Regulation of Emerging Technology

Laboratory Developed Tests Under Scrutiny: FDA Questions Validity and Utility of Oncotype Dx and Prolaris Tests for Personalized Cancer Treatment

Posted on Mar 8, 2016

In November 2015, FDA published a startling report, The Public Health Evidence for FDA Oversight of Laboratory Developed Tests, which enumerated serious concerns with the current framework it uses to oversee laboratory developed tests (LDTs). LDTs are tests used by physicians to diagnose disease, predict risk of disease, and guide critical therapy decisions. This report revealed grave shortcomings in test accuracy, reliability, and ability to provide clinically meaningful information to physicians and patients in a number different tests, ranging from tests to determine personalized oncology treatment, to fetal genetic tests, to tests to predict heart disease risk and pharmacogenetic response to statin therapy. The report listed that testing inaccuracies resulted in false positives, where patients were informed they had a condition they did not have, producing psychological distress and overtreatment. Other tests produced false negatives, where patient illnesses went undetected and the patient failed to receive appropriate and timely treatment.

Under the FD&C Act of 1976, FDA has the authority to regulate LDTs as medical devices, subject to registration, pre-market review, and adverse reporting to ensure the test’s analytic and clinical validity: that product is properly designed, manufactured consistently, and that the test is accurate at what it purports to predict. Up to this juncture, FDA has enforced these provisions with discretion and has not subjected certain LDTs to these regulatory requirements, so FDA has not assessed the analytic and clinical validity of certain tests that are currently on the market and relied upon by physicians. Indeed, FDA admitted concern that physicians and patients are using these LDTs without being aware that some are not FDA approved and that the FDA has not evaluated their analytic and clinical validity.

In 2014, FDA promulgated Draft Guidance Framework for Regulatory Oversight of Laboratory Developed Tests designed to phase in implementation of a more stringent regulatory approval process in the next several years. However, these classifications and requirements are not yet in place, and numerous faulty LDT tests are on the market being actively used and relied upon by physicians and patients.

Oncotype Dx and Prolaris, two LDTs recommended by the National Comprehensive Cancer Network and used by oncologists to aid in treatment protocol for breast and prostate cancer, respectively, were listed in FDA’s report. Both cancers are diseases of high visibility and frequency- almost certainly affecting someone we personally know. In the United States annually, 231,840 women are diagnosed with invasive breast cancer, and 220,800 men are diagnosed with prostate cancer. The aim of such tests lays at the heart of precision medicine– we want more effective strategies that account for individual variability that allows physicians to predict more accurately which treatment strategies for a particular disease will work.

Increasing the effectiveness of treatment, however, assumes that the oncologist’s testing tools are accurate.

Oncotype Dx, manufactured by Genomic Health, assesses 21 genes expressed in a patient’s tumor and a RNA based HER2 test, designed to detect whether the patient’s cancer is HER2 positive or negative. Genomic Health designed the HER2 RT-PCR portion of the test to provide physicians and patients personalized treatment based on this tumor profile with pharmacogenomic implications. Physicians likely believe in the test’s accuracy and reliability- both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) incorporate Oncotype Dx into their treatment guidelines, and the highly respected New England Journal of Medicine recently published a prospective validation of the HER2 RT-PCR component.

Despite the sterling support from the medical community, the HER2 RT-PCR component is not included in ASCO’s guidelines as a test to specifically decide whether certain drugs such as Herceptin, a drug commonly used to treat HER2 positive tumors, is indicated. FDA’s report evaluated evidence set forth by a group of independent pathologists who found discrepancies in test specificity and found the test produced false negatives, missing the diagnosis of patients with HER2 positive tumors and misinforming subsequent treatment decisions. Specificity of HER2 status is imperative to guiding appropriate treatment- patients whose tumor is HER2 positive may elect to add Herceptin to the treatment protocol based on its targeted indication for treating HER2 positive cases. Alternatively, potential overtreatment of patients with Herceptin is not only ineffective, but raises significant risks including cardiomyopathy, pulmonary toxicity, and death.

FDA’s report also profiled Prolaris, manufactured by Myriad Genetics, a prostate cancer biomarker test that examines 46 genes associated with the proliferation of prostate cancer cells and prognosticates the risk of cancer progression and survival rate. FDA assessed that there was insufficient evidence for Myriad Genetics’ marketing claims and questioned the test’s ability to meaningfully improve clinical outcomes, concluding that physicians relying on this test may over or undertreat patients accordingly. This is particular disconcerting because physicians do in practice rely on the result of this test, one study showing it impacted 65% of physicians’ treatment plans. The ramifications of overtreatment of prostate cancer are also considerable. Patients who elect to undergo a radical prostatectomy face a 70% risk of impotence, 25% risk of complete incontinence, and loss of fertility.

The accuracy and validity of such LDTs constitutes a critical key in both physicians’ clinical judgment and informed decision-making by patients when diagnosing illness and deciphering appropriate corresponding care. It is imperative that both physicians and patients be aware that these tests, as well as select other widely relied upon molecular diagnostic tests, are not currently FDA approved to ensure their accuracy and reliability despite any evidence set forth by the corporation offering the LDT and rely upon them with caution.

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