management/administration – Page 18

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 In October of 2014, the FDA put out two new draft guidance documents for 120-day comment periods.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.

What’s That Interference?

I’ve heard it said that there is no such thing as a lab test with no interferences, and I have to admit, I believe that to be true. For every method devised to measure a specific analyte, something else can interfere with that measurement. For example, photometric measurements using absorbance assume that only the analyte of interest absorbs light at the wavelength being used. Quite often, many other compounds absorb light at that wavelength as well. In chromatography methods, we assume only the compound of interest elutes from the column at a specific time point, and again, many other compounds often do. Various types of mass spectrometry are touted as specific for the compounds being measured, however, even using mass spectrometry, compounds may fragment in similar patterns when looking at mass spectra, or fragment into the same size precursor and/or product fragments using tandem MS.

Thus, we routinely report test results knowing that most often what we are reporting is accurate. However, we must always be aware that the result we’re reporting may not be accurate due to interferences.

I recently had an occurrence related to test interference. Like all such cases, the tech responding to the clinician’s call used our standard response. He located the original sample and repeated the test. The assay gave the same results on the repeat and the result was reported back to the clinician as real and accurate, even when questions were raised by the healthcare staff about the result not fitting the clinical picture. And in fact, although the result was reproducible and in the realm of possibility, in this case the result was wrong.

The analyte in this case was plasma free hemoglobin which is performed in our lab by an assay which measures absorbance at one of the wavelengths at which hemoglobin absorbs light and subtracts a background wavelength reading. The test was persistently giving very high plasma free hemoglobin results even though the patient had no other evidence of hemolysis. When the healthcare staff became adamant about the discrepancy, the sample was sent to an outside lab which performs the assay using a full spectrophotometer, and the sample was found to have no hemoglobin present. An interferent in this patient’s sample was being measured as hemoglobin by our method.

Of course, once it’s been determined that a test is experiencing interference the next question from the healthcare provider is always, what is interfering? That’s a much more difficult question to answer, although occasionally it can be answered with some investigation. Looking into the patient’s drug regimen can help, as well as checking other health parameters to see what else is occurring. In the case of the elevated plasma free hemoglobin, the patient did have an elevated myoglobin which may have interfered.

The take home message here is that no matter how reproducible the results are, interferences are possible. As laboratory professionals, we should always be ready to look for ways to prove our results other than by repeating them, especially when the result does not fit the clinical picture and is being questioned by our healthcare colleagues. Sending the test to be run by a different method is one good way of determining interference. Another way is to check the patient’s chart for drugs or other substances that are known to interfere and are listed in the package insert. Finally, understanding the realities of assay interferences, and being willing to continue looking for answers is also important in the laboratory.

MERS Outbreak in the Republic of Korea

Lablogatory spoke to Kyung Jin Cho, PhD, from the Department of Health and Environmental Science at Korea University about the current outbreak of MERS in the Republic of Korea. This is what he had to say.

Lablogatory: What can you tell us about MERS in the Republic of Korea?

Dr. Cho: MERS is a viral respiratory infection caused by Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The MERS-CoV belongs to the coronavirus family (beta coronavirus). Many MERS patients developed severe acute respiratory illness with symptoms of fever, cough, expectoration, and shortness of breath. The cause of MERS is not yet fully understood. Some infected people had mild symptoms or recovered. Incubation period is known as 2-14 days. The incubation periods are still under dispute since a few cases in Korea reported incubation periods longer than 14 days. Fortunately, the MERS outbreak appears to be subsiding with one or two new cases are reported daily. Many people under the house quarantine at the peak of MERS outbreak are now released.

STATISTICS
The Korean MERS portal reported that there are 27 deaths from 175 cases as of June 23, since the first MERS patient was confirmed on May 20, 2015 (Fatality rate: 15.4%). Most of the people who died had an underlying disease such as chronic lung and kidney disease, cancer, and diabetes mellitus. Of the 27 deaths, 74.1% were male and all were over the age of 40. Of the 175 confirmed cases, male 107 (61.1%), female 68 (38.9%); the Inpatient/outpatients 80 (45.7%), family members/visitors visiting sick persons 62 (35.4%), staff and other hospital employees 33 (18.9%). Most of the MERS cases were infected within the medical facilities. The cumulative number of released individuals from quarantine is 10,718. The current number of isolated is 2,805 (home 2,091 and institution 714).

Lablogatory: How fast is it traveling within Republic of Korea?

Dr. Cho: The major second place of MERS spread was a mammoth hospital which is a top-class institution in Seoul. Within a large hospital, the Hospital S, nearly half of the cases (82 of 166 cases, As of Jun 20, 2015) were exposed to the MERS during June 5th through June 10th. The hospital S admitted the 14^th case of MERS and became the epicenter of the second generation of MERS cases. The health authority failed to carry out timely control measures against MERS. The authority and the hospital S were harshly blamed for the late response in the beginning of MERS outbreak.

During the MERS outbreak, a few doubtful MERS patients roamed about a few institutions. Some local hospitals had to refer their untreated cases to the tertiary hospitals located in big cities, like Seoul or Busan, which have excellent specialists and more resources. Unfortunately, some of the hospitals could not cope with the unexpected MERS outbreak. The triage systems in some medical institutions and the house quarantines were not operated successfully at the beginning, which contributed to the spread.

Lablogatory: Beyond the basic protocols, what other measures are being put in place, or SHOULD be put in place to stop the spread of this virus?

Dr. Cho: The Government’s rapid-response team (RST) should have activated much earlier. Government should have timely announced the list of hospitals in which MERS cases appeared and should have issued the compulsory order for the closure or partial closure of the few target hospitals much earlier. We realized that there are too few officials who are working for the government as experts in the epidemiology.

Also, the number of efficient Airborne Infection Isolation Room (AIIR) is largely insufficient. The possibility of MERS spread within the patients’ rooms and emergency room might be much higher than we would have expected.

Even though the government and some hospitals didn’t make timely responses, they disclosed the list of 84 hospitals (As of June 20th, 2015) that had MERS cases onset or MERS cases passed by. They also announced the list of 251 safe hospitals so that general citizens and respiratory patients can take the treatment under the safe conditions.

Seoul City authority asked citizens of Seoul to report MERS outbreak to Dasan Call Center (120) or official website of the Seoul metropolitan city. Citizens of other areas can report the outbreak to Korea government’s official website.

Through text messages or phone calls, the Hospital S tried to reach all the people who visited the Hospital S during the periods of high MERS exposure. Most of citizens are now well complying with the government measures.

Since some MERS patients in Korea exhibited symptoms beyond the two-week latency period, local health authorities will maintain a tent at the entrance of the town for more five days with staff to monitor if any villagers show symptoms.

The health authority is monitoring three hospitals intensively ( Hospital G in Seoul, Hospital A in Chungcheong province and Hospital G in Busan) that could possibly become new epicenters for the spread of MERS.

Lablogatory: How should institutions protect laboratory workers? What steps can clinical laboratory scientists take to protect themselves?

Dr. Cho: Information can be found here:“The Guidelines on Diagnostic Testing for MERS.” These guidelines include information about specimen collection, transport, and testing.

Continue reading “MERS Outbreak in the Republic of Korea”

Computers and Diagnostic Algorithms

As sophisticated as computers are now, isn’t about time we began using them more to help with the diagnosis of disease? Physicians tend to be diagnosticians, and primary care physicians need to have a massive breadth of knowledge these days in order to correctly diagnose the multitude of disorders in patients that may walk through their doors. The same goes for ER physicians. Currently, new doctors are relying more and more on information at their fingertips rather than information remembered. Perhaps relying even more on computers than we already do makes sense. Currently, we routinely use simple computer algorithms in clinical laboratory testing. Things like test results above an AMR causing the computer to direct the instrument to dilute and repeat the assay on that sample before reporting a result. Or diagnostically, a negative monospot test for Epstein Barr Virus (EBV) on a child under 4 years of age can be programmed to automatically order an EBV IgM and IgG, since the utility of the monospot test is unclear in that age group. This sort of “reflex” testing is already in use, and requires no operator intervention.

Here’s an example of a diagnostic approach that could be used: A sick infant comes in to the ED and has blood work run immediately. The initial results show a low pH, low bicarbonate and high pCO2. When a software program sees that combination of results, it could reflexively order more tests based on the differential diagnoses associated with a high anion gap metabolic acidosis (for example, ordering a blood glucose to detect diabetic ketoacidosis). If that is ruled out, the software then looks at the next most common cause of metabolic acidosis, and so on. The computer would not be diagnosing the child; the software would simply be ordering the appropriate next step tests to allow a rapid diagnosis, and probably doing it faster than the average multi-tasking ED doctor.

Software-based diagnostic systems exist and are on the market. So why are we so slow to adopt these systems into everyday use? We should let technology help us as much as we can. Software-based diagnostic systems have not been shown to be better than humans for diagnosing (http://www.nejm.org/doi/full/10.1056/NEJM199406233302506), and may never be. However, I would opine that they are faster than humans at deciding what tests to order based on lab results, or on a combination of lab results and clinical signs and symptoms. Using them this way would then leave the human to human interactions and the final diagnosis to the doctor and his patient when he has all the necessary test results at hand.

Food and Drug Administration and Next Generation Sequencing

As readers of this blog are probably aware, The Food and Drug Administration (FDA) is currently considering how to tailor its oversight of Next Generation Sequencing (NGS), methodologies that can produce extremely high quantities of genetic sequences. In turn, these sequences can be used to identify thousands of genetic variants carried by a particular patient. NGS will usher in an age of truly personalized medicine in terms of patient risk assessment, diagnostics, and personal treatment plans.

Currently, the FDA approves all in vitro diagnostic (IVD) tests with the exception of laboratory defined tests (LDTs). These tests are used in clinical laboratories and typically detect one substance or analyte in a patient sample, and this result is used to diagnose a limited number of conditions. (One example would be a cholesterol test; every manufacturer that makes the analyzer and reagents to detect cholesterol in a blood samples has to get their methodology approved.) However, NGSs have the potential to detect billions of base pairs in the human genome, and therefore the potential exists to diagnose or discover thousands of diseases and risk factors for disease. Also, many NGS tests are developed by individual laboratories, not big companies, and so would be considered an LDT.

The FDA has opened a public docket to invite comments on this topic. American Society for Clinical Pathology, as well as other professional societies—American Association of Clinical Chemistry and Association for Molecular Pathology among them—has publically commented on the FDA preliminary discussion paper “Optimizing FDA’s Regulatory Oversight of Next Generation Sequencing Diagnostic Tests.” In its comments to the draft paper, ASCP stated that the “CLIA framework offers a more logical model for providing federal regulatory oversight of LDTs.” Similar points were made by AACC and AMP. The associations also agree that any regulations should not interfere with the practice of medicine.

What do you think? How involved should the FDA be in genomic testing in the clinical setting?

Further reading:

AMP comments

AACC comments

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.

How to Say “No”

Saying “no” to things is a learned skill that takes continuous practice, and a good amount of balance. The balance is because when you’re starting out in your career, I firmly believe that it’s important for you to agree to requests and to take on new tasks. It gets you out there, introduces you to new people and new skill sets, and teaches you so much you might not learn just performing your regular job. But then we get into a habit of saying ‘yes”, and we all know how hard habits are to break. We think things like, “if I don’t do it, no one will” or “if I do it, it will be done correctly.” Or more than just those things, we all like to please people, especially our friends and colleagues. So when a friend asks you to take on another research project or review a paper or look over some data or run a test or cover their call, we all readily agree to taking on just one more task.

As with every other aspect of life though, there is such a thing as too much of a good thing. Saying “no” occasionally is good for your overall health and sanity. It’s entirely possible to reach a stage where you’re so over-whelmed that you cannot do a good job at any of the tasks you have undertaken. Thus learning the art of saying “no” is also important, and is something I myself am just still struggling to learn.

Here are some points to remember that may help you when you need to say “no:”

Don’t give an immediate response, especially if you have any concerns about having time for this new task. Tell the person you will get back to them after some thought, and tell them when you will reply to them.
Give yourself time to consider whether the new task can be accommodated in your current workload, or whether you will have to short something else to accommodate it.
Be firm once you’ve decided. Don’t use phrases like “I don’t think I can.” Say “I cannot. ” And be persistent because you may have to turn down this opportunity more than once.
Always remember, you are turning down a request, not a person. It is especially hard when the request comes from a friend, but sometimes it is necessary.
Accepting a task that you don’t have time for is not doing any favors for yourself or the person asking. If the requestor has to then become a nagger to get you to complete their task, they will not thank you for it.

In conclusion, it’s important to maintain a balance at work without overloading yourself with too many tasks to allow you to accomplish any of them well. Learning to say no to requests is an important part of keeping that balance.

Letters of Recommendation

Have you ever been asked to write a letter of recommendation? One of my favorite tasks is to write such a letter for someone who I believe is totally worthy of the honor for which he/she is being considered, or completely suited to the position or new career for which they are headed. Conversely, one of my least favorite tasks is to write such a letter for someone I’m unconvinced fits either of those categories.

Writing a letter of recommendation for someone you know well and believe in is a joy. It’s easy to write, easy to find examples, easy to express concepts. It almost writes itself. Writing a letter for someone you don’t know well, or aren’t sure fits the reason for the recommendation, can be a painful, tedious project.

A colleague once told me that if I can’t write a glowing recommendation for someone, I should decline to write one at all. That’s good advice because the recipient of the letter can often tell when you’re enthusiastic, and when you’re not. I have also received letters of recommendation for applicants from people who actually write a bad recommendation – why not to hire the person or admit him/her to the program. I’m appalled that people would agree to write a letter if they are going to write a bad recommendation. Yes, it is hard to say no to someone who comes asking, but it is far better to say no than to write a bad letter of recommendation.

Occasionally you may not have any options, and may need to write a letter of recommendation. For example a person may need a letter from their boss and have only worked in the job they currently have. Or they need a letter from their most recent instructor, and that’s you! These are especially hard to write because you may feel obligated to write a reference, but not have enough personal experience with the person to write a glowing one. In these cases, all you can do is write about as many positive aspects of the person as you are aware of and leave it at that. Sometimes I have talked to the person’s immediate supervisor or work colleagues to gain some insight before writing the letter.

I have declined to write a letter of recommendation on occasion. In general, I decline because I have not had enough direct contact with the individual asking me to provide them with a good recommendation. Once in a while I decline because I truly can’t recommend the person.

From the opposite perspective, when asking someone to write a letter of recommendation for you, always ask for a GOOD recommendation. Also, try to always ask people who know you well and know your work and work ethic well. You’ll be doing both them and yourself a favor.

Test Turnover

What’s your lab’s procedure for getting rid of an obsolete test, or bringing in a new one? Any change to the test menu has some level of difficulty associated with it, however my opinion is that replacing a test with a new method that gives different results is the easiest to accomplish, followed by introducing a completely new test, and lastly removing an obsolete test. In that last case I’m specifically talking about removal of a test that is no longer the best way to diagnose a disease or monitor treatment.

In any of these cases, does your lab use the “rip the band aid off” method? For example, do you send a succinct notification that as of the first of the month this test will no longer be available in your lab, or this test will have results 33% higher than the doctors have been previously seeing? Or do you use a more gentle method, such as offering to run the old and new method together for 2-6 months to let the doctors get used to the new values? Or in the case of removing a test, do offer to try to find them an alternative lab which is still running the old test? Or do you simply leave the old test in place and hope it eventually dies a natural death from lack of use? Unfortunately, some tests never seem to die – like CKMB and bleeding time.

A lot of the difficulty, both in getting rid of old tests and in bringing in completely new ones, can probably be laid on the doorstep of human nature. Just like other humans, doctors like what they’re used to and don’t like changing their routine. Even when overwhelming evidence suggested that a new test is better (troponin), they want to use what they have always used to diagnose and treat their patients (CKMB). When the evidence for a test’s utility is not so clear cut, it’s even more difficult to introduce a new test. Examples of this include Cystatin C and fructosamine. Cystatin C is becoming more widely used and will no doubt survive as a test, but fructosamine? Part of the issue with fructosamine may have been the silly name they gave it. Fructosamine? Really? If they had called it glycated proteins/albumin it may have fared better. Fructosamine sounds too much like a fruit drink.

Maintaining a test menu that is appropriate for your population and that doesn’t include unnecessary or obsolete tests is an interesting balancing act. It definitely requires having a good rapport with your clinicians and getting their input along the way.

Management and Administration Housekeeping Items

A few items relevant to your interests have crossed the editor’s desk over the past few days.

1. As we mentioned several months ago, laboratories need to provide lab results to patients (or their representative) when requested to do so. The Privacy Rule amendments went into effect on October 6, 2014. Is your lab compliant? Read the regulations to be sure.

2. The Draft Guidance for the FDA regulation of LDTs has been published. You can read them here and here. The FDA will accept comments about the draft for the next 110 days.