FDA Watch

Agency Finalizes Rule on Off-Label Uses Liability and Rights of Laboratories to Create LDTs

On Aug. 2, 2021, the U.S. Food and Drug Administration (FDA) published the long-awaited final rule updating its “intended use” regulations for medical devices and drugs. Here is a quick briefing of the new rules, which took effect on Sept. 1.

The “Intended Use” Regulations

In 2015, FDA proposed to eliminate a regulatory requirement that a manufacturer “provide adequate labeling” to account for unapproved, i.e., off-label uses, about which it “knows, or has knowledge of facts that would give him notice.” A 2017 final rule did remove the provision but also required manufacturer to incorporate an unapproved use into the labeling if the “totality of the evidence” establishes that the manufacturer objectively intended to introduce the product for that use. But the agency delayed the effective date of the final rule in response to industry concerns over the “totality of the evidence” clause.

So, the agency went back to the drawing board, issuing a new proposed rule in September 2020, clarifying that:

  • Knowledge of off-label use of a product by a physician cannot by itself establish a manufacturer’s intended use for the product; and
  • Any relevant source of evidence may be considered as establishing “intended use,” not just the manufacturer’s promotional claims about the product.

The 2021 Final Rule

The newly published final rule reaffirms that the agency may consider “any relevant source of evidence,” including “a variety of direct and circumstantial evidence” in determining “intended use.” Nothing in the Federal Food, Drug, and Cosmetic Act (FDCA) limits FDA to relying only on promotional statements. Besides, the final rule adds, the ability to rely on a broader base of evidence about a product’s intended use enables the agency to curb “distribution of dangerous and fraudulent products” more effectively.

However, the final rule reassures that a manufacturer will not be automatically deemed to have intended an off-label use based solely on knowledge that its approved product is being used or prescribed off-label. The basis of this approach is FDA’s longstanding “practice of medicine exemption” of not regulating off-label use of a lawfully marketed drug/device by a licensed health care practitioner in the context of caring for an individual patient.

The LDTs Provisions

Of more direct concern to laboratory test makers, the final rule language also preserves the ability of laboratories to develop laboratory-developed tests (LDTs) using either in vitro diagnostic (IVD) or research use only (RUO) components, provided that the LDTs comply with Clinical Laboratory Improvement Amendments (CLIA) regulations in their development and are offered on the order of a health care provider.

Note that the final rule applies to both devices granted marketing authorization (thus covering those brought to market via the de novo pathway) and those brought to market through 510(k) clearance or PMA approval, as well as to those exempt from premarket notification.

FDA also left in place a complimentary provision under which a third party may be held liable for furthering an off-label use. Specifically, a distributor, seller or other person who receives an article and furthers its commercialization for a different, unapproved purpose is required to supply adequate labeling for that use, or risk liability for marketing a misbranded article.

Here are some of the key new FDA EUAs and clearances announced in September 2021:

New FDA Emergency Use Authorizations (EUAs) & Approvals

Manufacturer(s) Product
Paige de novo marketing authorization for Paige Prostate
MeMed 510(k) clearance for MeMed BV test on MeMed Key platform
Takeda Pharmaceutical Accelerated approval for mobocertinib (Exkivity) for previously treated, metastatic non-small cell lung cancers harboring EGFR exon20 insertion mutations
Quanterix EUA for Simoa SARS-CoV-2 N protein antigen test expanded to include testing with saliva samples and for asymptomatic serial testing with nasal swab samples
Cairn Diagnostics Expanded clearance for 13C-Spirulina Gastric Emptying Breath Test, or GEBT, to include at-home under virtual supervision
Cepheid EUA for Xpert Xpress COV-2/Flu/RSV plus, a new version of its multiplex SARS-CoV-2, influenza, and respiratory syncytial virus test
Yale School of Public Health EUA for SalivaDirect DTC Saliva Collection Kit and SalivaDirect test
Swiss Precision Diagnostics Clearance for home-use Clearblue Early Digital Pregnancy Test
Atlas Link Technology 510(k) clearance for 3 over-the-counter pregnancy tests
Atlas Link Technology *Atlas One Step hCG Urine Pregnancy Test (Strip)
Atlas Link Technology *Atlas One Step hCG Urine Pregnancy Test (Cassette)
Atlas Link Technology *Atlas One Step hCG Urine Pregnancy Test (Midstream)
Abbott Laboratories Clearance for use of i-Stat Chem8+ cartridge with i-Stat 1 System
Inova Diagnostics 510(k) clearance for Aptiva Celiac Disease IgG Reagents
Diazyme Clearance for use of PLAC Test for Lp-PLA2 Activity on automated clinical chemistry analyzers
Ark Diagnostics Clearance for Ark Lacosamide Assay
Ortho Clinical Diagnostics Clearance for Vitros Chemistry Products PHBR Slides
Assure Tech Clearance for AssureTech DOA Dipstick Screen Panel Tests
CD Diagnostics Clearance for Synovasure Alpha Defensin Lateral Flow Test Kit
InBios International EUA for point-of-care SCoV-2 Detect IgG Rapid Test
Visby Medical 510(k) clearance and CLIA waiver for Visby Medical Sexual Health Click Test
Mount Sinai Hospital EUA for Mount Sinai SARS-CoV-2 Assay
Empire City Laboratories EUA for ECL COVID Test System and ECL COVID Test System-1
CellMax Life Breakthrough Device Designation for FirstSight colorectal precancer and cancer detection blood test
Thermo Fisher Scientific Clearance for Oncomine Dx Target Test
Thermo Fisher Scientific Clearance for Thermo Scientific EliA SmDP-S test for aiding in diagnosis of systemic lupus erythematosus (SLE)
Thermo Fisher Scientific Pre-market approval for Oncomine Dx Target Test as companion diagnostic to identify isocitrate dehydrogenase-1 (IDH1) mutated cholangiocarcinoma (CCA) patients who may benefit from treatment with ivosidenib (Servier Pharmaceuticals’ Tibsovo)
Becton Dickinson EUA for BD Veritor At-Home COVID-19 Test
Becton Dickinson Clearance for BD Cor system along with BD Onclarity HPV Assay for extended genotyping of human papillomavirus
Siemens Healthineers de novo authorization for Enhanced Liver Fibrosis blood test
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