altona Diagnostics Receives Emergency Use Authorization for Zika Virus Diagnostic Test

On May 13th, altona Diagnostics received Emergency Use Authorization (EUA) from the FDA for their RealStar Zika Virus RT-PCR Kit U.S. for the qualitative detection of RNA from Zika virus in serum or urine (collected alongside a patient-matched serum specimen) from individuals meeting CDC Zika virus clinical criteria. This is the same kit that Houston Methodist Hospital and Texas Children’s Hospital used for their laboratory-developed Zika test.

FDA Letter of Authorization

altona Diagnostics press release


AMP Submitts Written Testimony about LDTs

From the press release:

“The Association for Molecular Pathology (AMP), the premier global, professional society serving molecular diagnostics professionals, yesterday submitted written testimony to the House Energy and Commerce Subcommittee on Health for their hearing on “Examining the Regulation of Diagnostic Tests and Laboratory Operations.” AMP urged the Committee to use AMP’s proposal to modernize the Clinical Laboratory Improvement Amendments (CLIA) at the Centers for Medicare & Medicaid Services (CMS) as the basis for legislation that would preserve innovative patient care by building upon the current CMS-based system for oversight of laboratory developed procedures (LDPs).

‘Molecular pathologists are highly trained professionals and our professional judgment is used throughout the design, validation, performance, ongoing monitoring, and interpretation of test results. It is our mission to ensure that patients have access to innovative, accurate, reliable, and medically useful laboratory testing procedures,’ said Roger D. Klein, MD, JD, AMP Professional Relations Chair. ‘The AMP CLIA Modernization proposal preserves patient access to essential laboratory services that would no longer be offered if a costly FDA-based regulatory system were imposed upon academic medical centers, cancer centers, hospitals and small independent laboratories,’ he added.

To read the press release in full, visit

Regulation of Laboratory Developed Tests (LDTs) – Revisited

Two years ago this coming September I posted a blog about the FDA’s intent to regulate LDTs and the need for laboratory professionals to both keep an eye on what happens and to be a part of it. I believe it’s time for an update on what has been happening and a further exhortation to stay involved.

The FDA is definitely going to regulate all LDTs. This is no longer a future possibility, but is now an approaching reality. In October of 2014, the FDA put out two new draft guidance documents for 120-day comment periods. One document, “Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs)” lays out the FDA’s various risk categories and classifications for different LDTs and also lays out the FDA’s timeline for enforcing regulation of them. The second document, “FDA Notification and Medical Device Reporting for Laboratory Developed Tests (LDTs)” delineates how labs will report their LDT testing to the FDA and the protocol for adverse event reporting to the FDA, which all labs performing LDTs will be required to do.

During the 120-day comment period, many groups commented, weighing in on their perspective about the FDA regulation of LDTs. AACC and the Association for Molecular Pathology (AMP) published position statements. CAP Today did a comprehensive article. Although nearly everyone agrees that some form of LDT regulation is necessary, there is a wide range of opinions on what that regulation should entail, and even who should ultimately be responsible for it.

Despite many suggestions that perhaps the FDA should approach this regulation differently, they plan to move forward. Their “Framework . . .” document lays out about a nine-year timeline for regulating all LDTs, starting first with the highest-risk group. LDTs will broadly be classified into three groups: low-risk, which are also known as “traditional” LDTS, moderate-risk and high-risk. Traditional LDTs are those developed by a single lab for use on a single patient population. This classification will cover many hospital-based LDTs and it will have the least rigorous regulation by the proposed guidance documents. Moderate and high-risk LDTs will be tackled first by the FDA and will require pre-market review and approval as part of the regulatory requirements.

The FDA is perhaps listening to some of the comments being generated however. Most recently the FDA has announced that an interagency taskforce will be formed to deal with LDT regulation. Currently that task force includes the FDA and CMS, although many laboratory associations are hoping it will be expanded to include more groups. As laboratory professionals, it’s up to us to stay informed of this new regulation headed our way, and to do our best to be involved in the process.

-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

Why We Should Care and Act on the Proposed FDA Regulation of LDTs

So, I wrote briefly to bring awareness about this topic when the U.S. Food and Drug Administration (FDA) first formally proposed in July of 2014 that they intend to begin regulating laboratory developed tests (LDTs). Now that draft regulations have been released, I want to encourage you to not only learn more about this issue but also to decide where you stand and most importantly, to act — to add your individual voice to strengthen a collective voice, whichever side of the argument you choose to stand by. You can read the FDA’s proposed Framework for Regulatory Oversight of LDTs (which are currently non-binding recommendations) to help decide your opinion on this issue.

Congress declared that most diagnostic tests are considered “medical devices” in the Medical Device Amendments (MDA) of 1976. The FDA oversees medical device regulation, but until recently, had only exercised “enforcement discretion” with respect to LDTs. There are 3 classifications for a medical device based on the presumed risk and regulation thought necessary to ensure validity and safety: class 1–general controls for devices considered low risk for human use, class 2–performance standards for devices considered moderate risk for human use, and class 3–premarket approval for devices considered high risk for human use.

So, what is a LDT? Lab developed tests are neither FDA-cleared or approved and are validated and performed in the same lab in which they are developed. While the majority of molecular genetic pathology tests that are currently offered in clinical labs are LDTs (often referred to as “home brew” or “in-house developed” tests), labs can—and do—develop tests for all areas of the laboratory. They would most likely fall under class 2, or for the more highly complex tests, class 3. And the time is now for the pathology workforce to show their value as the diagnostic experts in the development, validation, and interpretation of such tests.

The completion of the Human Genome Project and the basic and translational research that followed has ushered in a new clinical practice landscape. Personalized or precision medicine is a buzz word often touted in the media these days. I was a graduate student researching transcriptional regulation and signal transduction pathways during the Human Genome Project. It was an exciting time where those of us in research could imagine a future where our discoveries would form the foundation for clinical decisions to treat disease. It was a dream that we knew would take at least a decade to begin to achieve its first nascent steps. But personalized/precision medicine, albeit still immature, has arrived and is progressively demanding our care and attention.

It is a term that can be employed to incorrectly exaggerate the implications of diagnostic tests. It can be especially dangerous when misused to support testing that lacks a transparently or rigorously vetted validation process. And inflated clinical claims by a handful of test providers have focused the FDA’s attention in the direction of LDTs. No one disagrees that these highly complex diagnostic tests should require both analytic and clinical validation and continuous monitoring. The questions are who is the best to ensure that these parameters are met? And how can we best encourage the flexibility necessary to incorporate innovation and new discoveries into timely clinical care?

Currently, the Centers for Medicare and Medicaid (CMS) are charged with overseeing all clinical laboratory testing and enforcing adherence to Clinical Laboratory Improvement Amendments (CLIA) that regulate testing on patient specimens. So, all LDTs are under the purview of CLIA regulation and their analytic validation is reviewed biannually. However, CLIA does not address clinical test validity which falls under the FDA’s purview over medical devices during the PMA process. These two regulatory schemes are meant to be complementary and the FDA also includes a more rigorous analytic validation process.

Many clinical labs also participate in the College of American Pathologists (CAP) peer-reviewed biannual inspection process which has requirements more comprehensive than those currently required by CLIA. And having just co-inspected a new molecular genetic lab for the CAP last week, I can state that I believe in the peer-review inspection process. Inspectors must have specific and extensive training in the inspection topic area(s) in order to be certified to inspect those types of labs after successful completion of a certification process. We also have access to resources available through a large network of volunteer inspectors and CAP support so that we are not overburdened and can perform a thorough inspection. Those of us who are certified inspectors also hold the conviction that fastidiously enforcing compliance to accreditation standards is the best for patient care. This is because we know that we are the frontline–we not only know how to develop and validate these tests but need to make sure that other labs follow the same standards.

The average time and cost to complete the FDA approval process from concept to market can be prohibitive to patient care, on the order of 3-7 years and an average $24 million for a successful PMA. Even the time for 510(k) fast track FDA premarketing notification for class 2 devices that are “substantially equivalent” to a pre-existing marketed device (predicate) in terms of safety and effectiveness averages at least 6 months and this process has been criticized as flawed by the Institute of Medicine (IOM). Additionally, both the time and cost for approval have progressively increased over the years, making it more difficult to obtain with the exception of highly financially solvent commercial labs.

At this point, I want to be very clear that these are my personal opinions and not those of any of the organizations that I am affiliated with who may hold more moderate or opposing opinions to mine. Since we all have personal bias, I’ll fully disclose mine: 10 years of basic science research utilizing molecular and cell biology and transgenics, completion of a basic science graduate degree with molecular based research, a future molecular genetic pathology (MGP) fellowship, and hopefully, a future career as a public health (molecular epidemiology/biomarker discovery) focused physician-scientist practicing diagnostics and molecular hematopathology research. So I may have a more vested interest toward a particular view. But what is most important to me and one of the reasons I blog, is that others become aware and inspired to become more informed and engaged in the public health policy process, not that they necessarily agree with me.

Let me give an example of where I stand on this issue which I feel would be a more cogent argument than merely stating my opinion. Advanced non-small cell lung cancer (NSCLC) patients without an EGFR mutation prior to the discovery of the EML4-ALK fusion protein had very few effective therapeutic options. The FDA gave accelerated approval in August of 2011 and regular approval in November of 2013 for the use of crizotinib, a tyrosine kinase inhibitor, for ALK-positive lung cancers diagnosed with a break-apart probe ALK rearrangement fluorescent in-situ hybridization testing kit (Abbott Vysis) on genomic material derived from formalin-fixed paraffin embedded tissue.

Subsequently, ROS1, another tyrosine kinase like ALK, regardless of fusion partner, has also been shown in NSCLC to show 72% tumor shrinkage in response to crizotinib. Since there is no FDA-approved companion test for ROS1, under the current definition of an LDT and proposed regulation (of which this would fall under “LDT for Unmet Needs”), patient specimens would either need to be sent to a lab with an FDA-approved LDT to detect ROS1 rearrangement (of which, none currently exist) or receive diagnosis and treatment at the same facility that has a developed LDT. Currently, these types of specimens can be sent to one of the CLIA-approved labs for this test and the patient treated at their home institution.

Additionally, since the aforementioned FDA approval, genomic material derived in cases of tissue limitation from cytology specimens (eg – pleural effusions) and tested through alternative methods (IHC, qRT-PCR) has been shown to yield at minimum, similarly sensitive, and concordant results. Access to these options would be unavailable if the labs that developed these LDTs could not afford the cost to undergo the FDA PMA or 510(k) process. And even if labs could afford these costs, these tests would not be available to patients in a rapid enough timeframe from the initial discovery of a biomarker and its responsiveness in clinical trials to a targeted therapeutic. If FDA regulation of LDTs does become a reality, what I would like to see is an interdisciplinary conversation that results in an expedited approval process that would still ensure test validity and patient safety.

In response to healthcare reform, many academic based labs are increasingly implementing multidisciplinary clinical care and research teams and utilizing highly complex testing platforms such as next-generation sequencing and microarrays to guide diagnosis, prognosis, and/or treatment. More so now than ever before, healthcare professionals and trainees need to learn to continuously evaluate and practice evidence-based medical care – to really scrutinize whether these tests are valid, safe, and efficacious before recommending them to their patients. The highly dynamic and fast-paced momentum of “-omics” based research demands timely recognition, clinical validation, and test incorporation in order to provide the most up-to-date personalized/precision medical care. Government regulation has proven in the past to be unable to adequately meet this challenge, but I do admit that it is possible. So the time has come for stakeholders (and I hope you realize that you are one) to become informed and stand united behind their principles on this topic. Advocacy is a potentially powerful way that we can shape the current and future healthcare landscape that we will navigate as practitioners and patients. Many of our pathology and other subspecialty advocacy organizations have come out with position statements and signed on to currently available petitions. So FIND YOUR VOICE, STAND UP, and BE COUNTED!

A recent and well-written blog post by a current patient with metastatic lung cancer on this topic can be found at


  1. Centers for Medicare and Medicaid (CMS). CLIA Overview: Frequently Asked Questions. Published online on 10/22/13. Accessed on 2/15/2015 at
  2. A Gutierrez, RB Williams, GF Kwass. FDA’s Plan to Regulate Laboratory Developed Tests (webinar powerpoint). Published online on 9/3/14. Accessed on 2/15/15 at
  3. Institute of Medicine (IOM). Medical Devices and the Public’s Health: 510(k) Clearance Process. Released 7/29/11. Accessed on 2/15/15 at
  4. National Cancer Institute (NCI) at the National Institutes of Health (NIH): Clinical Trials at Crizotinib Improves Progression-Free Survival in Some Patients with Advanced Lung Cancer (updated). Last updated on 12/4/14. Accessed on 2/15/15 at
  5. Schorre. How long to clear 510(k) submission? Published online on 2/2014. Accessed on 2/15/15 at
  6. H Thompson. How much Does a 510(k) Device Cost? About 24 Million. Published online on 11/22/10. Accessed on 2/15/15 at
  7. KM Fargen, D Frei, D Fiorella, CG McDougall, PM Myers, JA Hirsch, J Mocco. The FDA Approval Process for Medical Devices. J Neurointervent Surg, 2013; 5(4): 269-275. Accessed on 2/15/15at


-Betty Chung, DO, MPH, MA is a third year resident physician at Rutgers – Robert Wood Johnson University Hospital in New Brunswick, NJ.

CLSI Publishes New Guide for Laboratory-Developed Tests

From the press release:

“The Clinical and Laboratory Standards Institute (CLSI) has published Quality System Regulation for Laboratory-Developed Tests: A Practical Guide for the Laboratory.This guide converts the requirement complexities of US Food and Drug Administration (FDA) regulations into plain language, offering intuitive assistance on how to conform to the Quality System Regulation (QSReg), 21 CFR 820, when creating laboratory-developed tests (LDTs). This CLSI practical guide can help laboratorians learn how to address the new demands, beyond the Clinical Laboratory Improvement Amendments (CLIA) regulations, within their unique laboratory settings.

“LDTs are in vitro diagnostic devices that are intended for clinical use and are designed, manufactured, and used within a single laboratory. This practical guide is intended to clarify how to implement the QSReg that may be required for some classifications of LDTs. On October 3, 2014, the FDA issued draft guidance for regulating LDTs that includes notification or registration of LDTs with the FDA, reporting adverse events, and other requirements. This document only addresses the QSReg that is currently applicable to manufacturers and is expected to become applicable for some classifications of LDTs when the final guidance is published.”

To purchase this guide for your laboratory, visit the CLSI website.

LDTs: Public Perception

It seems like everyone is getting into the act these days, related to the regulation of laboratory developed tests (LDTs). Even politicians and lawyers are talking about LDT regulation. A recent online post ( reported that several lawmakers are now writing to the Office of Management and Budget (OMB), asking it to quickly approve the FDA’s guidance document for FDA regulation of LDTs, in order to protect the public from the depredations of the evil lab people developing tests that will harm the public. That last clause is my paraphrase of course, but is not that far off what the post actually says.

The harm in posts like this is that the general public, including lawmakers and politicians, have no understanding of the laboratory field in general, and definitely no understanding of the regulatory environment that all reputable labs operate under. The majority of hospital labs and big reference labs are accredited and operate under the regulations of an accrediting agency including such agencies as CMS, CLIA, various State regulatory bodies, CAP and The Joint Commission. The combined regulations of these agencies result in labs which not only produce test results using good laboratory practice, but when these labs develop tests (LDTs) they do so meeting many regulatory standards already. FDA oversight of these labs is overkill, in my opinion.

Where FDA oversight of LDTs would be useful is in the plethora of start-up companies offering the public a variety of tests to diagnose disease, monitor their health, or determine their genetic code. Many of these labs have no accreditation and have used LDTs as a loophole for bypassing FDA regulation of their tests. In fact it’s likely that many of them are in need of regulation from some agency.

John Q. Public in general is just beginning to understand what a lab test is. He has no idea that he should be looking for an accredited lab, and asking for some sign that minimum standards were used to develop tests. He simply Googles his symptoms and gets 4 million options for lab tests he can have run to diagnose his disorder. Laboratory professionals have an obligation to try harder to educate the public. We need to be involved and be visible. FDA regulation of laboratory tests is a “hot” issue currently that is being picked up by the public. We should take every opportunity to set the record straight.



-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.