A whopping 3.3 billion in-vitro diagnostic (IVD) tests are run each year in the U.S. according to a recent report from the Pew Charitable Trusts (Pew), the global public policy and research charitable organization. (Summary here, complete report here.) These tests analyze human samples, such as blood, saliva, tissue, and urine, and are used to diagnose disease and other health conditions and guide treatment decisions. Obviously, they are essential to modern medical practice. But the FDA actively regulates only some of these tests for safety and effectiveness, while an unknown number of other IVD tests go on the market without any FDA review.
For historical reasons we’ll get to in a moment, the level of review a test must undergo is based not on its potential for harm to the public from incorrect test results, but on where it comes from. As you’ll see, this distinction is nonsensical in today’s market. A bill currently before Congress attempts to rectify this by imposing a risk-based regulatory scheme that covers all IVDs.
(Caveat: Regulation of lab tests is extremely complex and I am simplifying my overview, hopefully without oversimplifying.)
First, a bit of background is necessary to understand how we got here. The FDA regulates IVDs as medical devices. However, in the past, the agency did not use its authority to regulate what are known as “laboratory-developed tests” (LDTs), tests developed and performed at a single laboratory, with all samples sent to that particular lab for testing. Instead, it focused on commercial test kits, which are broadly marketed to laboratories or the public. These tests must undergo the same pre-market approval process as other medical devices regulated by the FDA, including, in some cases, clinical studies demonstrating that the device is safe and effective for its intended use. The test must show both analytical validity, that is, whether it detects what it’s intended to detect, and clinical validity, whether it accurately diagnoses or predicts the risk of a particular clinical outcome.
Historically, LDTs were developed by hospitals, researchers and academic medical centers for their own use. That is no longer true. In the past couple of decades, there has been an explosion in the use of LDTs by commercial labs and biotechnology companies, with testing behemoths like Quest, Genova, and LabCorp now in the LDT business. One estimate is that there are about 11,000 LDTs offered by 2,000 laboratories but, as the recent Pew Report acknowledged, no one really knows the number of LDTs on the market or the extent of their use. (See the Congressional Research Service Report’s exhaustive analysis for more on the history and current use of IVDs, including LDTs.)
There is some regulatory oversight of labs that offer LDTs. A federal law, The Clinical Laboratories Improvement Act (CLIA), requires assessment of whether a lab is able to test according to instructions and the LDT’s analytical validity. However, a key element is missing in that evaluation: clinical validity.
And that is not the only way FDA-regulated IVDs and LDTs differ. This chart included in the Pew Report highlights the incongruities:
The end result is that, because the difference in regulation has nothing to do with the test itself, FDA-regulated IVDs and LDTs may do the same thing, but the former has undergone essentially the same premarket review as a medical device whereas the latter has not undergone any premarket review. Naturally, this has led manufacturers of FDA-reviewed tests to claim there is a double standard, and they are right.
In fits and starts, the FDA has tried to bring LDTs into the regulatory fold via its authority to regulate medical devices. However, in 2020, the Trump administration threw a monkey wrench into that plan by rescinding all previously-issued FDA guidance documents and informal statements of policy concerning LDTs, taking the position that any FDA regulation can be legally accomplished only through the process of notice and rule-making or new legislation passed by Congress, both of which can take years.
Needless to say, this greatly affected the FDA’s ability to oversee COVID-19 tests. Prior to the administration’s pulling the FDA’s jurisdiction, labs wanting to market COVID-19 LDTs were required to get emergency use authorizations (EUAs) from the FDA. Under this procedure, labs could begin using self-validated LDTs as long as they submitted an EUA to the FDA within 15 days, a requirement that had proven effective in weeding out some bad tests.
Before we get to Congress’s latest effort, the Verifying Accurate Leading-edge IVCT Development (VALID) Act of 2021 (a somewhat tortured name apparently designed to yield a snappy acronym), let’s look at some of the practical effects of this nonsensically bifurcated regulatory scheme. We’ll also take a brief look at how fringe medical practitioners and quacks exploit lab testing.
According to research done by Pew,
LDTs are being used today for different reasons [than originally intended] and in new ways that increase the risk of faulty tests. For example, LDTs are increasingly used to identify and manage the treatment of more common and serious diseases where the risks posed by inaccurate results are dangerously high, such as for cancer, prenatal conditions, and genetic diseases.
Of the more than 40 noninvasive prenatal tests, all are LDTs and therefore none have been cleared by the FDA. These tests are used to determine the risk of genetic abnormalities like Down syndrome and “some companies advertise these tests for use in populations where their accuracy is less established, or to diagnose a broader range of conditions despite the limited evidence for those uses”, raising the possibility that expectant parents are misled about the risk of a chromosomal abnormality.
According to Pew, direct-to-consumer (DTC) genetic tests are almost exclusively LDTs. One study estimated that more than 26 million people had taken a DTC genetic health or ancestry test as of January 2019, expected to reach 100 million by the end of this year. Quality varies among manufacturers, with one small study finding that 40% of harmful genetic variants reported to consumers using a DTC test were false positives.
I would add that DTC genetic tests are also abused by fringe practitioners like self-appointed genetic “expert” and naturopath Ben Lynch. Lynch has misused DTC genetic tests to build a quack empire based on convincing people that MTHFR genetic “mutations” are the cause of all manner of health problems (both real conditions and those invented by naturopaths, like “adrenal fatigue“) and that his dietary supplements are the remedy, a business model he has exported to fellow naturopaths and other dispensers of dubious medical advice via his “educational” courses. So-called “functional medicine” practitioners have cooked up a similar scheme, which has been denounced by experts in genetic medicine.
Consumers can even skip the visit to a practitioner and get health advice directly from labs selling DTC genomic profiling tests claiming the ability to “predict traits such as sexual orientation, ‘loneliness’, and social communication problems” as well as giving “personalized” dietary advice to “optimize” your nutrition and assessing your “vaginal health“. Most disturbingly, a DTC genetic testing company has marketed a so-called “liquid biopsy” for early cancer detection which, as Dr. David Gorski explained, may be a “recipe for the ultimate in overdiagnosis” and its consequences, like overtreatment.
Of course, likely the most famous LDT of all times is the Theranos “Nanotainer” device, which falsely claimed the ability to run numerous tests based on blood drawn with a single finger stick. Theranos founder Elizabeth Holmes is now on trial in federal district court on a dozen felony fraud charges, facing up to 20 years in prison.
Call for reform
Pew recommends, sensibly, that LDTs be held to the same standards for reliability and accuracy that apply to other IVDs which, they say, “requires risk-based oversight from FDA and increased transparency from the entire diagnostics industry”.
In fact, the VALID Act of 2021 (Senate bill here) does create a tiered, risk-based system for what it calls In Vitro Clinical Tests (IVCT), which includes both the IVDs that are already subject to FDA regulation as medical devices as well as LDTs, thereby erasing the false distinction based on the test’s origin and folding all tests into one category for the purposes of regulation. As is true of medical devices, the FDA would subject high-risk IVCTs to a pre-approval review.
“High risk” means that, when used as intended, an “undetected inaccurate result . . . presents an unreasonable risk for serious or irreversible harm or death . . . or would otherwise cause serious harm to the public health” or ” is potentially likely to result in the absence, significant delay, or discontinuation of life-supporting or life-sustaining medical treatment”.
Middle tier IVCTs would also obtain approval but with less strict requirements. Low-risk IVCTs could come to market after listing with the FDA. The Act authorizes the FDA to establish performance standards that IVCTs can use to demonstrate clinical validity, analytical validity, and safety as applicable.
Per analyses of the VALID Act in The National Law Review, the FDA itself would “actively regulate” the highest risk IVCTs (about 10% of all tests), with “a robust third-party review program in place to handle the significant volume of low- and moderate-risk IVCTs”, a scheme that is “similar to existing third-party review programs for traditional medical devices”.
Through a novel “technology certification” program, an IVCT developer could submit a representative test to FDA for review and, if the agency approves, the developer could then use the technology certification to develop tests that are within the scope of that approval without submitting a test for FDA review each time. Certification would last for four years, with an option for renewal.
The FDA could establish performance standards for IVCTs “in much the same way standards are presently used for medical devices” and there would be registration and listing requirements for IVCTs that would, for the first time ever, provide an accurate record of tests on the market. Some IVCTs would require labels indicating, for example, their intended use, warnings and limitations of the test. Adverse event reporting would be required and the FDA would have the authority to recall tests.
A “grandfather clause” would exempt from the Act’s requirements any IVCT marketed prior to enactment if certain criteria are met. Notably, even grandfathered tests must meet the registration, listing and adverse event reporting requirements, and test results must carry a version of the Quack Miranda Warning, stating that the test has not been reviewed by the FDA. Also, any modification of an exempt test may trigger FDA review requirements.
(You can read a section-by-section summary of the bill here.)
Reaction to the VALID Act of 2021 has been mixed. While Pew and 17 patient advocacy organizations initially praised the bill and urged Congress to pass it, Pew has since called for changes to prioritize patient safety. AdvaMed, a trade group representing medical device and lab test manufacturers, called modernization “overdue” and has been generally positive. On the other hand, the American Clinical Laboratory Association (ACLA), in reviewing the 2020 version of the VALID Act, objected to requiring that all LDTs meet the same standards as other IVDs and to the registration requirements (which I find absolutely vital to reform). The ACLA says it is currently reviewing the 2021 bill, which retains the provisions the ACLA finds objectionable.
The meaningless distinction between LDTs and other IVDs must be eradicated and all tests subject to regulation based on what they do (or don’t do), not where they were made. The VALID Act is certainly a big improvement, although I wish it more directly addressed the threat to consumers from quack and DTC diagnostic tests. Even though it has some bipartisan support, given the inability of Congress to do much of anything, I am not optimistic.