Overview of IVD Regulation
This section provides an overview of how FDA regulates IVDs. It does not operate to bind FDA or the Public. Manufacturers can find detailed information about complying with the Food, Drug and Cosmetic Act from the Device Advice: Device Regulation and Guidance section. For more information, see IVD Guidance Documents.
- What is an in vitro diagnostic product (IVD)?
- How are IVDs classified?
- What is a General Purpose Reagent?
- What are Analyte Specific Reagents?
- What are General Controls?
- What are the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88)?
- What is the "Pre-Submission" Process for IVDs?
- What is an Investigational Device Exemption (IDE)?
- What is a Premarket Notification [510(k)]?
- What is the 510(k) Paradigm?
- What is De Novo Classification for IVD devices?
- What is a Premarket Approval (PMA)?
- How does FDA regulate OIVD classified devices in clinical laboratory automation?
- What are the requirements for IVD labeling?
- How does FDA look at Quality Control?
- What is Establishment Registration?
- What is Medical Device Listing?
- What are Good Manufacturing Practices (GMPs) and Quality System Regulations (QSRs)?
- What is Medical Device Reporting?
- What happens to products that are in violation of laws administered by FDA?
- How does OIVD ensure compliance with the Federal Food, Drug, and Cosmetic Act?
- What is the Medical Device User Fee and Modernization Act of 2002 (MDUFMA)?
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 medical devices as defined in section 210(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 also subject to the Clinical Laboratory Improvement Amendments (CLIA '88) of 1988.
FDA classifies IVD products into Class I, II, or III according to the level of regulatory control that is necessary to assure safety and effectiveness. The classification of an IVD (or other medical device) determines the appropriate premarket process.
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).
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).
IVDs, and all other medical devices, are subject to General Controls.
General Controls are the basic provisions (authorities) of the May 28, 1976 Medical Device Amendments to the Food, Drug and Cosmetic Act, that provide the FDA with the means of regulating devices to ensure 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.
- 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.
The Pre-Submission" process was established under MDUFA III and defined in the Commitment Letter as:
A Pre-Submission includes a formal written request from an applicant for feedback from the FDA which is provided in the form of a formal written response or, if the manufacture 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 provides the opportunity for an applicant to obtain FDA’s feedback prior to submission of an Investigational Device Exemption (IDE) or marketing application. The request must include specific questions regarding review issues relevant to a planned IDE or marketing application (e.g., questions regarding pre-clinical and clinical testing protocols or data requirements). A Pre-Submission is appropriate when FDA’s feedback on specific questions is necessary to guide product development and/or application preparation.
The FDA encourages use of the Pre-Submission program 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 FDA and promote greater understanding.
- to reduce the cost of research studies by focusing in on the important information needed for FDA approval (or clearance) and eliminating unnecessary or burdensome studies, and
- to speed the review process for the future marketing application since FDA will already be familiar with the device.
Pre-Submissions and 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 Agency.
- An IDE allows an investigational device to be used in a clinical study in order to collect safety and effectiveness data to support PMA or 510(k) submission.
- 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.
- A 510(k) is a premarketing submission made to FDA to demonstrate that the device to be marketed is as safe and effective, that is, substantially equivalent (SE), to a legally marketed device that is not subject to premarket approval (PMA).
- Each person who wants to market Class I, II and some III devices intended for human use in the U.S. must submit a 510(k) to FDA at least 90 days before marketing unless the device is exempt from 510(k) requirements.
- FDA reviews 510(k) submissions in a 90-day timeline. If there are unaddressed scientific issues, the review scientists can ask for additional information and put the submission temporarily on hold.
- If FDA finds the information provided by the sponsor meets the standard of equivalency, the product is cleared for marketing in the United States. If FDA finds that there is no predicate for the device, or that the new device does not have equivalent performance to the identified predicate, then the device is found not substantially equivalent.
- There is no 510(k) form but instead a format for the submission is described in 21 CFR 807.
Review of a 510(k) is based on the 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 Required to Demonstrate Substantial Equivalence
The types of studies required to demonstrate substantial equivalence include the following:
- In the majority of cases, analytical studies using clinical samples (sometimes supplemented by carefully selected artificial samples) will suffice.
- For some IVDs, the link between analytical performance and clinical performance is not well defined. In these circumstances, clinical information may be required.
- 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.
Limitations to FDA Review
There are several limitations to FDA’s review of 510(k) applications:
- FDA does not have the facilities to perform wet lab product evaluation, instead it bases its review on the materials submitted by the sponsor;
- There are few performance standards on which to ensure that regulatory decisions are based on clearly defined scientific parameters.
- The 510(k) Paradigm presents device manufacturers with two new optional approaches for obtaining marketing clearance for devices subject to 510(k) requirements:
- Special 510(k) Option for manufacturers who modify their own legally-marketed device
- Abbreviated 510(k) Option when a guidance document exists, a Special Control has been established, or FDA has recognized a relevant consensus standard.
- A manufacturer considering either a special or abbreviated 510(k) should first consult 21 CFR 807.81(a)(3).
Prior to the FDA Modernization Act of 1997 (FDAMA), all devices on the market as of May 28, 1976 were classified according to their risk. Any device that was not classified was automatically assigned to Class III, requiring a premarket approval (PMA) application. A device could be moved out of Class III only through a cumbersome reclassification process.
FDAMA amended Section 513(f) to provide a new mechanism for classifying new Class III devices for which there is no predicate device. It allows the recipient of an NSE (not substantially equivalent) letter to request a risk-based classification determination to be made for the device.
In some cases, this allows a manufacturer to use the De Novo process to submit a 510(k) for a new IVD that would otherwise have to get to market via the PMA process.
- A PMA is an application submitted to FDA to request approval to market, or continue marketing, a class III medical device.
- PMA approval is based on scientific evidence providing a reasonable assurance that the device is safe and effective for its intended use or uses. 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.
- FDA reviews PMA submissions in a 180-day timeline. If there are unaddressed scientific issues, the review scientists can ask for additional information and put the submission temporarily on hold. If a product is a first of a kind, or if it presents unusual issues of safety and effectiveness, it is generally reviewed before it is approved by an advisory panel of outside experts. Approval of a PMA requires review of the manufacturing processes, an inspection of the manufacturing facility, a bioresearch monitoring audit of clinical data sites, as well as comprehensive review of the premarket data.
- If FDA finds that a product is safe and effective, it receives an official approval order for marketing in the United States. If FDA finds that a product is not safe and effective, it may be non-approved.
- A manufacturer considering a PMA should consult 21 CFR 814.
Studies Required to Demonstrate Safety and Effectiveness
For most PMAs, sponsors identify surrogate endpoints and establish the device performance (clinical sensitivity and specificity or agreement) with relation to the identified endpoints in corollary studies using randomly collected clinical studies.
Limitations to FDA Review
There are several limitations to FDA's review of PMA applications:
- Lack of a "gold standard" against which to judge performance;
- Bias may occur in the collection of data to establish safety and effectiveness, through problems in the study design or conduct;
- It can be challenging to determine the minimum performance required for approval.
automated instrument– a laboratory instrument that may or may not be connected to a laboratory information system (LIS), hospital information system (HIS), and/or laboratory automation system (LAS), which performs measurements on a patient's sample; NOTE: These instruments may have specific hardware and/or software modifications that allow interface to a laboratory automation system.
laboratory automation system, LAS – a system of information and hardware technology that allows the operation of the clinical laboratory process without significant operator intervention; NOTE: Typical functionality includes information system control of the instruments through direct LAS interfacing, including any technology that manipulates the specimen (i.e., centrifuge); transportation of the specimen; result evaluation, repeat testing, reflex testing; and quality assessment and results reporting.
laboratory information system, LIS - the information system that is responsible for management of data regarding patient specimen identification, tests requested, results reported, quality control testing, and other aspects of sample analysis; NOTES: a) The LIS interfaces directly with the LAS to communicate patient, visit, container, test orders, specimen status, and results about specific testing to be done; b) Instrument or specimen processing and handling devices may be interfaced with the LIS or the LAS to direct specific testing and to retrieve results for reporting; c) The LIS is frequently also interfaced to a clinical information system for use by physicians and other medical personnel.
Clinical laboratory automation helps diagnose health conditions in a timely and effective manner. OIVD uses a risk-based regulatory approach to these products to ease the burden on industry while ensuring public safety.
Stand alone automated clinical analyzers are exempt class I devices and do not require Premarket Notification [510(k)].
When an automated clinical analyzer measures a specific analyte, the analyzer plus the associated reagents become a test system. These test systems are considered Combination Devices, i.e., devices combined with devices, and are NOT considered Combination Products, and are classified in the highest of the predicate device classifications. Therefore automated clinical analyzers are not exempt from premarket notification when they include any class I reserved device or a class II device. Automated clinical analyzers that include class III devices are subject to Premarket Approval.
Laboratory Information Systems (LIS) and Laboratory Automation Systems (LAS) meet the definition of combination devices when a manufacturer makes an integration claim to a specified analyzer, with the following exceptions:
If the device only receives information for the patient record and neither transmits any instructions to any interfaced device (other than test orders) nor controls any device functions or alarms, no premarket notification is required.
If the device performs only simple physiological and clinical calculations, as long as the algorithms are established and well accepted by the clinical community, no premarket notification is required.
Examples of when the LAS takes over the function of an analyzer:
If the LAS takes over the pipetting that the analyzer normally does for analysis, or the LAS hands off the sample ID directly to the analyzer without the analyzer performing the sample identification, then a premarket notification IS required.
Regardless of classification, devices automated with computer software are subject to Design Controls under the Quality System Regulation 21 CFR Part 820.
*Clinical and Laboratory Standards Institute. Laboratory Automation: Bar Codes for Specimen Container Identification; Approved Standard - Second Edition. CLSI document AUTO2-A2 [ISBN 1-56238-000-0]. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2005.
In Vitro Diagnostic Products have special labeling requirements under 21 CFR 809, Subpart B, In Vitro Diagnostic Products for Human Use. Before a manufacturer obtains clearance or approval for an IVD product, they must label the product in accordance with labeling regulations.
- Quality control (QC) is a material or mechanism which, when used with or as part of a test system, monitors the analytical performance of that test system. It may monitor the entire test system or only one aspect of it.
- FDA regulates the material or mechanism as a medical device; it does not monitor how a QC component is used within a laboratory (i.e. how often other QC types should be run, or whether the QC replaces other, more traditional external types of QC).
- FDA makes sure that products have QC materials, reviews labeling for accuracy, and determines if manufacturers have protocols to ensure stability.
- How a QC component is used within a laboratory is not within FDA's jurisdiction. Other Agencies, such as of the Centers for Medicare and Medicaid Services (CMS), the College of American Pathologists (CAP), or the Joint Commission Accrediting Hospital Organization (JCAHO) have jurisdiction over the procedures and practices within laboratories.
- A manufacturer developing a quality control material or mechanism should consult 21 CFR 862.1660 and 21 CFR 862.9.
- 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 clearance to market. Unless exempt, premarketing clearance is required before a device can be placed into commercial distribution in the U.S.
- Most medical device establishments required to register with FDA must list the devices they have in commercial distribution including devices produced exclusively for export.
- Listing keeps FDA advised of the generic category(s) of devices an establishment is marketing.
- Listing of a device does not provide FDA clearance to market. Unless exempt, premarketing clearance is required before a device can be placed into commercial distribution in the U.S.
The GMP requirements are part of 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. The QS Regulation is contained in 21 CFR 820.
- The Medical Device Reporting (MDR) regulations require manufacturers who have received complaints of device malfunctions, serious injuries or deaths associated with medical devices to notify FDA of the incident.
- MDR regulations 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.
- 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, 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 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.
OIVD works with manufacturers throughout the total product life cycle to ensure compliance with the Medical Device Amendments in the least burdensome manner. This approach enables manufacturers to receive assistance and feedback in a timely manner and may reduce the need for compliance actions.
The Medical Device User Fee and Modernization Act of 2002 (MDUFMA), P.L. 107-250, amends the Federal Food, Drug, and Cosmetic Act to provide FDA important new responsibilities, resources, and challenges. MDUFMA was signed into law October 26, 2002. MDUFMA has three particularly significant provisions:
- It establishes fees for premarket reviews of medical devices;
- It permits establishment inspections by accredited persons (third-parties); and
- It provides new regulatory requirements for reprocessed single-use devices.