publication date: Jan. 8, 2016

AMP Responds to FDA Report

On Regulation and Oversight 


The Association for Molecular Pathology responded to the FDA’s call for oversight of laboratory developed tests, rebutting 20 case studies published by the federal agency that illustrated possible harms inflicted on patients when laboratories did not follow FDA requirements.

The AMP said the agency’s collection of case studies “grossly misrepresents the public health concerns of laboratory developed testing procedures,” and said that FDA oversight would likely prevent few of the potential patient harms.

In the case of clinical trials performed at Duke University using a faulty genomics predictor to assign cancer treatment to individual patients, the AMP said that that test did not cause patient harm, and was not used in a clinical setting.

Ahead of a congressional hearing on the role of the FDA in November, the agency offered warnings of the dangers of marketing tests without proven clinical validity, and listed the possible harms from false positive and false negative results. (The Cancer Letter, Nov. 20.)

The AMP said that asking academic medical centers, hospitals and health systems, and cancer center laboratories to submit lab-developed tests to FDA for pre-introduction approval would be financially and administratively infeasible. “Any such service for which FDA-clearance or approval is required will very likely cease to be offered, and patients will lose access to innovative and accurate laboratory testing procedures,” the association said.

“The 20 tests described by FDA are mostly a hodgepodge of outlier assays including tests that were never offered, tests for which comparable FDA assays perform poorly, tests for poorly defined disorders with psychologic components, and use of an FDA-approved test off-label,” said Roger Klein, professional relations chair of the AMP. “Also included are examples of tests that are widely regarded as major scientific breakthroughs and which are recommended in major medical guidelines.”

The association said that the CLIA program, run by the Centers for Medicare and Medicaid Services, would be a better choice than the FDA for addressing the problems posed by laboratory developed tests. The CLIA program covers approximately 251,000 laboratory entities, according to CMS.

“AMP believes that the most reasonable and effective path forward is for Congress to insist that the CLIA program modernize, expand its current network of third party medical experts, and utilize scientific expertise from FDA and CDC rather than relinquishing its duties regarding the accuracy and reliability of [laboratory-developed testing procedures, or LDPs],” said AMP President Charles Hill.

“AMP strongly urges the Department of Health and Human Service [sic] 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.”

The AMP report, published Dec. 13, is titled: “Facts FDA Ignored: An analysis of the FDA report, ‘The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies.’”

The association’s report said that, in some of the FDA’s examples, the patient harms stemmed from issues that would not be solved with FDA oversight, such as problems “with treating physicians using treatments outside accepted medical practice,” or “failure of treating physicians to follow up a screening test with a diagnostic confirmation test.”

In the FDA’s specific example regarding genomic assays used in three clinical trials at Duke University, the AMP said that the “test was not offered in a clinical setting and did not cause patient harm,” even though the assays were directly used to assign patients to specific cancer treatments, on the claim that the tests could predict an individual patient’s response.

One patient in the Duke trials, breast cancer survivor Joyce Shoffner, spoke with The Cancer Letter, detailing the biopsy procedures she underwent and the side effects of her subsequently assigned chemotherapy treatment. Altogether, 117 patients were enrolled in the Duke trials (The Cancer Letter, May 22).

The case of the faulty predictors used in the trials led to an investigation conducted by the Institute of Medicine—and the retraction of scientific papers in Nature Medicine, the Journal of Clinical Oncology, and the New England Journal of Medicine, among others, totaling 27 complete or partial retractions, according to the FDA’s report.

In court, attorneys for Duke also stated that no patients were harmed in its clinical trials.

“Plaintiffs cannot show that a different course of treatment would have made any difference in their care or chance of survival,” reads a motion filed by the university’s attorneys in January. “Expert testimony in this case has not established that any clinical trial available in the United States in 2010 would have prolonged plaintiffs’ life expectancy or treated them more effectively. Therefore, plaintiffs cannot meet causation of damage elements of their negligence per se claim.” (The Cancer Letter, Jan. 23.)

The AMP said that FDA ignored certain facts in its report when citing the Duke case, namely that “the controversies surrounding the clinical trials in question resulted from investigator misconduct and data falsification involving this NIH-supported research,” and not due to the performance of a laboratory-developed test itself.

“The trials were initially suspended and then permanently stopped in 2010. Interestingly, FDA reviewed one of the studies in 2009, several years after its initiation, and concluded that the study would require an Investigational New Drug application, which had not been submitted,” the AMP report said.

“An FDA audit in 2011 further showed that an Investigational Device Exemption application had not been filed, but otherwise found no significant deficiencies in Duke’s Institutional Review Board conduct. FDA oversight of LDPs is unlikely to have solved problems of research data falsification and investigator misconduct.”

The AMP’s conclusion was that the test was not offered in a clinical setting and did not cause patient harm, and that FDA review “would not uncover scientific misconduct and data falsification within a broader research study.”

Regarding the report produced by the Institute of Medicine in the aftermath of the Duke controversy, the FDA report said: “In the IOM’s assessment, greater FDA oversight and involvement may have uncovered errors and validation issues before the test was used in clinical trials…At a minimum, said the IOM, researchers should discuss LDTs with FDA prior to initiating validation studies, particularly when the test is intended for future clinical use.”

Regarding the FDA’s case of the Oncotype DX breast cancer recurrence test, the AMP said the test’s HER2 biomarker is not intended to be used independently for therapy decisions, including the use of trastuzumab. “FDA seems to presume an intended use that does not exist,” AMP wrote in its report.

“There is no distinct [laboratory-developed test] called ‘Oncotype DX HER2 RT-PCR.’ The Oncotype DX Breast Cancer Test is a standard of care test that predicts risk of breast cancer recurrence in patients with early stage disease. This information is extremely useful to oncologists in eliminating overtreatment of low risk patients. Although HER2 is among the markers in the test, it is not intended to be independently used for therapy decisions,” the AMP report said.

“Although treating physicians requested the individual information for HER2 as a comparator for the commonly used HER2 tests, which occasionally yield ambiguous results, the HER2 information provided as part of the Oncotype DX Recurrence Score must be assessed by physicians in the context of the other clinical and laboratory data in their evaluation of the patient.”

The FDA said the HER2 test had poor sensitivity, and that many test samples that were reported as having normal HER2 levels actually had high HER2 levels.

“The underlying issue is that there is no demonstrated direct correlation between number of RNA copies of the gene, the basis for Oncotype Dx HER2 RT-PCR, and the number of protein copies on the cell surface,” the FDA’s report said. “As a consequence, it is not possible to infer that high or low amounts of RNA correspond to high or low amounts of HER2 protein.”

“In 2011, a group of prominent pathologists from three independent laboratories found discrepancies between this HER2 RT-PCR and the FDA-approved tests. The LDT reported large numbers of tumors that tested positive on FISH-HER2 as equivocal (33% of FISH-positive cases) or negative (39% of FISH-positive cases).

“In 2014, the LDT missed all three HER2-positive patients included in a study, diagnosing two as negative and one as equivocal. As a result, the two patients who tested HER2-negative failed to receive trastuzumab, placing them at higher risk for cancer progression.”

The FDA report estimated the cost of each false-negative at $775,278.

The AMP’s conclusion was that the “Oncotype Dx Breast Cancer Test is used to predict risk of breast cancer recurrence in patients with early stage disease, not to guide decisions about the use of trastuzumab. The test is valid for its intended purpose and FDA review would not have revealed any issues with analytical and clinical validity.”

A PDF of AMP’s report is available on their website.

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