False-negatives have the potential to greatly impact on patient care when a test results in a negative result, when the disease or condition is actually present. Since the FDA have been looking to control LDTs, new data has come out (courtesy of the FDA, funny that) showing their most recent document of 20 Laboratory Developed Test (LDT) case studies of and their impact on society. For those who have time, I’d recommend reading the Public Health Evidence for FDA Oversight of Laboratory Developed Tests that takes you on a journey through some of these alarming statistics/results. This being said, I’m slightly biased that you’re in the right place, enjoy my short summary below.
However, before I begin, I must point out that in a previous post I covered the various biomarkers involved in breast cancer, HER2 being the largest biomarker targeted by the largest cancer drug currently in the world: trastuzumab. Which leads me to my next point, although I’m not too sure why the FDA focused on this therapy in particular, its market share, popularity and application may be some of the reasons why they chose this in combination with Genomic Health’s OncotypeDX: A 21-gene signature test (including HER2), the Oncotype Dx test provides individualized breast cancer treatment options and recurrence risk estimates based on the genes expressed in a tumor.
In the report, the FDA argues that, despite the contention from some that “CLIA is enough,” the tes
ts described in their report were offered from laboratories following the minimum requirements of CLIA. Using some logic there and going on the data I’m providing below (sorry – spoilers), I think they’re saying “CLIA isn’t enough”, right??
The FDA’s case study: Oncotype DX HER2 Breast Cancer RT-PCR Test
|LDT Name||Oncotype DX HER2 RT-PCR|
|Description||Rapid PCR test for tumor HER2 receptors|
|Purpose||Use HER2 receptor level to guide treatment|
|Target Population||Newly diagnosed Stage I and II breast cancer patients|
|Alternatives||FDA-approved HER2 receptor tests|
|LDT Problem 1||Test has poor sensitivity – many tests reported as normal HER2 levels will actually have high HER2 levels|
|Clinical Consequence||Patients with false-negative tests won’t receive appropriate treatment, and cancer may progress|
|Potential Impact of FDA Oversight||Assurance the test meets minimum performance standards|
|Cost Impact of Inaccuracy||$775,278 estimated cost per false-negative case|
Table: The FDA saying it as it is. $775,278 is a lot of money! But if you think about it….it’s someone’s life, seriously. Which is worth more?
How is this calculated?
(Warning, read on only if you’re a techy geek): Ultimately, it’s (wait for it) “the social cost when a patients fail to receive appropriate trastuzumab therapy”. Got it? No? Okay here we go: You can arrive at this number by multiplying the number of years a patient could gain from appropriate cancer treatment by the value of a statistical life-year (VSLY), also known as Quality of Life Years (QUALY) by NICE. Currently, standard estimates for the VSLY are $129,213, $258,426, and $387,639.
Furthermore, the projected life expectancy is 3 years longer for HER2 positive patients who receive trastuzumab in addition to chemotherapy, compared to those receiving chemotherapy alone.
The FDA-patented equation therefore comes out as:
Cost = ((life expectancy with drug) – (life expectancy without drug)) x middle VSLY
Voila! Nailed it. The cost to society for each patient who fails to receive trastuzumab comes out as a cooly calculated $775,278. My life insurance policy isn’t even worth that – thanks FDA, quite generous.
Why is this happening?
It’s probably worth pointing out that this is the whole point of what the FDA is trying to point out…. Laboratory Developed Tests (LDTs) by definition are not FDA-approved, and the FDA want power of oversight. In Oncotype DX’s case, the underlying issue is that there is no demonstrated direct correlation between number of RNA copies of the gene and the number of protein copies on the cell surface. 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.
You may think the FDA has unfairly singled-out Oncotype DX. However, as much as I hate to say it, but they may have a point. For example, in 2014, the LDT missed all three HER2-positive patients included in a study by Park et al., 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.
What does this mean?
In a previous post I covered an EQA scheme which should up to 28% of laboratories reported incorrect results (the majority being false-negative). What the FDA is highlighting through these case studies that this ‘problem’ isn’t confined to a single one test. I further must caveat that the RNA-based form of HER2 test is not included in the guidelines issued by the American Society of Clinical Oncology (ASCO) as a test to be used to decide whether trastuzumab is indicated.
What do we need?
Do we need more cake analogies? (Thanks for getting in touch John!) Probably not. Do we need more difficult concepts and more regulation? That’s a tricky one…However, I do know there’s a lot of improvements to be made in the industry when a life is in the balance, something I’ve stressed before: accuracy is still king, even in LDTs. I don’t have all the answers, but better education of patients and clinicians on the proper use and limitations of new genomics-based diagnostics would, in my opinion, be a great start.