AMP, FDA Debate Regulation of Laboratory-Developed Tests

December 17, 2015

Update 1:56: The language of AMP's rebuttal was updated on Thursday afternoon. On page one, instead of stating that some examples were "fabricated by the FDA," the updated language says that some examples were, "highly speculative." In the Oncotype DX example, the updated conclusion begins, "FDA seems to presume an intended use that does not exist." Links below direct the reader to the updated rebuttal, but quotes refer to the original posted on Dec 13. 

By Allison Proffitt

December 17, 2015 | The Association of Molecular Pathology (AMP) accused the Food and Drug Administration of fabricating some of the examples included in a recent FDA report outlining the public health evidence for FDA oversight of laboratory-developed tests.

The FDA’s report, The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies, was released in mid-November. The report presented 20 instances in which FDA believes laboratory-developed tests, “may have caused or have caused actual harm to patients.” FDA argues that with its own regulatory oversight, that harm could have been avoided.

In a 15-page rebuttal posted on Sunday, AMP called the FDA’s report “irresponsible”, and warned that it may, “cause unwarranted stress to patients, needlessly scare the American public, and lead patients to unduly question the quality of care,” they received.

AMP detailed its concerns with each of the 20 cases FDA highlighted. AMP conceded that a few of the tests could cause harm that FDA oversight might have prevented, but said the remaining examples, “were either fabricated by the FDA; reflected a problem with treating physicians using treatments outside accepted medical practice; [reflected] analytical errors…; or [resulted from] failure of treating physicians to follow up a screening test with a diagnostic confirmation test.”

AMP urged, “the Department of Health and Human Services and the Office of Management and Budget to perform a thorough, scientifically unbiased analysis of potential harms and benefits of FDA regulation of LDPs prior to embarking on a massive new regulatory program that would be enormously disruptive to health care and would likely have profound adverse consequences for patients across the country.”

Instead of FDA oversight, AMP argues that the Centers for Medicare & Medicaid Services (CMS), “has the statutory authority to evaluate these tests through the CLIA program utilizing a robust network of third party network of medical and scientific experts.” (FDA announced plans to regulate LDTs in July 2014. For background, see "What You Need to Know About the FDA's Push to Regulate Laboratory Developed Tests.")

20 Problems

A number of the 20 cases highlighted by FDA are “examples of non-standard practice,” explained Roger Klein, a molecular and clinical pathologist at Cleveland Clinic, AMP board member, and chair of the professional relations committee that authored the report. Any potential or actual patient harm came from physician error, and, AMP points out, “FDA has no authority under the Food, Drug, and Cosmetics Act to regulate the practice of medicine.”

The instances of “non-standard practice” include a pertussis diagnostic test for which results were incorrectly interpreted by physicians, a vitamin D deficiency test for which some calibration materials may have been faulty, and several screening tests which were never intended to be diagnostic.

“When a test happens to be a part of that broader pattern of behavior, it’s unfair to blame the test. It’s actually erroneous and very harmful to patients to blame the test and use that as a rationale or reason for stepping in and regulating all of laboratory developed tests,” Klein contends.  

In addition, AMP contested the source materials used to build the cases FDA presented. FDA said case details came from, “well-documented cases from publicly available information in medical journals, media reports and FDA Warning Letters.” FDA knows of more cases, the report asserts, but only reported ones with sufficient data and no confidential commercial information.

AMP asserts that FDA’s data sources are of particular concern. “Unfortunately, rather than referencing peer reviewed studies published in scientific journals, FDA in this report makes dubious claims, fails to provide significant context for the information provided, and relies on articles from the lay news media to assert its scientific positions,” the AMP response stated.

In a statement to Bio-IT World, FDA defended their source material: “To assess the public health impact of problematic LDTs, we identified 20 well-documented cases from publicly available information in medical journals, media reports and FDA Warning Letters.   We used peer-reviewed sources wherever possible, but not all problems with medical products are reported in the medical literature, and so we relied on media reports in those instances.   All 20 cases were reviewed by the appropriate FDA review division.”  

Challenging Standards of Care

Of the 20 examples, Klein was personally disappointed with the inclusion of the Oncotype DX Breast Cancer test and non-invasive prenatal testing as a class.

The Oncotype DX case is one AMP claims is a fabrication on the part of FDA. Oncotype DX is a test from Genomic Health that predicts risk of breast cancer recurrence in patients with early stage disease. It is the only genomic test for early-stage breast cancer that is included in the National Comprehensive Cancer Center Network (NCCN) and the American Society of Clinical Oncology (ASCO) treatment guidelines.

FDA’s analysis considered one part of that test which looks for a HER2 marker as a standalone LDT. By inappropriately considering just the HER2 marker test and not the full Oncotype DX test as used, “FDA is reporting a case study that does not exist,” the AMP report said.


“They’re taking a test that really helps women. It helps solve a problem and the problem is that women with breast cancer with low risk of metastasis were over treated… It’s simply unfair to mischaracterize it,” Klein said. “They’re taking something widely viewed as an advance and denigrating it.”

As for non-invasive prenatal testing (NIPT), FDA considered cell-free DNA testing as a class, mentioning four tests offered in the U.S. FDA cited concerns with the tests’ validities and expressed concern about false-positive and -negatives rates.

Klein disagrees: “This is a revolutionary test… that appears to be far superior to the current alternatives, which, by the way, are also laboratory developed.”

AMP noted that NIPT is a screening test, not a diagnostic, and that existing treatment guidelines from the American College of Obstetrics and Gynecology and the American College of Genetics and Genomics recommend confirmatory testing. “This falls within the practice of medicine, and FDA oversight would not address physicians who inappropriately follow up on screening tests,” AMP said.

FDA, of course, stands by the report. In a statement, FDA assured Bio-IT World: “We stand by all of the examples, and strongly disagree with the Association for Molecular Pathology’s characterization of FDA’s report regarding the public health evidence for FDA oversight of laboratory developed tests. FDA examined events involving 20 LDTs that illustrate, in the absence of compliance with FDA requirements, that these products may have caused or have caused 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.”

Representative Cases

But regardless of the details of the 20 cases FDA highlighted, AMP asserts that a selection of 20 cases would never be appropriate grounds for changing the way laboratory developed tests are developed as a whole.

“Most important,” AMP’s rebuttal highlighted, “the [FDA] report fails to acknowledge that even if all of the case studies presented had concerns that might have been addressed by FDA oversight (although, this is clearly not the case), these tests are a miniscule fraction of the thousands of LDPs that are designed, developed, validated, and interpreted by appropriately trained and qualified health care professionals.”

This is the sticking point for Klein. “There’s a disingenuousness to the document. It’s so unrepresentative of what goes on in day to day laboratory work. It’s unfair and shouldn’t be used as justification for what FDA is proposing.”

In molecular pathology, almost all genetic and genomic tests are laboratory developed, Klein said, in part to keep up with fast-moving technology. “We’re benefiting patients on a daily basis. We have continual increases in knowledge; the technologies are improving. We rely on really highly trained professionals. Our members are physicians or PhD scientists who have Board certifications in the testing area,” he said. “What the laboratories are really relying on is the expertise of these professionals to supply testing to patients that otherwise wouldn’t be available. We’re the ones bringing discoveries into the clinic to help manage patients.”

FDA regulation for tests would be extremely expensive, costing hundreds of thousands to millions of dollars, Klein estimated. For many AMP members in academic medical centers or major cancer centers, these costs would be prohibitive, Klein said.

“We don’t even get paid for a lot of these tests… Cost of submission for FDA could never be justified… Even for the really large commercial reference laboratories, FDA regulation would be extremely onerous and our members in those settings tell us it would result in discontinuation of many tests.”