Safety Tips for Laboratorians
This section provides safety tips for conducting laboratory
tests properly.
Troponin: What
Laboratorians Should Know to Manage Elevated Results
(posted 8/26/05)
FDA, using input provided by Advanced Medical Technology Association
(AdvaMed), has developed this document in response to numerous adverse
event reports of falsely elevated results sent by manufacturers
and users of troponin assays and many published articles related
to this subject.
1. What is the Purpose and Scope of this Communication?
The purpose of this communication is to inform laboratorians
about the possibility of falsely elevated troponin results when
troponin is used as a cardiac marker, and to provide information
as to how to identify and verify cases of suspected falsely elevated
results. This communication may also be of interest to cardiologists,
primary care physicians, and emergency care physicians.
In this document, we use the term “false-positive” troponin
test result to refer to cases when the troponin immunoassay result
is positive in the absence of acute myocardial infarction (AMI)
or any other clinical condition in which troponin markers may be
elevated.
This document addresses issues related to false-positive troponin
results only when troponin testing is used in the diagnosis of acute
myocardial infarction and not when it is used to diagnose other
diseases. The information applies to both cardiac troponin I and
cardiac troponin T immunoassays since the issue of falsely elevated
results applies to both assay systems.
Cardiac troponins are highly sensitive and specific biochemical
markers of myocardial cell necrosis and are widely used for the
diagnosis of acute myocardial infarction.1,2
Troponin levels rise and fall with acute myocardial
infarction and with other clinical syndromes associated with
infiltrative/inflammatory causes of myocyte death.
Troponin testing is subject to analytical interfering factors
and assay malfunctions; both may lead to a falsely elevated troponin
result. In addition, there are clinical conditions in which the
troponin level may rise in the absence of an acute myocardial infarction
. Although the elevation of troponin in association with non-AMI
is generally rare, it may mislead the clinician to suspect that
the patient has an acute myocardial infarction when that is not
the case.
Therefore, it is important that laboratorians, working in conjunction
with physicians who order the test, are aware of falsely elevated
results and non-AMI causes of elevated troponin results in order
to assist physicians to properly utilize troponin results in patient
management.
3. Can Results of Different Troponin Assay Systems Be
Compared?
No. The results of different troponin assays are not generally
comparable. A large variation in cardiac troponin I concentration,
in terms of absolute value, may be observed for a given patient
specimen with different analytic methods.3 Until recently,
there was no accepted reference standard for troponins. However,
a new Standard Reference Material for Human Cardiac Troponin Complex
(SRM 2921)4 has been introduced by the National Institute
of Standards and Technology (NIST) which should aid in the future
standardization of troponin assays. The SRM 2921 is intended for
use in evaluating the accuracy of clinical procedures for the determination
of cardiac troponin I in human serum.4
The analytical variability among troponin assays is due to the
fact that different troponin assays have wide variations in lower
detection limits, upper reference limits, diagnostic cut points,
assay imprecision (coefficient of variation),5 and specimen
matrices (i.e., serum versus plasma samples). The presence of a
large number of manufacturers of troponin assays in the United States
market makes standardization more difficult.
4. What Are the Analytical Interfering Factors That May
Lead to Falsely Elevated Troponin Results?
Some of the analytical interfering factors that may lead to falsely
elevated troponin results include: 3,6,7
- fibrin clots in serum as a result of incompletely clotted specimen,
e.g. in patients with coagulopathy or on anticoagulant therapy8
- heterophile antibodies, human anti-animal antibodies9
, rheumatoid factor10,11, and autoantibodies
- interference from other endogenous components in the blood
such as bilirubin and hemoglobin12
- immunocomplex formation13
- microparticles in specimen
- high concentration of alkaline phosphatase14
- analyzer malfunction15
5. What Are Interfering Antibodies (Heterophile and Human
Anti-Animal) and How Can Laboratorians Address This Issue?
A. Definition and Sources
Circulating heterophile antibodiesi and anti-animal
antibodiesii have the potential to interfere with two-site
(sandwich) or competitive immunoassays, such as troponin assays,
by cross-linking the capture and label antibodies in the absence
of specific analyte. 6,16 The estimated prevalence
of interfering antibodies in the general population is up to 40%
of normal serum samples.17,18
Most modern immunoassays contain nonspecific blocker immunoglobulins
(which originate from the same species as the analyte-specific
antibodies) in order to limit the effect of the interfering antibodies.19
However, in some instances the blocking proteins can not sufficiently
neutralize the interfering antibodies. Thus, analytical errors
may occur. In case of troponin assays, the presence of high levels
of these antibodies may lead to falsely elevated values.
An individual may acquire these antibodies from a variety of
sources including the use of mouse monoclonal antibodies in diagnostic
imaging and cancer therapy; exposure to microbial antigens; exposure
of veterinarians, farm workers, and food preparers to foreign
proteins; the presence of domestic animals in the home; or autoimmune
diseases which can give rise to autoantibodies such as rheumatoid
factor. 7,16
i Heterophile antibodies are antibodies produced against
poorly defined antigens (frequently foreign proteins). The general
term "heterophile antibodies" is sometimes used in the
literature interchangeably to refer to heterophile antibodies, human
anti-animal antibodies, rheumatoid factor, and autoantibodies.
iiHuman anti-animal antibodies are circulating human
antibodies reactive with animal proteins.9 Circulating
antibodies with specificities for a wide range of animal immunoglobulins
have been reported such as mouse, rat, rabbit, and others.9
B. Laboratorians May Suspect or Recognize the Presence
of Interfering Antibodies in a Specimen Tested for Troponin
Because of a broad range of interfering antibodies, there is
not a specific test to verify or rule out their presence in an
assay. Laboratorians should suspect the occurrence of interfering
antibodies in a troponin assay when the test result:
- does not agree with the patient’s clinical information
for an acute myocardial infarction (see items 6 & 7 for
more information)
- may not be reproducible on the same or different assay system
- is not linear after serial dilutions
C. Methods to Reduce or Remove Interfering Antibodies
from Troponin Assays
After ruling out the possibility of technical errors and analyzer
malfunction and after repeating the assay, the following methods
may be applied for reducing or removing the effect of interfering
antibodies from troponin assay results.9
- Run the specimen on a different assay system
- Use commercially available heterophile blocking reagents
- Remove endogenous immunoglobulins by adding endogenous immunoglobulin-free
serum samples to the specimen. For example, use normal mouse
(animal) sera as blocking reagent
6. If a Troponin Test Result Does Not Match the Patient’s
Clinical Picture for Acute Myocardial Infarction, What Should Laboratorians
Consider Doing?
If the troponin test result does not match the patient’s
clinical picture for acute myocardial infarction, it is possible
that the test result is falsely elevated due to analytical interfering
factors, and/or analyzer malfunction. The laboratory should investigate
the presence of any potentially interfering factors and verify the
test result by taking the following steps.
- Find out whether the patient is on anti-coagulant therapy or
has coagulopathy.
- Check for bilirubin and/or hemoglobin interference.
- Visually examine the specimen tube for any particles or clots
(fibrin interference). If present, centrifuge the specimen for
a second time.
- Rerun the specimen after doing a serial dilution and look for
interfering antibodies by examining the linearity of results.
- If sufficient amount of specimen is available, save the sample
for further testing by the laboratory or the manufacturer.
- Rerun the same specimen on a different assay system, if available,
to verify the results. If another assay system is not available,
send out the specimen to another laboratory to be run on a different
assay system.
- Examine the analyzer thoroughly to investigate the presence
of any malfunction.
- Communicate to the treating physician the discrepancy between
the test result and clinical information, and inform him/her of
the possibility of a false-positive value.
- If the problem does not get resolved, report the issue to the
manufacturer and FDA and send the specimen to the manufacturer
for further testing and investigation.
7. If a Troponin Test Result Does Not Match the Patient’s
Clinical Picture for Acute Myocardial Infarction, What Should Physicians
Consider Doing?
In cases when a troponin test result does not match the patient’s
clinical picture for acute myocardial infarction, it is important
that the physician gather all the available information and reassess
the patient. The physician may:
- consider the possibility that some other clinical condition
may be causing an elevated troponin level in the absence of acute
myocardial infarction.
- communicate with the laboratory about the test result and ask
the laboratory to rule out technical errors, analytical interfering
factors, and analyzer malfunction.
- consider repeating the blood draw and retesting.
- review the clinical presentation and consider additional diagnostic
testing (e.g. reconsider the nature of chest pain, repeat ECG,
etc.); bear in mind that the troponin test result is only one
piece of the diagnostic puzzle.
8. Is It Important that Laboratorians Follow Manufacturers’
Recommended Instructions?
Yes. For troponin testing, it is critical that patient specimens
be collected and processed according to the manufacturers’
recommendations included in the device product insert. Improper
collection, handling, and preparation of specimens can impact the
accuracy of results.
- Store unused collection tubes and blood specimens according
to the manufacturers’ recommendations.
- Follow manufacturers’ instructions for using collection
tubes with anticoagulants. Some may contain insufficient anticoagulant
and lead to elevated or decreased results.
- Mix the content of tubes properly at the time of blood collection
to prevent incomplete clot formation (serum) and platelet clumping
or clotting (plasma).
- Process specimens according to the tube manufacturer’s
recommendations. Different types of tubes may have different requirements.
- Use a refrigerated, horizontal centrifuge head for best results.
Use the centrifuge settings recommended by the tube manufacturer.
- Inspect samples for clots, fibrin, particulate matter, and
other debris prior to processing them on an analyzer. Cellular
debris from grossly hemolyzed samples may elevate test results.
- Follow manufacturer’s recommendation for running proper
quality control samples. At least one control should be
run at the cutoff level. If the risk stratification and
acute myocardial infarction cutoff are different, separate controls
should be considered at those levels.
- Follow the manufacturers’ recommended calibration and/or
maintenance schedules. Analyzer malfunction is one of the common
assay interfering factors that leads to inaccurate results. Laboratories
reporting troponin results should perform thorough and regular
system maintenance to ensure peak performance of their analyzers
and to reduce the possibility of inaccurate results.
9. What Are the Current Cardiology Practice Guidelines
for Troponin Reference Intervals and Decision Limits?
Current practice guidelines issued by the American College of
Cardiology (ACC), the National Academy of Clinical Biochemistry
(NACB), and the European Society of Cardiology (ESC) make similar
recommendations regarding reference intervals, decision limits,
and precision. These recommendations include: 1,2,20
- establishing an upper reference limit at the upper 99 th percentile
of normal population
- using a single cutoff positioned at or slightly above the upper
reference limit
- accomplishing a total imprecision (coefficient of variation)
≤10% at the decision limit (Currently, few commercially available
assays can achieve this precision level .)
10. What Are Some Clinical Conditions Associated with
Cardiac Troponin Elevations in the Absence of Acute Myocardial Infarction?
Myocardial cell damage (reversible or irreversible) and elevation
of cardiac troponins can occur under conditions OTHER
than acute myocardial infarction due to obstructive coronary artery
disease. A short list of some of these clinical conditions includes
but is not limited to:21,22,23
- myocardial cell trauma
- congestive heart failure
- left ventricular hypertrophy
- myocarditis
- pulmonary embolism
- renal failure
- infiltrative disease with cardiac involvement
- acute neurological disease including cerebrovascular accidents
and subarachnoid bleeds
- rhabdomyolysis with cardiac injury
REPORTING TO FDA
If there are any questions or concerns regarding the performance
of troponin test method, contact the assay manufacturer. You should
report all occurrences of unusual test performance to the manufacturer,
and you are encouraged to also report them to FDA. To obtain more
information about medical device reporting you can refer to the
FDA’s web site at: http://www.fda.gov/cdrh/mdr/index.html
All reports should be sent to:
Food and Drug Administration
Center for Devices and Radiological Health
Medical Device Reporting
P.O. Box 3002
Rockville , MD 20847-3002
For any questions or concerns regarding the content of
this communication contact:
Ms. Ruth Chesler
Food and Drug Administration
Center for Devices and Radiological Health
Office of In Vitro Diagnostic Device Evaluation and Safety
2098 Gaither Road , HFZ-440
Rockville , MD 20850
Phone: (240) 276-0686
Fax: (240) 276-0651
Email: ruth.chesler@fda.hhs.gov
REFERENCES:
1 Heterophile antibodies are
antibodies produced against poorly defined antigens (frequently
foreign proteins). The general term "heterophile antibodies"
is sometimes used in the literature interchangeably to refer to
heterophile antibodies, human anti-animal antibodies, rheumatoid
factor, and autoantibodies.
2 Human anti-animal antibodies
are circulating human antibodies reactive with animal proteins.
9 Circulating antibodies with specificities for a wide range of
animal immunoglobulins have been reported such as mouse, rat, rabbit,
and others. 9
3 Alpert JS, Thygesen K, Antman
E, Bassand JP. Myocardial Infarction Redefined - A Consensus Document
of The Joint European Society of Cardiology/American College of
Cardiology Committee for the Redefinition of Myocardial Infarction.
The Joint European Society of Cardiology/American College of Cardiology
Committee. Journal of the American College
of Cardiology 2000; 36(3):959-969.
4 Wu AHB, Apple FS, Gibler
WB, Jesse RL, Warshaw MM, Valdes R Jr. National Academy of Clinical
Biochemistry Standards of Laboratory Practice: Recommendations for
the Use of Cardiac Markers in Coronary Artery Diseases. Clinical
Chemistry 1999; 45(7):1104-1121.
5 Ng SM, Krishnaswamy P, Morrisey
R, Clopton P, Fitzgerald R, Maisel AS. Mitigation of the Clinical
Significance of Spurious Elevations of Cardiac Troponin I in Settings
of Coronary Ischemia Using Serial Testing of Multiple Cardiac Markers.
The American Journal of Cardiology 2001; 87:994-999.
6 National Institute of Standards
and Technology. http://www.nist.gov/srm
Certificate of Analysis Standard Reference Material 2921, Human
Cardiac Troponin Complex. 2004.
7 Apple FS. Cardiac Troponin
Assays Analytical Issues and Clinical Reference Range Cut Points.
Cardiovascular Toxicology 2001; 1(2):93-98.
8 Ringdahl EN, Stevermer JJ.
False-Positive Troponin I in a Young Healthy Woman with Chest Pain.
The Journal of the American Board of Family Practice 2002;
15(3):242-245.
9 Roongsritong C, Warraich
I, Bradley C. Common Causes of Troponin Elevations in the Absence
of Acute Myocardial Infarction – Incidence and Clinical Significance.
Chest 2004; 125(5):1877-1884.
10 Kazmierczak SC , Sekhon
H, Richards C. False-Positive Troponin I Measured with the Abbott
AxSYM Attributed to Fibrin Interference. International Journal
of Cardiology 2005; 101(1):27-31.
11 Kricka LJ. Human Anti-Animal
Antibody Interferences in Immunological Assays. Clinical Chemistry
1999; 45(7):942-956.
12 Krahn J, Parry DM, Leroux
M, Dalton J. High Percentage of False Positive Cardiac Troponin
I Results in Patients with Rheumatoid Factor. Clinical Biochemistry
1999; 32(6):477-480.
13 Dasgupta A, Banerjee
SK, Datta P. False-Positive Troponin I in the MEIA Due to the Presence
of Rheumatoid Factors in Serum - Elimination of This Interference
by Using a Polyclonal Antisera Against Rheumatoid Factors. American
Journal of Clinical Pathology 1999; 112:753-756.
14 Hawkins RC. Hemolysis
Interference in the Ortho-Clinical Diagnostics Vitros ECi cTnI Assay.
Clinical Chemistry 2003; 49(7):1226.
15 Plebani M, Mion M, Altinier
S, Girotto MA, Baldo G, Zaninotto M. False-Positive Troponin I Attributed
to a Macrocomplex. Clinical Chemistry 2002; 48(4):677-679.
16 Dasgupta A, Chow L, Wells
A, Datta P. Effect of Elevated Concentration of Alkaline Phosphatase
on Cardiac Troponin I Assays. Journal of Clinical Laboratory
Analysis 2001; 15:175-177.
17 Galambos C, Brink DS,
Ritter D, Chung HD, Creer MH. False-Positive Plasma Troponin I with
the AxSYM Analyzer. Clinical Chemistry 2000; 46(7):1014-1015.
18 Yeo KTJ, Storm CA, Li
Y, Jayne JE, Brough T, Quinn-Hall KS, Fitzmaurice TF. Performance
of the Enhanced Abbott AxSYM Cardiac Troponin I Reagent in Patients
with Heterophilic Antibodies. Clinica Chimica Acta 2000;
292:13-23.
19 Gibson TN, Hanchard B.
False Positive Troponin I in a Case of Metastatic Small Cell Bronchogenic
Carcinoma Complicated by Pulmonary Thromboembolism. West Indian
Medical Journal 2001; 50(2):171-172.
20 Fleming SM, O’Byrne
L, Finn J, Grimes H, Daly KM. False-Positive Cardiac Troponin I
in a Routine Clinical Population. The American Journal of Cardiology
2002; 89:1212-1215.
21 Fitzmaurice TF, Brown
C, Rifai N, Wu AHB, Yeo KTJ. False Increase of Cardiac Troponin
I with Heterophilic Antibodies. Clinical Chemistry 1998;
44(10):2212-2214.
22 Morrow
DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson
DH, Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub
WS, Braunwald E; TACTICS-TIMI 18 Investigators. Ability of Minor
Elevations of Troponins I and T to Predict Benefit from an Early
Invasive Strategy in Patients with Unstable Angina and Non-ST Elevation
Myocardial Infarction: Results from a Randomized Trial. Journal
of the American Medical Association 2001; 286(19):2405-2412.
23 Jaffe AS. Elevations
in Cardiac Troponin Measurements: False False-positives The Real
Truth. Cardiovascular Toxicology 2001; 1:87-92.
24 Hamm CW, Giannitsis E,
Katus HA. Cardiac Troponin Elevations in Patients without Acute
Coronary Syndrome. Circulation 2002; 106:2871-2872.
25 Li D, Keffer J, Corry
K, Vazquez M, Jialal I. Nonspecific Elevation of Troponin T Levels
in Patients with Chronic Renal Failure. Clinical Biochemistry
1995; 28(4):474-477.
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Home Pregnancy Tests – How to Use a Popular
Test Wisely
(posted 4/2/04)
The first home pregnancy tests were marketed in the mid 1970’s.
These tests are one of the most popular products for home diagnostic
testing. It is estimated that about 33% of women have used these
tests. The tests are popular because they allow women rapid access
to highly sensitive and personal information. These tests can lead
to earlier diagnosis and can provide pregnant women an opportunity
to seek earlier health care intervention.
FDA is involved in the premarket review of these tests. Since the
1976 Medical Device Amendment, FDA assures that new pregnancy tests
perform as well as those tests on the market since 1976. Premarket
compares test performance between a new test and an established
test. In these kinds of pregnancy devices the new test is compared
to varying levels of the hormone human chorionic gonadotropin (hCG)
that is the marker for pregnancy.
Recent investigators point out that the FDA review of analytical
performance does not always mean a woman is pregnant. This discrepancy
is because different tests have different abilities to detect low
levels of hCG. Also hCG levels differ between pregnant women depending
on the timing of the onset of pregnancy with regard to a menstrual
period and depending on each woman’s unique biology.
The result is that pregnancy tests may be labeled up to 99% accurate
when compared to other hCG tests, not to pregnancy. This
may be true based on information submitted to the FDA. Therefore,
labeling of these tests should clearly indicate that there is a
possibility for both false positive tests and false negative tests,
so patients should contact their health care provider to discuss
any result.
Patients may frequently recognize incorrect results with the passage
of time. False negatives may be detected by ongoing failure to have
a period or the development of other obvious signs of pregnancy.
False positives may be demonstrated by the unexpected onset of menses
(regular vaginal bleeding associated with “periods”.)
Repeat testing and/or other investigations such as ultrasound may
provide corrected results.
If a patient has a negative result, it is always wise to consider
this a tentative finding. Women should not use medications and should
consider avoiding potentially harmful behaviors, such as smoking
or drinking alcohol, until they have greater certainty that they
are not pregnant.
Since September of 2003, studies for pregnancy tests have been
posted on the Office of In Vitro Diagnostic Web Page (www.fda.gov/cdrh/oivd/)
under new 510(k)s – decision summaries. FDA is considering
what educational or regulatory tools might be available to help
clarify the status, use, and interpretation of these tests.
![Top](https://webarchive.library.unt.edu/eot2008/20081004002004im_/http://www.fda.gov/cdrh/images/go-top.gif)
Practice Caution in Using Bio-Rad Platelia™
Aspergillus EIA
FDA has cleared for marketing, the Platelia™ Aspergillus
EIA, manufactured in France by Bio-Rad, Marnes-la-Coquette and distributed
by Bio-Rad Laboratories, Redmond, WA, which detects Aspergillus
galactomannan antigen in serum samples, and is an aid in the diagnosis
of Invasive Aspergillus infection. Invasive Aspergillosis
is a life-threatening invasive fungal infection that often occurs
in leukemia patients, organ and bone marrow transplant patients,
and patients whose immune systems are compromised by illness or
chemotherapy.
There have been reports in the literature, in the U.S. and from
Europe, of potential drug and device interaction that may occur
when using the Platelia™ Aspergillus EIA galactomannan
antigen assay to test sera from patients who are receiving piperacillin/tazobactam
(Zosyn®), an injectable antibacterial combination product from
Wyeth Pharmaceuticals, Inc. Recent reports 1,2 have indicated that
positive galactomannan antigen tests results may occur in serum
samples from patients treated with Zosyn®, but without Invasive
Aspergillosis. Additional studies have also demonstrated positive
galactomannan antigen test results in certain batches of Zosyn®.
These results are highly suggestive of reactivity of the Platelia™
Aspergillus EIA with Zosyn®. Nevertheless, as Platelia™
Aspergillus EIA can detect galactomannan antigen well before
clinical or radiological signs appear, the occurrence of Invasive
Aspergillosis cannot be ruled out. Therefore, patients treated with
Zosyn® with positive test results should be followed carefully.
Bio-Rad has notified their customers and modified the Platelia™
Aspergillus EIA package insert to include a new Limitation
of Use alerting laboratory users that positive test results in patients
treated with Zosyn® should be interpreted cautiously and confirmed
by other diagnostic methods.
It is therefore recommended that when reporting a positive Platelia™
Aspergillus EIA galactomannan test result, laboratories
should inform physicians of the limitations of the test with regard
to the potential interaction with Zosyn® and that the patient’s
previous drug therapy should be taken into account.
FDA reminds users that life threatening or potentially threatening
adverse device failures should be reported to the agency through
MEDWATCH medical device reporting system. This may be done by visiting
the MEDWATCH site at http://www.fda.gov/medwatch/
or calling 1-800-FDA-1088. Less serious adverse device failures
may be reported to the FDA by sending an e-mail to fdalabtests@cdrh.fda.gov.
References:
- Sulahian, A., S. Touratier, T. LeBlanc, P. Rousselot, F. Derouin,
P. Ribaud. False Positive Aspergillus antigenemia related
to concomitant administration of Tazocillin. Abstract M-2062a,
43rd ICAAC Program.
- Viscoli, C., M. Machetti, C. Cappellano, B. Bucci, P. Bruzzi,
A. Bacigalupo. False-Positive Platelia Aspergillus test
in patients receiving Piperacillin/Tazobactam. Abstract M-2062b,
43rd ICAAC Program.
Cautionary Note: Use of Backup Testing
for Negative Rapid Group A Strep Tests
(posted 11/5/03)
Pharyngitis (sore throat) is caused by a number of different viruses
or bacteria which set up shop in the throat and tonsil area. One
of the most clinically significant bacterial organisms is group
A beta-hemolytic streptococcus (GAS). Infection with GAS causes
local pain and redness, bad breath, tonsillar or pharyngeal exudates
and systemic symptoms like fever. Alternatively, patients may present
with only mild throat pain and no fever. Anecdotal experience shows
that some patients may only complain of bad breath and a history
of GAS in a schoolmate or family member.1,2,3
Serious complications of GAS include rheumatic fever, rheumatic
heart disease and death. Historically, treatment with intramuscular
penicillin within the first several days of symptoms prevented the
rheumatic complications. Because intramuscular injection of penicillin
is painful this has evolved into treatment with oral penicillins.1,2
While the local throat infection may clear on its own in many patients,
these untreated patients are still thought to be at increased risk
of rheumatic complications. Unfortunately, the literature is clear
that physical examination is insufficient to accurately distinguish
GAS from other causes of pharyngitis which do not present any risk
of rheumatic complications. Therefore, if a patient presents with
appropriate signs and symptoms a throat test for strep is performed.
The historic test of choice was throat culture. A variety of very
useful non-culture based methods are available which offer quick
results. These rapid tests are invaluable when they are positive
for strep, but caution is required when they are negative for a
variety of reasons. Pediatric practice guidelines recommend all
negative rapid tests in the face of overt clinical symptoms need
to be supported with follow up testing.1,4,5 This is
conventionally viewed as throat culture on media which is designed
to augment growth of GAS, though newer methodologies may change
this recommendation.6 Notwithstanding, there is at least
one study supporting clinical superiority of a rapid method compared
to culture method.7
The situation in adults is more complex. While 15%-30% of children
who present with pharyngitis have GAS, the percentage in adults
may be as low as 5%-10%.2,3 Also, it has been reported
that adults who get GAS are at a lower risk for rheumatic complications.
This has been offered as a rational supporting the lack of need
for confirmatory testing in adults with a negative rapid test.8
However, there are studies suggesting that the rate of rheumatic
complications in adults who present with local suppurative disease
is equal to the rate in children.3 Further, some sources
quote that up to 20% of first attacks occur in middle to later life.2
Since no rapid test has been cleared, approved, or waived through
the regulatory process as a stand alone test in the face of locally
suppurative disease, lack of a backup method for a negative rapid
GAS test result constitutes off label use.
While the practice of medicine is not the province of FDA regulation,
regulatory medicine, like clinical medicine, is always in the process
of change and FDA welcomes information from academia or industry
which may contribute to the evolution of this opinion.
Bibliography:
- Committee on Infectious Diseases, Red Book: 2003 Report of the
Committee on Infectious Diseases, 26’th Edition, Elk Grove
Village IL, American Academy of Pediatrics, 2003, p 573-584.
- Cotran RS, Kumar V, Collins T. Robbins Pathologic Basis of Disease,
6’th Edition, Philadelphia PA, WB Saunders Company, 1999,
p 572.
- Mandell GL, Bennett JE, Dolin R. Mandell. Douglass and Bennet’s
Principles and Practice of Infectious Disease, 5’th Edition,
Philadelphia PA, Churchill Livingstone, 2000, p 2119.
- Bisno AL, et al. Diagnosis and management of Group A Streptococcal
pharyngitis: A practice guideline. Clinical Infectious Diseases.
1997; 25:574-583.
- Gieseker KE, et al. Comparison of two rapid Streptococcus pyogenes
diagnostic tests with a rigorous culture standard. Pediatr Infect
Dis J, 2002; 21:p 922-926.
- Gieseker KE, et al. Evaluating the American Academy of Pediatrics
diagnostic standard for Streptococcus pyogenes pharyngitis: backup
culture versus repeat rapid antigen testing. PEDIATRICS June 2003.
111(6): e666-e670.
- Uhl JR, et al. Comparison of LightCycler PCR, Rapid Antigen
Immunoassay, and culture for detection of Group A Streptococci
from throat swabs. J Clin Microbiol Jan 2003, 41(1): p 242-249.
- Bisno AL, et al. Practice guidelines for the diagnosis and management
of Group A Streptococcal pharyngitis. CID 2002; 35: p 113-125.
Follow Good Laboratory Practices with Waived Laboratory Tests
Background:
The Department of Health and Human Services has evaluated laboratory
tests for complexity since 1992 as part of the implementation of
the Clinical Laboratory Amendments of 1988 (CLIA '88). The more
complicated the test, the more stringent the CLIA '88 requirements.
Tests designated as high or moderate complexity can be used only
by clinical laboratories that comply with CLIA '88 standards for
quality assurance, quality control, and patient test management,
and personnel. Simple tests designated as waived can be used by
laboratories that enroll in CLIA and pay the fee but are exempt
from CLIA '88 standards (i.e. community clinics, physicians' offices,
or other small laboratories).
By law, waived tests should be simple to use and must provide acceptable
results in the hands of untrained users. However, users must follow
the manufacturer's instructions as well as good laboratory practices
to ensure that test results are reliable.
Recommendations for Running Waived Tests:
In order to maximize the performance and reliability of waived
tests, laboratories are encouraged to consider the following:
- Read and follow the information found in the package inserts.
Small deviations from the written instructions about product
storage or procedural steps can have a significant impact on results.
Test kits and reagents must be stored under the proper conditions
and used prior to their expiration dates. You should take precautions
to make sure that the correct reagents are used for each test,
and reagents from different test kits are not inadvertently mixed
up.
- Follow the manufacturer's recommendations for running quality
control (QC).
Many waived tests have built-in quality controls that only monitor
certain aspects of the test. In these cases, external quality
controls may be the only way to monitor the entire test system.
Read the information concerning built-in controls carefully. Manufacturers
list minimum frequency requirements for their products in the
package insert, but they may not be adequate for all laboratories.
Take into account the environment where testing is performed when
deciding how often you should run external QC. There are many
factors that may be unique to your laboratory that can effect
this decision, such as:
- what information is provided by the built-in control;
- the extent of safe-guards that are provided with the test
system (such as a temperature monitor that alerts you when the
test has been stored outside of acceptable limits),
- the ambient environmental conditions of your laboratory;
- storage conditions (such as whether the freezer has recycling
phases);
- personnel issues (understaffing or high turnover); or
- the danger of a false negative test result.
Select concentrations of control materials to challenge the medical
decision points of the test. Selecting a control that has a concentration
three times the cutoff concentration of a qualitative test will
not allow you to detect reagent deterioration until patient results
have already been compromised.
- Train staff members to perform tests correctly. Make
sure your staff is familiar with product operating instructions,
quality control procedures, and record keeping. Professional organizations
sponsor educational and proficiency testing programs geared toward
staff that performs waived tests in outpatient or clinic laboratories.
Some training courses are available over the internet.
See Also:
Centers
for Medicaid and Medicare Services: CLIA '88 Program
Tests
Waived by FDA from January 2000 to Present
Performance and Cautions in Using Rapid Influenza Virus Diagnostic
Tests
FDA has cleared for marketing 7 rapid influenza diagnostic tests that can produce results within 30 minutes. These tests directly detect influenza A or B virus associated antigens or enzyme in throat swabs, nasal swabs, or nasal washes.
For the various products that have been FDA cleared for marketing Becton Dickinson’s Directogen Flu A test can detect only antigens associated with influenza A virus. Binax’s NOW Flu A, Binax’s NOW Flu B, and Becton Dickinson’s Directogen Flu A+B can detect and distinguish between influenza A and B virus antigens. Quidel’s QuickVue Influenza and Thermo BioStar FLU OIA can detect but do not distinguish between influenza A and B antigens. ZymeTx's ZstatFlu test can detect neuraminidase the presence of which denotes a high probability that infectious virions are present; it also does not distinguish between influenza A and B.
The Quidel Quick Vue and ZymeTx’s ZstatFlu and Quidel’s QuickVue influenza tests are considered low complexity and may be used in physicians’ offices. The other five tests mentioned above are considered moderately complex and are for use in a hospital or clinical reference laboratories.
If performed on individuals with signs and symptoms consistent with influenza, rapid influenza diagnostic tests appear to be moderately to reasonably accurate for detecting influenza virus dependent on when testing is performed during the influenza season. Potentially the rapid time for results can be very useful for managing patients with suspected influenza and for detection of institutional influenza outbreaks. However, positive testing must not be used alone to determine the cause of an individual’s symptoms. Often an individual may be co-infected with another pathogen that is the underlying cause of the symptom. Use of rapid influenza virus testing and missing an underlying cause was the subject of a public health advisory from the Centers for Drugs Evaluation and Research. 1,2 The basis for this advisory were several deaths where individuals were treated with antiviral medication but died from an underlying bacterial infection.
Laboratories should make sure that physicians using these rapid test results understand the limitations of the tests, use clinical experience, further laboratory testing, and consider local surveillance data about circulating influenza viruses when interpreting test results.
1 Public Health Advisory, Food And Drug Administration Public Health Advisory Subject: Safe And Appropriate Use Of Influenza Drugs, 12 January 2000, http://www.fda.gov/cder/drug/advisory/influenza.htm
2 FDA Talk Paper, FDA Reminds Prescribers of Important Considerations Before Prescribing Flu Drugs, January 12, 2000, http://www.fda.gov/bbs/topics/ANSWERS/ANS00995.html
The accuracy of an influenza test is determined by the sensitivity and specificity of the test to detect influenza virus antigens/enzyme compared with a reference method (cell culture) and the prevalence of influenza in the population being tested. Sensitivity is the percentage of culture confirmed influenza virus isolates detected by a test. Specificity is the percentage of virus negative cell cultures with negative rapid test results. Positive predictive value (PPV) of a test is the percentage of rapid test positive patients that have influenza virus isolated from cell culture. Negative predictive value (NPV) is the percentage of rapid test negative patients that do not have influenza virus isolated from cell culture.
Although the sensitivity and specificity of a test are unaffected by the prevalence of disease, the PPV and the NPV of a test are affected by disease prevalence. An influenza test will have the highest PPV (and lowest NPV) during peak influenza activity and the lowest PPV (and highest NPV) during periods of low influenza prevalence, i.e., at the beginning and ending of the influenza season.
Diagnostic antigen/enzyme tests for influenza are more likely to produce false positive results when the prevalence of influenza virus infections is low, such as during the late spring, summer, and early fall in North America. Confirming positive test results with viral culture is particularly important during this time period. Even when a positive test result reflects true influenza virus infection, this does not rule out the possibility of other co-existing infections. Persons with influenza are at risk for bacterial superinfections, and coincidental dual infections with other pathogens. Since some bacterial infections may have a fulminant course requiring urgent intervention, a positive test for influenza should not be used as a reason for withholding antibacterial therapy if clinical evaluation suggests a need.
False negative test results will be more common during periods of high influenza activity, such as during the winter in North America. Clinical judgment and local influenza surveillance data should be utilized to guide patient management. When compared to culture, FDA has found that the majority of rapid influenza virus assays have sensitivity >= 80 and <= 90%, and specificity in the same range. Most of these studies were performed during influenza season in the U.S. or the Southern Hemisphere.
Proper sample collection is the major determinant for obtaining accurate results. It has been reported in the literature and shown during studies conducted by companies that throat swabs are the poorest specimen source with properly collected nasal swabs or washes being the best. The adequacy of samples being tested should be carefully monitored before performing rapid tests and should be factored into interpretation of results.
FDA reminds users that life threatening or potentially threatening adverse device failures should be reported to the agency through the MEDWATCH medical device reporting system. This may be done by visiting the MEDWATCH WWW site at http://www.fda.gov/medwatch/ or calling 1-800-FDA-1088. Less serious adverse device failures may be reported to the FDA by simply sending an e-mail to fdalabtests@cdrh.fda.gov.
For additional information on using rapid tests for detecting influenza A viruses go to http://www.fda.gov/cdrh/oivd/tips/rapidflu.html
References
- Covalciuc KA, Webb KH, Carlson CA. Comparison of four clinical specimen types for detection of Influenza A and B viruses by optical immunoassay (FLU OIA Test) and cell culture methods. J Clin Micro 1999; 37:3971-3974.
- Boivin G, Hardy I, Kress A. Evaluation of a rapid optical immunoassay for influenza viruses (FLU OIA Test) in comparison with cell culture and reverse transcription-PCR. J Clin Micro 2002; 39:730-732.
- Schultze D, Thomas Y, Wunderli W. Evaluation of an optical immunoassay for the rapid detection of influenza A and B viral antigens. Eur J Clin Microbiol Infect Dis 2001; 20:280-382.
- Tucker SP, Cox C, Steaffens J. A flu optical immunoassay (ThermoBioStar’s FLU OIA): a diagnostic tool for improved influenza management. Philos Trans R Soc Lond B Biol Sci 2001; 356:1915-1024.
- Yamazaki M, Mitamura K, Kimura K, Komiyama O. et al. Clinical evaluation of an immunochromatography test for rapid diagnosis of influenza. Kansenshogaku Zasshi. 2001; 75:1047-1053.
- Rodriguez WJ, Schwartz RH, Thorne MM. Evaluation of diagnostic tests for influenza in a pediatric practice. Pediatr Infect Dis J 2002; 21:193-196.
- Reina J, Padilla E, Alonso F, Ruiz DGE et al. Evaluation of a new dot blot enzyme immunoassay (Directigen flu A+B) for simultaneous and differential detection of influenza A and B virus antigens from respiratory samples. J Clin Micro 2002;40:3513-3517.
- Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatric Infect. Dis. J 2003; 22:164-177.
Updated 09/21/06
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Functions and Limitations of Built-in Controls for Single
Use Disposable Tests
Single-use disposable tests, such as visually read tests used for
pregnancy or drug testing, often contain a built-in control. These
controls are sometimes referred to as process or procedural controls.
The following tips will help you understand how these controls function
and their limitations.
- Built-in controls may not monitor the entire test system. There
is significant variability among different devices in terms of
how procedural controls work and the functions they serve. It
is recommended that you read the package insert carefully, and
pay particular attention to the description of the chemical or
immunological reaction that takes place at the control line in
the device being used. Use this information to determine what
aspects of the test are monitored by the control and what variables
are not monitored.
- Built-in controls are sometimes not a good indicator of the
viability of test reagents. This is because the reactions occurring
at control lines may be more robust than reactions occurring at
the test line. For some immunochromatographic tests, the presence
of a control line merely indicates that an adequate volume of
sample was added and that the membrane strip is intact.
- You should select external control materials that have concentrations
of the targeted analyte that are near to the cutoff concentration
or medical decision level of the test. This will optimize your
ability to detect early stages of reagent degradation.
- External controls are often the only way to monitor the entire
test procedure, including pre-analytical steps, operator technique,
procedural steps, and reagent viability.
- If the control line does not appear within the read time identified
in the package insert, or if the appearance of the line or the
background varies from the description provided by the manufacturer,
e.g., the line is speckled instead of solid, you should not report
patient results.
- When determining when and how often external controls should
be run all laboratories should follow local, state, and federal
regulatory requirements. Decisions about control frequency and
type should be made in the context of the particular operating
environment for the laboratory taking into account operator proficiency,
the stability of the environment, the volume of testing, and other
relevant factors.
Updated 5/1/03
Common Problems with the Use of Glucose Meters
Glucose Testing Tips:
Diabetes care has come a long way since the introduction of insulin
and the first oral anti-hyperglycemic medicines. Life span and quality
of life have improved for majority of affected individuals. Even
better, a large part of diabetic care formerly performed in hospital
clinics can now be managed at home with use of well designed home
based glucose meters, a telephone and a good patient-doctor relationship.
The Office of In Vitro Diagnostics (OIVD) is charged with the job
of evaluating many devices, including glucose meters. OIVD helps
these meters come to the public market. Another of its tasks is
the continuous evaluation of the same devices for long term safety
and effectiveness not just of the devices, but of how the devices
are used.
OIVD is taking this opportunity to provide some friendly tips in
Point of Care glucose testing inspired by some comments we have
received from manufactures and users of these devices.
Causes of false results may be patient/sample based or user/device
based. Some common problems and their effects on meter glucose readings
are listed below.
Problem |
Results |
Recommendation |
Sensor strips not fully inserted into meter |
false low |
always be sure strip is fully inserted in meter |
Patient sample site(for example the fingertip)
is contaminated with sugar |
false high |
always clean test site before sampling |
Not enough blood applied to strip |
false low |
repeat test with a new sample |
Batteries low on power |
error codes |
change batteries and repeat sample collection |
Test strips/Controls solutions stored at temperature
extremes |
false high/low |
store kit according to directions |
Patient is dehydrated |
false high |
stat venous sample on main lab analyzer |
Patient in shock |
false low |
stat venous sample on main lab analyzer |
Squeezing fingertip too hard because blood is
not flowing |
false low |
repeat test with a new sample from a new stick |
Sites other than fingertips |
high/low |
results from alternative sites may not match
finger stick results |
Test strip/“Control” solution vial
cracked |
false high/low |
always inspect package for cracks, leaks, etc. |
Anemia/decrease hematocrit |
false high |
venous sample on main lab analyzer |
Polycythemia/increased hematocrit |
false low |
venous sample on main lab analyzer |
The advantage of Point of Care testing is eliminated if proper
technique is not followed. In addition to the above recommendations,
laboratory professionals must remember to wash hands and change
gloves between patients. Also, clean the surface of the meter if
blood gets on it. This each time, every time approach helps
protect both the patient and the health care worker from blood borne
agents like HIV and HCV.
All operators, from patients to non-lab health care workers to
medical technologists and physicians, should be thoroughly familiar
with any device prior to using it. The best way to do this is to
read the package insert and user manual carefully before
using a device for the first time. It sounds simple, and it is.
If you have any questions, ask someone who is familiar with the
device. Another option is calling the customer service telephone
number located on most package inserts. The people on the other
end are there to help. Another good tip is to reread the package
insert every few months. It is a good practice and their may be
changes.
Next, watch an experienced laboratory professional, doctor, nurse
or diabetic educator perform the test. Then perform the test in
front of someone who has experience in using the glucose meter and
instructing others on its performance. Ask for tips.
Specific problems come up from time to time including glucose readings
that don’t make sense. For example you might feel fine when
the glucose meter reading is obviously too high or too low. Remember,
the best way to resolve any questionable result, and the best sample
from any sick patient, is still a venous blood sample tested at
a central lab. Even then any result that does not fit the clinical
picture needs to be investigated and, at a minimum, repeated.
For more information also see FDA’s diabetes website at:
http://www.fda.gov/diabetes/
Updated 5/1/03
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Make sure glucose meters used in testing neonates are FDA cleared
for testing in neonates
Glucose Monitoring in Neonates:
Glucose determination in the blood or plasma is used in the diagnosis,
monitoring and treatment of persons with diabetes mellitus. Neonates
(full term birth to 30 days old) and premature infants (gestational
age in weeks at birth up to original due date) represent a mixed
group of individuals in whom glucose monitoring is crucial and who
have a physiology that differs significantly from older children
and adults. Prevention or treatment of hypoglycemia (low blood sugar)
in this group is just as important as the recognition and treatment
of hyperglycemia (high blood sugar.)
Most full term neonates are born with glucose reserves that last
for about 6-24 hours and if feeding or intravenous nutrition is
not started in that time period, glucose levels can fall dangerously
low. Since if left untreated the child can die or survive with serious
impairment, it is common practice to measure the blood glucose of
neonates.
When “bedside” glucose monitors were first used for
neonates, it was discovered that increased hematocrit levels could
interfere with the function of some glucose monitors and produce
false low glucose results. The precise mechanism of this interference
is debated and may be method dependant. Some people think that the
blood may interfere with color based reactions by interfering with
light transmittance. An analogy is trying to count the raised fingers
on someone’s hand when seen through glass versus tissue paper.
In the first case it is easy. In the second situation the hand with
some fingers may be recognized but the precise number is undefined.
For other methods the blood may be too thick for the chemical reactions
to go to completion so less glucose is detected.
FDA has published guidelines to aid the makers of these devices
and several have been cleared for use in the neonatal period.
Clinicians should carefully review the claims made to help determine
if the device in question is appropriate for neonatal use. It is
also a good idea to perform a literature search to see if there
are studies published in refereed journals investigating the candidate
glucose meter in the population in question (e.g.: healthy full
term newborns or critically ill preterm neonates.) Even so, no matter
what device is used it is crucial that the end user clinicians validate
the meters they are considering for use. The clinicians should work
closely with the central lab and compare candidate devices against
their central laboratory’s current reference method. Given
the acuity of care, it may also be a good idea to periodically reevaluate
these meters against the reference standard and to develop quality
assurance and quality control programs.
In closing, increased hematocrit may interfere with some blood
glucose meters. If a result does not make sense the clinician needs
to do two things. First, reassess the patient. Second, if it is
clinically appropriate, get a new sample and verify the result using
an accepted reference method.
Bibliography:
Anonymous. Points to consider for portable blood glucose monitoring
devices intended for bedside use in the neonate nursery. FDA Guidance
Document (http://www.fda.gov/cdrh/ode/122.pdf).
February 20, 1996.
Anonymous. Review Criteria Assessment of Portable Blood Glucose
Monitoring In Vitro Diagnostic Devices Using Glucose Oxidase, Dehydrogenase
or Hexokinase Methodology (Draft Document). FDA Guidance Document
(http://www.fda.gov/cdrh/ode/gluc.html).
February 14, 1996.
Girouard J, et al. Multicenter Evaluation of the Glucometer Elite
XL Meter; an Instrument Specifically Designated for Use With Neonates.
Diabetes Care. 23(8); 1149-1153. August 2000.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods,
19’th Ed. Philadelphia, WB Saunders, 1996. pp 197-199.
Perkins SL, et al. Laboratory and Clinical Evaluation of Two Glucose
Meters for the Neonatal Intensive Care Unit. Clinical Biochemistry.
31(2); 67-71. 1998.
Soldin SJ, Devairakkam PD, Adarwalla PK. Evaluation of the Abbot
PCx® Point of Care Glucose Analyzer in a Pediatric Hospital.
Clinical Biochemistry. 33(4); 319-321. 2000.
St-Louis P, Ethier J. An Evaluation of three glucose meter systems
and their performance in relation to criteria of acceptability for
neonatal specimens. Clinical Chimica Acta. 322; 139-148. 2002.
Updated June 19, 2003
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Glucose Meter Test Results: Useful Tips to
Increase Accuracy and Reduce Errors
Have you ever wondered why you got a bad glucose meter test result
when there is nothing obvious wrong with your meter, your test strips
are new, and you’ve been running glucose tests for years?
The simple answer is that glucose meters are not perfect, and neither
are the people who use them! This chart lists some tips to help
you get the most accurate results from your glucose meter.
Make
sure you... |
Because |
- follow the user instructions about sample size. Repeat
the test if you have any doubt that enough blood was added.
|
If there is insufficient blood on the test strip,
the meter may not be able to read the glucose level accurately.
Although many meters are designed to alert you when the sample
size is too small, some meters detect only large errors. There
have been cases where meters have displayed glucose levels that
were less than half the actual levels without displaying error
messages. |
- insert the test strip completely into the meter guides.
|
When a test strip is not fully inserted into
the meter, the meter cannot read the entire strip area. Many
meters are designed to detect strip placement errors and will
not provide a result. But, just as described above, many meters
detect only large problems. There have been cases where meters
have displayed glucose levels that were significantly higher
or lower than the actual levels when there was only a small
error in strip placement. |
|
Even small amounts of blood, grease, or dirt
on a meter’s lens can alter the reading. |
- check the test strip package to make sure the strips are
compatible with your meter.
|
Test strips are not always interchangeable, and
meters cannot always detect incompatible strips. Test strips
that look alike may have different chemical coatings. Small
variations in strip dimensions can also affect results. |
- check the expiration date on the test strips.
|
As a test strip ages, its chemical coating breaks
down. If the strip is used after this time, it may give inaccurate
results. |
- enter the correct calibration code from the outside of
the strip bottle each time you run a test (if applicable).
|
Results can vary significantly between manufactured
lots of reagent strips; the calibration codes help the meter
compensate for these variations. |
- run quality control as directed.
|
Running quality control is typically the only
way to know when test strips have gone bad. Test strips do not
always last until the expiration date on the bottle. This may
be because the manufacturer has over-estimated the dating or
because the cap was not replaced promptly after use. |
- check the results from your meter against laboratory results
as often as possible.
|
Over time, test systems can drift apart. Since
results from either test system maybe used to treat your patients,
it is important for the systems to remain synchronized. |
- question results that are not consistent with physical
symptoms. If a test result seems wrong, have a blood sample
tested by the main laboratory.
|
There may be many reasons why a test result is
incorrect. In addition to the items above, some physiological
conditions such as dehydration, hyperosmolarity, high hematocrit,
or shock may significantly affect test results. |
Updated July 14, 2003
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Reporting Problems with Laboratory Tests
and Equipment
Once an IVD device goes into widespread use, unforeseen problems
can arise. FDA's premarket review cannot always detect adverse events
that are rare or if the problems are related to the clinical use
of the device, manufacturing problems, product labeling (including
instructions for use), or user technique and skill. To identify
these problems, FDA and manufacturers depend on reports from the
individuals and facilities that use IVD devices.
What types of problems should be reported?
- Device problems including
- reagent or instrument failure
- defects in product design or development
- product instability
- any other device problems that compromise patient health
or safety
- failure to perform according to performance characterized
in package insert
- incorrect test results that cause or contributed to an incorrect
patient diagnosis and/or treatment
- Use-related problems including
- inadequate and/or misleading labeling or confusing user
instructions
- inadequate packaging or poor package design
- any other user problems that compromise patient health
or safety
Who should report IVD device problems?
- User facilities, including hospitals, ambulatory surgical facilities,
nursing homes, outpatient treatment facilities, or outpatient
diagnostic facilities are required to report
- device-related events that have caused, or may have caused
or contributed to a death to both the FDA and the manufacturer.
- device-related events that have caused, or may have caused
or contributed to a serious illness or injury to the manufacturer.
If the medical device manufacturer is unknown, the serious
injury is reported by the facility to FDA.
- All other IVD device users, including doctors and patients,
are encouraged to voluntarily report device problems directly
to the manufacturer and/or FDA whenever it is suspected that the
product caused or contributed to an adverse outcome. FDA is interested
in reports of:
- product problems such as erroneous results (false positive
or false negative),
- unexplained quality control (QC) failures,
- inaccurate or unreadable instructions for use,
- packaging or product mix-up,
- contamination or stability problems,
- defective devices,
- product confusion caused by name, labeling, design, or
packaging,
- "near misses" where under slightly different circumstances,
a serious injury or death might have occurred, or
- use error
How should IVD device problems be reported?
If you want to notify OIVD directly of a problem with a laboratory
test or other equipment, contact us at fdalabtest@cdrh.fda.gov.
What happens to your report?
When FDA receives a report from a user facility, device user or
an individual healthcare professional, it is entered in the medical
device postmarket surveillance database. FDA continually reviews
the database to detect problems, trends, and potential hazards.
When FDA detects risks or potential risks associated with the use
of a particular product, the agency can take corrective actions
and notify the public.
Who has access to your report?
FDA is aware that IVD device users are concerned about the issue
of confidentiality and public availability of reports. For all reports,
FDA holds the patient's identity in strict confidence and protects
it to the fullest extent of the law. FDA will not release any patient
identifiers to the public. Reporters can assist in this process
by not using the patient's name, initials, or other identifying
information. The reporter's identity, including the identity of
a self-reporter, may be shared with the manufacturer unless requested
otherwise (there is a check-off box on the report form). However,
FDA will not disclose the reporter's identity in response to a request
from the public, pursuant to the Freedom of Information Act.
See also:
Medical Device Reporting for User Facilities
MedWatch: The FDA Safety Information
and Adverse Event Reporting Program
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