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Final Rule Clarifies Liability for Off-Label Uses and Lab’s Right to Create LDTs

by | Sep 13, 2021 | Articles, Essential, FDA-lir, Laboratory Industry Report, LDTs-lir

On Aug. 2, 2021, the FDA published the long-awaited final rule updating its “intended use” regulations for medical devices and drugs. Here’s 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 can’t 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 […]

On Aug. 2, 2021, the FDA published the long-awaited final rule updating its “intended use” regulations for medical devices and drugs. Here’s 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 can’t 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 won’t 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 lab test makers, the final rule language also preserves the ability of labs 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 August 2021:

New FDA Emergency Use Authorizations (EUAs) & Approvals

Manufacturer(s) Product
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 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
Kwokman Diagnostics EUA for Kwokman Diagnostics COVID-19 Home Collection Kit
Roche Clearance for Ventana MMR RxDx immunohistochemistry panel as a companion diagnostic to select patients for treatment with GlaxoSmithKline’s newly cleared anti-PD-1 agent dostarlimab-gxly (Jemperli) for patients with previously treated, mismatch repair-deficient, or dMMR, solid cancers
Roche EUA for RT-PCR-based Cobas SARS-CoV-2 nucleic acid test for use on the Cobas Liat system
STS Lab Holdco (Amazon subsidiary) EUA for Amazon Multi-Target SARS-CoV-2 Real-Time RT-PCR Test
Cleveland Clinic EUA for SelfCheck COVID-19 TaqPath Multiplex PCR test
Qiagen + Ellume EUA for QiaReach SARS-CoV-2 Antigen Test
Pillar Biosciences Premarket approval for OncoReveal Dx Lung and Colon Cancer Assay tissue-based companion diagnostic test for qualitative detection of somatic mutations in DNA from non-small cell lung cancer and colorectal cancer tissue samples
Thermo Fisher Scientific EUA for COVID-19 Fast PCR Combo Kit 2.0 to detect SARS-CoV-2 nucleic acid in saliva samples
Thermo Fisher Scientific EUA for TaqPath COVID-19 MS2 Combo Kit 2.0 PCR-based test
Access Bio EUA for CareStart COVID-19 Antigen Home Test chromatographic, digital immunoassay
LumiraDx EUA for SARS-CoV-2 Ab Test (total antibodies test)
Phase Scientific International EUA for Indicaid COVID-19 Rapid Antigen Test
NYU Langone Health 510(k) clearance for Genome PACT genetic test for solid tumors

NEW CE MARKINGS IN EUROPE

Manufacturer(s) Product
Agilent Technologies Expanded use of PD-L1 IHC 22C3 pharmDx companion diagnostic assay for identifying esophageal cancer patients for treatment with anti-PD-1 cancer drug pembrolizumab (Merck’s Keytruda) using a combined positive score of at least 10
DiaCarta QuantiVirus SARS-CoV-2 Variant Detection Test
Prenetics Circle HealthPod point-of-care SARS-CoV-2 testing system
Becton Dickinson and Viasure SARS-CoV-2 Variant Real Time PCR Detection Kit for BD Max
CerTest Biotec Viasure SARS-CoV-2 Variant Real Time PCR Detection Kit for BD Max
Accelerate Diagnostics New configuration of Accelerate PhenoTest BC kit
EliTechGroup SARS-CoV-2 Elite MGB Kit for use with saliva
Cepheid Xpert HIV-1 Viral Load XC PCR-based test
Cepheid Xpert HIV-1 Qual XC PCR-based test

Other international clearances announced during the period:

Manufacturer(s) Country(ies) Product(s)
Aegirbio Thailand Saliva test for COVID-19 detection
Exact Sciences Japan Oncotype DX Breast Recurrence Score test and software
Amoy Diagnostics, Riken Genesis and Precision Medicine Asia Japan AmoyDx PLC Panel as a companion diagnostic to identify non-small cell lung cancer patients eligible for Merck KGaA’s tepotinib (Tepmetko)
SpeeDx Australia PlexPCR SARS-CoV-2 test

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