases of prostate cancer and about 26,120 related deaths.
This is a busy policy arena, with health, fear and big money in play. When the Preventive Services Task Force, made up mostly of distinguished physicians and academics, drafted its recommendation against using the PSA test for routine screening in 2011, one of the panel's most vocal opponents was Representative Tom Price of Georgia.
He used a common tactic, dismissing science-based recommendations as political meddling. In a letter, he and other representatives urged the head of the Department Health and Human Services to “push for the withdrawal” of the task force’s recommendations. The panel was made up of “bureaucrats,” his letter said.
Among his financial supporters, the health sector has contributed the most money to Price during his career in public service: $3,551,579, from health-industry-related individuals and PACs. According to the Wall Street Journal he traded in hundreds of thousands of dollars' worth of health industry stocks while sponsoring and advocating legislation that would benefit those companies. In February, he was confirmed as Secretary of Health and Human Services.
As a seventy-year-old male, I am fairly likely to have prostate cancer. My somewhat morbid confidence doesn’t derive from a medical test (I’ve been avoiding tests, so far, with real dedication). I’m just considering the odds. About a third of men have it by the time we’re fifty-five, and about 60 percent of us will have it if we make it to eighty.
But here’s the thing: For most of us, that’s no big deal. Although the lifetime risk of prostate cancer is 16 percent, the risk of dying from it is only 2.9 percent. In most men, it grows so slowly that they are symptom-free, and die of other causes. So I don’t know whether my own fairly likely prostate cancer is a four-alarm fire or a harmless smolder that can safely be ignored.
Most of us would go ahead with treatment just to allay anxiety, except that the cure is commonly worse than the disease. Treatment often means a radical prostatectomy—complete surgical removal of the prostate gland—or lots of radiation.
The largest, longest study of side-effects, published last fall in The New England Journal of Medicine, documents with precision what has long been known in general: Prostatectomy led to sexual dysfunction for more than half the men treated. Surgery and radiation can also lead to urinary and fecal incontinence. Though there’s some improvement over time, for most affected men these conditions persisted through the full six years of the study, as did their reports of coping with a great burden of anxiety.
Due to these high stakes, it would be a fine thing to know whether your prostate cancer is aggressive and calls for treatment, or can be left alone and monitored instead. That was the decision my friend Craig faced, after he and his doctor opted to use a diagnostic test called Prolaris. Which brings us back to the FDA.
One of the agency’s twenty examples of the need for more regulation involves Prolaris, made by Myriad Genetics, Inc. The FDA questioned the company’s claim that this test can be used to predict the ten-year risk of prostate cancer progression and the risk of death. “The test is being used to make patient management decisions,” agency staff wrote. “However, no study has prospectively examined whether these treatment decisions represent clinically appropriate management of prostate cancer. As a result, patients could be either over- or under-treated for prostate cancer.”
The FDA’s Mansfield told me that tests like Prolaris, because they can be the basis for critical treatment choices, require a high level of proof. What the research hasn’t yet done, she said, is to show whether a decision based on Prolaris “actually changes anything for those men. If you take an action based on the test results, does it make any difference? With cancer, there are a lot of areas where you would think making this kind of decision would make a difference, but in fact it doesn’t. People have the same course of disease, on treatment or off treatment.”
Myriad Genetics spokesman Ron Rogers says the FDA report is misleading and incomplete. He sent me a link to ten studies. “Prolaris is one of the most studied molecular diagnostic tests in history and is validated against real oncologic endpoints,” he wrote in an email.
Some of the studies were uniformly positive; some of them were carefully hedged, as good studies often are. One, for example, said that “cell cycle progression,” on which Prolaris is based, “after additional validation, could have an essential role in determining the appropriate treatment for patients with prostate cancer” (emphasis mine).
Then, there’s the fact that about half of the dozens of co-authors of this research (many of the same names were duplicated across several studies) are affiliated with Myriad Genetics—often as employees and sometimes as shareholders, too.
Rogers insists this does not compromise the effectiveness of the evaluations: “We are committed to mak[ing] available important information about our products and the science on which they are based, and do so in an objective, accurate, and balanced way.”
Dr. Jack Cuzick is lead author for three of the studies. He is the director of a UK cancer research center and has served on the Myriad Genetics speakers bureau for a decade and is paid for that, he told me (he estimated $5,000 to $10,000 in total payments for his appearances). Since the Prolaris papers were published, he and his employer have also reached an agreement to share royalties on sales of a new product Cuzick helped Myriad develop, he says.
Cuzick says public disclosure of these connections suffices. But when I asked about the details of the royalty arrangement, he replied, “That’s a confidential issue.” We must recognize, he said, that “progress is based on collaboration between industry and academia.” Perhaps so. It’s the nature of the collaboration that’s in question.
The FDA’s Mansfield told me her agency tends to be “very sensitive to those kinds of conflicts, because of implicit bias problems that are part of human nature, and are not necessarily any kind of malign intent. And we like to see things replicated by different people who didn’t develop the test, to assure that it wasn’t some structural bias or something else that actually affected their outcome.”
Sometimes the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of cancer centers that advertises itself as “Your Best Resource in the Fight Against Cancer®,” is offered up by health care providers as an alternative to the FDA for judgments about which medical tests should be on the market. NCCN guidelines, for example, back the use of Prolaris.
But a recent study of the authors of NCCN guidelines, published in the Journal of the American Medical Association, found that 108 of 125 guideline authors (86 percent) “had at least one reported financial conflict of interest.” Eight exceeded the maximum number set for guideline authors by the NCCN ($50,000 overall; $20,000 from any single company). The study’s authors remarked with some delicacy that these conflicts may “influence guideline authors in counterproductive ways.”
For us patients, of course, there’s no way to know whether this or that conflict of interest has bent the process. We must be uneasy with all of them.
Should you and I be signing up to take these new medical tests, based on sonorous corporate assertions and despite potentially compromised or premature research? Or should we wait for signs of the onset or worsening of serious disease, hoping that they don’t appear? I’ve hashed such questions over with a few family doctors, who struggle with what to tell patients like me—and what to tell themselves. Sometimes, they don’t have answers.
My friend Craig went ahead with a prostatectomy, and is doing okay after weeks of recuperation and lingering side-effects. But if the FDA had the political support to properly evaluate tests like Prolaris while it was being developed, patients and doctors might have a far better idea today what choices to make.
Instead, we are reduced to a kind of grim guesswork, navigating an increasingly hazardous geography of money, medicine, and political clout. As University of Chicago urologist Dr. Scott Eggener, a spokesman for the American Urological Association, has said of those prostate cancer products, “It’s very exciting to have these tests available, but it’s sort of the Wild West now.”