New FDA Guidance Tells IVD Makers How to Test for Biotin Interference

On June 13, the FDA issued a draft guidance explaining how makers of in vitro diagnostic devices (IVDs) should perform biotin interference testing and communicate testing results to labs, clinicians and other device end-users. Here are the key takeaways.

What Is Biotin Interference

Biotin, aka vitamin B7, is a common ingredient in multi-vitamins, prenatal vitamins and dietary supplements. Falsely high or falsely low test results have been known to occur in patients who consume high levels of biotin from such products. These results can lead to inappropriate patient management or misdiagnosis.

The FDA Response

The FDA first expressed concern about biotin interference on IVD performance in a November 2017. Since then the agency has worked with manufacturers of currently marketed devices to address the problem.

As the guidance points, devices using biotin/avidin technology have historically been assessed for biotin interference at the normal recommended daily doses of biotin of 30 μg per day, which results in plasma/serum biotin levels of < 1 ng/mL. Nevertheless, "unanticipated biotin interference with the performance of some IVDs due to consumer use of dietary supplements" have in some instances revealed much higher levels; extremely high biotin doses also have been observed of up to 300 mg per day, which results in plasma/serum biotin levels of > 1000 ng/mL.

The FDA's 6 Recommendations

The first five of the six recommendations contained in the new draft guidance involve testing methods. Specifically, the FDA recommends that:

• Sponsors contact the appropriate Center for Biologics Evaluation and Research (CBER) or Center for Devices and Radiological Health (CDRH) review division when biotin interference at clinically relevant analyte and biotin concentrations is demonstrated;
• Designing studies to test for biotin interference in accordance with the designs set out in the most current version of Clinical Laboratory Standards Institute (CLSI) EP07, Interference Testing in Clinical Chemistry; Approved Guideline;
• Concentrations of biotin be evaluated up to 3500 ng/mL to reflect current trends in biotin consumption;
• Test samples include analyte levels near the medical decision point(s) of the device;
• The concentration of biotin at which no interference is detected be determined for assays that are susceptible to biotin interference at concentrations less than 3500 ng/mL.

The draft guidance also recommends including information on biotin interference testing in the labeling of the device, including the percent difference or bias at each concentration tested for both qualitative and quantitative assays and the consequence of biotin interference, e.g., any falsely elevated or falsely depressed observed.

Takeaway: As with other FDA guidance documents, the new draft guidance doesn't carry the effect of law. The recommendations are just that—recommendations—not mandates (unless specific regulatory or statutory requirements are cited). Even so, because the guidance incorporates the FDA's expectations and standards, IVD makers are well advised to take it seriously.