Types of in Vitro Diagnostics

This white paper examines and compares the regulatory frameworks governing RUO (Research Use Only), IUO (Investigational Use Only), ASR (Analyte Specific Reagent), LDT (Laboratory Developed Test), CDx (IVD Companion Diagnostics) and GPR (General Purpose Reagents) product types. By clarifying their definitions, intended uses, and oversight requirements, the paper aims to provide a practical understanding of how regulatory distinctions shape diagnostic development and deployment within the U.S. healthcare system.

A medical device is officially defined as: “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is-- (1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them, (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or (3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.” ¹

Under that same section of the law, all IVDs for human use are medical devices. They are further defined officially as “those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.” ² The key words here are “in vitro”, meaning that the item is not for use in the body- these are literally, tests that are run outside the body on samples of tissue or blood, etc.

Products in this category are designed for research use only and are not authorized for use for clinical diagnostic purposes. The term, RUO, can be used to represent early stage prototype assays that may eventually develop into an IVD medical device product, or it can be used to represent a diagnostic product commercialized for research purposes, but is not itself the object of the research. Whichever the case, RUO products do not meet the definition of a medical device, and are therefore exempt from most regulatory controls, with the exception of specific labeling requirements. To avoid the risk of use for clinical applications, the FDA requires all RUO products distributed in the United States to be labeled “For Research Use Only. Not for use in diagnostic procedures”

IUOs is a term used for a diagnostic product that is being shipped or delivered for product testing that is not subject to 21 CFR part 812 (with the exception of 812.119, Disqualification of Clinical Investigator) prior to full commercial marketing.⁴ Typical IUO use scenarios for IVDs would be, for instance, comparison studies where archived or fresh clinical specimens are used to determine performance characteristics of the IUO product.

Importantly, IUO devices are not the same thing as an IDE device, which is undergoing testing for safety and effectiveness, and is therefore subject to the IDE regulations. IUO status applies only to those devices that are exempt from the IDE regulations.

Like RUOs, IUOs cannot be labeled for a specific clinical or diagnostic use. IUOs can be used to contribute to a clinical diagnosis, but confirmation by the use of another medically accepted test or procedure is always required.

Similar to RUO products, the labeling of an IUO device is required to have a disclaimer regarding its regulatory status. In the case of IUO devices, the disclaimer must state “For Investigational Use Only. The performance characteristics of this product have not been established”. (This is as opposed to the labeling of devices that are subject to the IDE regulations, which must state “"CAUTION--Investigational device. Limited by Federal (or United States) law to investigational use.".)

Lastly, similar to RUO products, IUO products do not meet the definition of a medical device and are exempt from the corresponding regulations.

Per the ASR rule (21 CFR 864.4020) promulgated in 1997, ASRs are defined as “antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reactions with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.".⁵ ASRs meet the definition of a medical device and are mostly categorized as Class I products subject to FDA’s general controls, including establishment registration and listing (21 CFR 807.20(a)), adverse event reporting (21 CFR 803), labeling requirements, 21 CFR 809.10(e), and compliance with the quality management system regulation ( 21 CFR 820, except 820.30), and are exempt from premarket applications. Class II and Class III ASRs are subject to both general and special controls and require marketing authorization from the FDA. Class II ASRs (e.g., a component in specific blood banking tests ) require premarket notification clearance, and Class III ASRs (e.g., a component of a test for a high risk disease) require premarket approval.

In addition to the above stated general controls, ASRs have restrictions with respect to their sale, use, distribution, labeling, advertising and promotion (21 CFR 809.30) including:

• LDTs that are developed using ASRs can only be ordered by physicians or other persons authorized by applicable State law
• A laboratory that develops an LDT using an ASR are required to add a statement disclosing the test has not been cleared or approved by FDA when reporting the test result to the practitioner
• Advertising and promotional materials making any claims for clinical or analytical performance of ASRs is prohibited.
• Advertising and promotional materials for Class I ASRs must include the statement “Analyte Specific Reagent. Analytical and performance characteristics are not established”.
• Advertising and promotional materials for Class II or Class III ASRs must include the statement “Analyte Specific Reagent. Except as a component of the approved/cleared test (name of approved/cleared test), analytical and performance characteristics are not established”.

An LDT is a type of in vitro diagnostic test that is designed, manufactured, and used within a single laboratory. While all vitro diagnostics intended for clinical diagnosis are under the jurisdiction of the FDA, the Agency has historically exercised enforcement discretion for LDTs, as the original tests were considered low risk and were designed to address unmet specialized needs. Accordingly, the tests were placed under the jurisdiction of Centers for Medicare & Medicaid Services (CMS) where they continue to be governed under the Clinical Laboratory Improvement Amendments (CLIA) regulations. However, the regulatory landscape for LDTs continues to be a topic of discussion, as the FDA has made efforts in recent years to end enforcement discretion and regulate LDTs as IVDs in response to LDT’s becoming more complex, more widely used, and carrying greater risks than before.⁶

While the laboratories performing the LDTs are indeed regulated, it is important to note the differences between how the FDA and CMS regulate IVDs and LDTs, respectively. Where the FDA’s primary focus is confirming safety and efficacy in the design and manufacture of IVDs, the CLIA regulations focus on confirming the quality of the laboratory, including assessing personnel qualifications, test performance, and quality control. Moreover, where the FDA requires review and authorization of premarket authorization applications for Class II and Class III IVDs prior to commercialization, the CMS requires that laboratories self-validate their tests, regardless of risk level, and do not require review and authorization by CMS prior to implementation and use. ⁷ Lastly, contrary to IVDs, LDTs do not have an adverse event or correction and removals reporting requirements to CMS, making post-market surveillance difficult.

Per FDA Guidance In Vitro Companion Diagnostic Devices⁸⁶, an IVD companion diagnostic device is an IVD that provides information that is essential for the safe and effective use of a corresponding therapeutic product. Examples of how companion diagnostics are used to ensure the safe and effective use of a corresponding therapeutic include:

• Identification of patients who are most likely to benefit from the therapeutic product
• Identification of patients likely to be at increased risk for serious adverse reactions as a result of treatment with the therapeutic product
• Monitoring a patient’s response to treatment with the therapeutic product for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness
• Identification of patients in the population for whom the therapeutic product has been adequately studied, and found safe and effective, i.e., there is insufficient information about the safety and effectiveness of the therapeutic product in any other population⁹

Per the guidance document, labeling for the IVD companion diagnostic device must include a statement stipulating its use with the brand name of the corresponding therapeutic drug(s) for which marketing authorizations were contemporaneously granted. Alternatively, in the case of oncology products, the FDA has issued guidance¹⁰ recommending labeling for IVD companion diagnostics to reference a specific group of oncology therapeutic products rather than a single brand name. Conversely, when considering labeling for the corresponding therapeutic, the FDA recommends against referencing a specific IVD companion diagnostic brand name in favor of including a statement stipulating use of the therapeutic with an FDA approved or cleared IVD companion diagnostic. The intent of using this more flexible approach is to encourage the development and use of more than one IVD companion diagnostic.

For novel therapeutic products, the FDA intends to review premarket applications for IVD companion diagnostics at the same time as the application for the therapeutic product and will generally not approve the new therapeutic or new indications for an existing therapeutic product if the IVD companion diagnostic is not approved or cleared for that indication; with the exception of certain circumstances where there is a clear benefit to allowing the commercialization of the therapeutic drug ahead of IVD companion diagnostic marketing authorization.

With respect to clinical trials, subject IVD companion diagnostics and subject therapeutic products can be combined into one investigational study, but the study must meet the requirements for both the device IDE (investigational device exemption) regulations (21 CFR 812) as well as the IND (investigational new drug) regulations (21 CFR 312).

Manufacturers who are developing companion diagnostics would be well-advised to seek a meeting with the relevant device and therapeutic product review divisions at the FDA should they have any questions, in order to ensure a smooth review process down the road.

A General Purpose Reagent (GPR) is defined as “a chemical reagent that has general laboratory application, that is used to collect, prepare, and examine specimens from the human body for diagnostic purposes, and that is not labeled or otherwise intended for a specific diagnostic application.”

GPRs cannot be labeled for a specific clinical or diagnostic use. However, GPRs can be combined with and/or used in conjunction with ASRs by the laboratory or IVD manufacturer that develops the finished test.

GPRs are not IVDs, but are classified as Class I medical devices. Therefore they are subject to the requirements for registration/listing, and MDR reporting. Due to their status as a Class I medical device, GPRs are exempt from the requirements for premarket notification. Additionally, they are only subject to compliance with sections 820.180 (records) and 820.198 (complaint files) of the QS Regs, unless the GPR is sold as sterile.

Understanding the distinctions between the different categories of IVDs and their corresponding framework is not merely an exercise in compliance; it is fundamental to ensuring that diagnostic innovations move efficiently and responsibly from concept to clinical application. The FDA’s increasing emphasis on risk-based oversight, combined with the evolving relationship between FDA and CMS under CLIA, underscores the need for stakeholders to anticipate regulatory expectations early in the development lifecycle. Misclassification or misunderstanding of regulatory intent can delay market entry, jeopardize patient safety, and erode confidence in emerging diagnostic technologies.

FOOTNOTE:

1. Section 201(h) of the Food, Drug & Cosmetic Act 
2. 21 CFR Part 201.119
3. 21 CFR 809.10(c)(2)(i)
4. Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only
5. Guidance for Industry and FDA Staff Commercially Distributed Analyte Specific Reagents (ASRs): FrequentlyAsked Questions
6. FDA News Release: FDA Takes Action Aimed at Helping to Ensure the Safety and Effectiveness of Laboratory Developed Tests
7. LDT and CLIA FAQs 10/22/2013
8. Guidance for Industry and Food and Drug Administration Staff: In Vitro Companion Diagnostic Devices
9. In Vitro Companion Diagnostic Devices; Guidance for Industry and Food and Drug Administration Staff
10. Developing and Labeling In Vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products