Testing for Biotin Interference in In Vitro Diagnostic Devices: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Testing for Biotin Interference in In
Vitro Diagnostic Devices
Guidance for Industry
For questions on the content of this guidance, contact Center for Biologics Evaluation and
Research (CBER), Office of Communication, Outreach, and Development (OCOD) at 240-402-
8010 or 800-835-4709, or email ocod@fda.hhs.gov. For questions about this document
concerning products regulated by Center for Devices and Radiological Health (CDRH), contact
the Office of In Vitro Diagnostics at 301-796-5900, or email CDRH-OIR-Policy@fda.hhs.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
Center for Devices and Radiological Health
October 2020

Testing for Biotin Interference in In
Vitro Diagnostic Devices
Guidance for Industry
Additional copies of this guidance are available from:
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., WO71, Room 3128
Silver Spring, MD 20993
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-
biologics/biologics-guidances
or
Office of Policy
Guidance and Policy Development
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., WO66, Room 5431
Silver Spring, MD 20993
Phone: 301-796-5900
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-
assistance/guidance-documents-medical-devices-and-radiation-emitting-products

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Table of Contents
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 1
III. 	BIOTIN TESTING RECOMMENDATIONS ............................................................... 2
IV. 	REFERENCES .................................................................................................................. 4

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Testing for Biotin Interference in In Vitro Diagnostic Devices
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.
I. 	INTRODUCTION
The Food the Drug Administration (FDA or we) is providing recommendations on the testing for
interference by biotin on the performance of in vitro diagnostic devices (IVDs). This guidance is
intended to help device developers and clinicians understand how FDA recommends biotin
interference testing be performed, and how the results of the testing should be communicated to
end-users, including clinical laboratories and clinicians. The recommendations apply to IVDs,
including devices that are licensed under section 351 of the Public Health Service Act (42 U.S.C.
262) and used in donor screening, that use biotin technology. This guidance finalizes the draft
guidance of the same title dated June 2019.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.
II. 	BACKGROUND
FDA has become aware of potential biotin interference with IVDs that use biotin/avidin
interactions as part of the device technology. Many IVDs use biotin technology due to its ability
to bond with specific proteins which can be measured to detect certain health conditions. For
example, biotin is used in hormone tests and tests for markers of cardiac health like troponin.
Biotin, also known as vitamin B7, is a water-soluble vitamin often found in multi-vitamins,
prenatal vitamins, and dietary supplements marketed for hair, skin, and nail growth (Ref. 1).
Biotin levels in samples from patients who consume more than the recommended daily intake for
biotin can cause falsely high or falsely low results, depending on the test principle. Incorrect test
results may lead to inappropriate patient management or misdiagnosis (Ref. 1). FDA’s concern
regarding biotin interference was expressed in Safety Communications on November 28, 2017
(Ref. 2) and November 5, 2019 (Ref. 3) and manufacturers of currently marketed devices have
been working with FDA to address interference when it occurs. Historically, devices using

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biotin/avidin technology have been assessed for biotin interference at the normal recommended
daily doses of biotin (30 μg per day, which results in plasma/serum biotin levels of < 1 ng/mL).
However, several recent reports (Refs. 4-6) have described unanticipated biotin interference with
the performance of some IVDs due to consumer use of dietary supplements that result in
plasma/serum biotin levels of > 1 ng/mL. In addition, extremely high biotin doses also have
been observed (up to 300 mg per day, which results in plasma/serum biotin levels of > 1000
ng/mL).
This guidance describes FDA’s recommendations for testing for biotin interference on devices
that use biotin/avidin technology and communicating the results of such testing to the end-users,
including via labeling. The recommendations in the guidance are consistent with recent advice
we have provided to individual manufacturers and sponsors that have consulted with the agency.
They reflect FDA’s thinking that labeling alone may not be sufficient to mitigate the risk of
incorrect results from biotin interference in all cases. Additional mitigation strategies may be
considered when the risk of potentially incorrect results from biotin interference could
significantly affect patient or public health.
III. 	RECOMMENDATIONS
• 	Sponsors should contact the appropriate CBER or CDRH review division if biotin
interference at clinically relevant analyte and biotin concentrations in patient samples is
demonstrated.
• 	We recommend that studies designed to test for biotin interference follow designs similar
to those included in the most current version of Clinical Laboratory Standards Institute
(CLSI) EP07, Interference Testing in Clinical Chemistry; Approved Guideline (Ref. 7).
• 	Concentrations of biotin that reflect current trends in biotin consumption should be
evaluated. Biotin should be evaluated up to 3500 ng/mL, three times the maximum
expected clinical concentration.
The evaluation of biotin at this level is consistent with the recommendations in the CLSI
standard and appropriate for minimizing the risk to patients from incorrect test results.
• 	The samples should include analyte levels near the medical decision point(s) of the
device.
• 	For assays that are susceptible to biotin interference at concentrations less than 3500
ng/mL, the concentration of biotin at which no interference is detected should be
determined.
• 	Information on biotin interference should be communicated to end users such as clinical
laboratories and clinicians, including via the labeling1 of the device. Relevant
1 Under 21 CFR 809.10(b)(10), the labeling accompanying an in vitro diagnostic product shall state known extrinsic
factors or interfering substances affecting results. More information regarding IVD labeling requirements is
available at https://www.fda.gov/medical-devices/device-labeling/vitro-diagnostic-device-labeling-requirements.

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information to include in the labeling may be the percent difference or bias at each
concentration tested for both qualitative and quantitative assays and the consequence of
biotin interference (e.g., falsely elevated, falsely depressed), if observed.

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IV. 	REFERENCES
1. 	Biotin: Fact Sheet for Consumers, accessed March 20, 2019.
https://ods.od.nih.gov/factsheets/Biotin-Consumer/
2. 	FDA Safety Communication. The FDA Warns that Biotin May Interfere with Lab Tests.
November 2017. https://www.fda.gov/medical-devices/safety-communications/fda-
warns-biotin-may-interfere-lab-tests-fda-safety-communication.
3. 	UPDATE: The FDA Warns that Biotin May Interfere with Lab Tests: FDA Safety
Communication. November 2019. https://www.fda.gov/medical-devices/safety-
communications/update-fda-warns-biotin-may-interfere-lab-tests-fda-safety-
communication.
4. 	Piketty, M.L., et al. (2017) High-dose biotin therapy leading to false biochemical
endocrine profiles: validation of a simple method to overcome biotin interference. Clin.
Chem. Lab Med. 55(6):817–825.
5. 	Chun, Kelly Y. (2017) Biotin Interference in Diagnostic Tests. Clinical Chemistry
63:619–620.
6. 	Barbesino, G. (2016) The Unintended Consequences of Biotin Supplementation:
Spurious Immunoassay Results Lead to Misdiagnoses. Clinical Laboratory News, Bench
Matters, December 1–3.
7. 	Clinical Laboratory Standards Institute. (2018) Interference Testing in Clinical
Chemistry, 3rd Edition: April. https://clsi.org/standards/products/method-
evaluation/documents/ep07/