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  5. Overview of IVD Regulation
  1. IVD Regulatory Assistance

Overview of IVD Regulation

This section provides an overview of how the FDA regulates in vitro diagnostic (IVD) products. It does not operate to bind the FDA or the Public. Manufacturers can find detailed information about complying with the Federal Food, Drug and Cosmetic Act (FD&C Act) from the Device Advice: Device Regulation and Guidance section.

What is an in vitro diagnostic product (IVD)?

Definition: In vitro diagnostic products are those reagents, instruments, and systems intended for use in 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. [21 CFR 809.3]

Regulatory Authority: IVDs are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act, and may also be biological products subject to section 351 of the Public Health Service Act. Like other medical devices, IVDs are subject to premarket and postmarket controls. IVDs are generally also subject to categorization under the Clinical Laboratory Improvement Amendments (CLIA '88) of 1988.

How are IVDs classified?

The FDA classifies medical devices, including IVD products, into Class I, II, or III according to the level of regulatory control that is necessary to reasonably assure safety and effectiveness. The classification of an IVD (or other medical device) determines the appropriate premarket process.

The Code of Federal Regulations lists the classification of existing IVDs in 21 CFR 862, 21 CFR 864, and 21 CFR 866.

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What is a General Purpose Reagent?

A general purpose reagent (GPR) is "a chemical reagent that has general laboratory application, is used to collect, prepare, and examine specimens from the human body for diagnostic purposes, and is not labeled or otherwise intended for a specific diagnostic application …[General purpose reagents] do not include laboratory machinery, automated or powered systems."

Classification information for GPRs can be found in 21 CFR 864.4010(a).

What are Analyte Specific Reagents?

Analyte specific reagents (ASRs) are "antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reaction 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."

Classification information for ASRs can be found in 21 CFR 864. 4020(a).

What are General Controls?

IVDs, and all other medical devices, are subject to General Controls, unless expressly exempt per the statute or regulations.

General Controls are the basic provisions (authorities) of the May 28, 1976 Medical Device Amendments to the FD&C Act, that provide the FDA with the means of regulating devices to reasonably assure their safety and effectiveness. The General Controls in the Amendments apply to all medical devices, including IVDs. They include provisions that relate to adulteration; misbranding; device registration and listing; premarket notification; banned devices; notification, including repair, replacement, or refund; records and reports; restricted devices; and good manufacturing practices.

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What are the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88)?

  • CLIA '88 establishes quality standards for laboratory testing and an accreditation program for clinical laboratories.
  • CLIA '88 requirements vary according to the technical complexity in the testing process and risk of harm in reporting erroneous results. The regulations established three categories of testing on the basis of the complexity of the testing methodology: a) waived tests, b) tests of moderate complexity, and c) tests of high complexity.
  • Manufacturers apply for CLIA '88 categorization during the premarket process.
  • Under CLIA, laboratories performing only waived tests are subject to minimal regulation. Laboratories performing moderate or high complexity tests are subject to specific laboratory standards governing certification, personnel, proficiency testing, patient test management, quality assurance, quality control, and inspections.

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What is the Pre-Submission Process for IVDs?

The Pre-Submission process was established under MDUFA III and further refined under MDUFA IV and the Q-Submission Program guidance.

A Pre-Submission includes a formal written request from a submitter for feedback from the FDA which is provided in the form of a formal written response or, if the submitter chooses, a meeting or teleconference in which the feedback is documented in meeting minutes. A Pre-Submission meeting is a meeting or teleconference in which the FDA provides its substantive feedback on the Pre-Submission.

A Pre-Submission is appropriate when the FDA's feedback on specific questions is necessary to guide product development and/or application preparation.

The FDA encourages use of a Pre-Submission under circumstances such as the following:

  • The device involves new technology, a new intended use, or a new analyte and it will be helpful to familiarize the FDA with the novel features in advance of the submission;
  • Assistance is needed in defining possible regulatory pathways;
  • The studies involve complex data and/or statistical approaches;
  • The predicate or reference method is unclear or uncertain; or
  • The new device is a multiplex device capable of simultaneously testing a large number of analytes.

A sponsor should submit a Pre-Submission if they would like the FDA's thoughts on their studies or proposals prior to starting their studies. The potential benefits of submitting a Pre-Submission are:

  • to begin a dialogue with the FDA and promote greater understanding.
  • to reduce the cost of research studies by focusing in on the important information needed for the FDA's approval (or clearance) and eliminating unnecessary or burdensome studies, and
  • to facilitate the review process for the future marketing application since the FDA will already be familiar with the device.

Pre-Submissions and associated meetings are strictly voluntary, and any comments or recommendations made in the review of protocols or during these meetings are not binding on the manufacturer or the FDA.

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What is an Investigational Device Exemption (IDE)?

  • An IDE allows an investigational device to be used in a clinical study to collect safety and/or effectiveness data to support a subsequent submission for marketing authorization.
  • An IDE permits devices to be shipped lawfully for the purpose of conducting investigations without complying with requirements of the FD&C Act that apply to devices in commercial distribution.
  • Many IVDs are exempt from IDE requirements.

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What is a Premarket Notification [510(k)]?

A 510(k) is a premarket submission made to the FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent (SE), to a legally marketed device [21 CFR 807.92(a)(3)] that is not subject to premarket approval (PMA).

There are three types of Premarket Notification 510(k)s that may be submitted to the FDA: Traditional, Special, and Abbreviated.

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What is the 510(k) Review Process for IVD devices?

For IVDs, the review of a 510(k) includes an evaluation of the analytical performance characteristics of the new device compared to the predicate, including:

  • the bias or inaccuracy of the new device;
  • the imprecision of the new device; and
  • the analytical specificity and sensitivity.

Studies to Demonstrate Substantial Equivalence

The types of studies typically used to demonstrate substantial equivalence may include the following:

  • In the majority of cases, analytical studies using clinical samples (sometimes supplemented by carefully selected artificial samples) are sufficient.
  • For some IVDs, the link between analytical performance and clinical performance is not well defined. In these circumstances, clinical information may be warranted.
  • FDA rarely requires prospective clinical studies for IVDs, but regularly requests clinical samples with sufficient laboratory and/or clinical characterization to allow an assessment of the clinical validity of a new device. This is usually expressed in terms of clinical sensitivity and clinical specificity or agreement.

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What is a De Novo Classification for IVD Devices?

The De Novo process provides a pathway to classify novel medical devices for which general controls alone, or general and special controls, provide reasonable assurance of safety and effectiveness for the intended use, but for which there is no legally marketed predicate device. De Novo classification is a risk-based classification process.

Devices that are classified into class I or class II through a De Novo Classification Request (De Novo request) may be marketed and used as predicates for future premarket notification [510(k)] submissions, if necessary.

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What is a Premarket Approval (PMA)?

Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices.  

For IVDs, there is a unique link between safety and effectiveness since the safety of the device is not generally related to contact between the device and patient. For IVD products, the safety of the device relates to the impact of the device's performance, and in particular on the impact of false negative and false positive results, on patient health.

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What are the Requirements for IVD Labeling?

In Vitro Diagnostic Products have additional labeling requirements under 21 CFR 809, Subpart B, In Vitro Diagnostic Products for Human Use. Before a manufacturer obtains marketing authorization for an IVD product, they must label the product in accordance with labeling regulations.

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How does FDA Look at Quality Control for IVD Devices?

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What is Establishment Registration?

  • Establishments involved in the production and distribution of medical devices intended for commercial distribution in the United States (U.S.) are required to register with the FDA.
  • Registration provides FDA with the location of medical device manufacturing facilities and importers.
  • Registration of an establishment is not an approval of the establishment or its devices by FDA. That is, it does not provide FDA authorization to market the device. Unless exempt, premarketing authorization is required before a device can be placed into commercial distribution in the U.S.

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What is Medical Device Listing?

  • Most medical device establishments required to register with the FDA must list the devices they have in commercial distribution including devices produced exclusively for export.
  • Listing keeps the FDA advised of the generic category(s) of devices an establishment is marketing.
  • Listing of a device on FDA's website does not constitute that FDA has authorized that device to be legally marketed. Unless exempt, premarketing authorization is required before a device can be placed into commercial distribution in the U.S.

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What are current good manufacturing practices (CGMPs) and Quality System (QS) Regulation requirements?

The requirements for CGMPs are prescribed in the Quality System Regulations. They require that domestic or foreign manufacturers have a quality system for the design, manufacture, packaging, labeling, storage, installation, and servicing of finished medical devices intended for commercial distribution in the United States, unless such device is expressly exempt from QSR per regulation, which would be identified in specific classification regulations in 21 CFR parts 862-892. The QS Regulation is contained in 21 CFR 820.

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What are Good Clinical Practice Requirements for Data Submitted from Clinical Investigations for IVD Device Premarket Submissions?

The requirements are described in Good Clinical Practice Requirements for Data Submitted from Clinical Investigations for IVD Device Premarket Submissions.

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What is Medical Device Reporting?

  • Section 519 of the FD&C Act and the Medical Device Reporting (MDR) regulations [21 CFR Part 803] require manufacturers who have received complaints of device malfunctions, serious injuries or deaths associated with medical devices to notify the FDA of the incident.
  • MDR regulations [21 CFR 803.30] require User Facilities (e.g., hospitals, laboratories) to report suspected medical device related deaths to both the FDA and the manufacturers. User facilities must report medical device related serious injuries to the manufacturer.

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What happens to products that are in violation of laws administered by the FDA?

  • In most cases, manufacturers and distributors voluntarily recall products that present a risk of injury or gross deception or are otherwise defective. 21 CFR 7 provides guidance so that responsible firms may conduct an effective recall.
  • In rare instances, where the manufacturer or importer fails to voluntarily recall a device that is a risk to health, the FDA may issue a recall order to the manufacturer under 21 CFR 810, Medical Device Recall Authority.
  • Under 21 CFR 806, Medical Device Correction and Removals, manufacturers (including refurbishers and reconditioners) and importers are required to make a report to the FDA of any correction or removal of a medical device(s) if the correction or removal was initiated to reduce a risk to health posed by the device or to remedy a violation of the Act caused by the device which may present a risk to health.

How does the FDA ensure compliance with the Federal Food, Drug, and Cosmetic Act for IVD devices?

The FDA works with manufacturers throughout the total product life cycle to ensure compliance with the FD&C Act in the least burdensome manner for medical devices. This approach enables manufacturers to receive assistance and feedback in a timely manner and may reduce the need for compliance actions.

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