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 CDRH Regulatory Manuals
website. For more information, see IVD
Guidance Documents, IVD Standards,
and IVD Advisory Panels.
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 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. |
How are IVDs classified?
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.
The Code of Federal Regulations lists the classification of existing IVDs in 21 CFR 862, 21 CFR 864, and 21 CFR 866.
See also:
Device Advice: Classify Your Medical Device
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.
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.
See also:
Device Advice: General Controls for Medical Devices
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.
See also:
CLIA '88 - Clinical Laboratory Improvement
Amendments Home Page
Search CLIA '88 Database
What is the "Pre-IDE" Process for IVDs?
The "pre-IDE" process is an informal "pre-submission" process. It may involve:
- sending analytical or clinical protocols to FDA for review and comment before proceeding with studies, or
- meeting with FDA to discuss protocols and/or possible regulatory pathways.
The term "pre-IDE" has been used for this process so that FDA can assign it an official tracking number, just as numbers are assigned to 510(k)s and PMAs. This does not mean that manufacturers are required to subsequently submit an IDE application. In fact, most IVDs are exempt from the medical device IDE regulations.
It is appropriate to request a protocol review or a pre-IDE meeting under circumstances such as the following:
- The new product involves cutting edge technology and it will be helpful to familiarize FDA with the technology in advance of the submission;
- Assistance is needed in defining possible regulatory pathways;
- The studies involve complex data and/or statistical approaches; or
- The study designs are complex and you are seeking advice on ways to simplify them.
A sponsor should submit a pre-IDE only if they would like FDA's thoughts on there studies or proposals prior to starting their studies. The potential benefits of submitting a pre-IDE 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-IDE 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. A submission made under the pre-IDE process is not an official IDE application as described at 21 CFR Part 812.
See also:
Device Advice: Pre-IDE Process
Pre-IDE Program: Issues and Answers - Blue Book Memo D99-1, March 1999
What is an Investigational Device Exemption (IDE)?
- An IDE allows 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 device 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.
See also:
Device Advice: Clinical Trials and Investigational Device Exemption
Guidance for FDA Staff: Regulating In Vitro Diagnostic Device (IVD) Studies
What is a Premarket Notification [510(k)]?
- 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.
510(k) Review
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.
See also:
Device Advice: premarket Notification [510(k)]
In Vitro Diagnostic Devices: Guidance for the Preparation of 510(k) Submissions
Screening Checklist for all premarket Notification 510(k) Submissions Text PDF
What is the 510(k) Paradigm?
- The 510(k) Paradigm presents device manufacturers with two new optional approaches for obtaining marketing clearance for devices subject to 510(k) requirements:
- 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).
See also:
The New 510(k) Paradigm: Alternate Approaches to Demonstrating Substantial Equivalence in premarket Notifications. Text PDF
Guidance for Industry: Frequently Asked Questions on the New 510(K) Paradigm
What is De Novo Classification for IVD Devices?
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.
See also:
FDA Modernization Act of 1997: Evaluation of Automatic Class III Designation
New Section 513(f)(2) - Evaluation of Automatic Class III Designation, Guidance for Industry and CDRH Staff Text PDF
What is a Premarket Approval (PMA)?
- 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.
See also:
Device Advice: Premarket Approval
How does FDA regulate clinical laboratory automation?
Clinical laboratory automation helps diagnose health conditions in a timely and cost-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 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 (non-stand-alone), with the following exceptions:
- If the device only receives information for the patient record and neither transmits any instructions to any interfaced device 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 fully explained and made readily available to the health care practitioner, no premarket notification is required.
- Regardless of classification, devices automated with computer software are subject to Design Controls under the Quality System Regulation.
What are the Requirements for IVD Labeling?
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.
See also:
Device Advice: Labeling Requirements for In Vitro Diagnostic Devices
Points to Consider Regarding Labeling and premarket Submissions for Home Use In Vitro Diagnostic Devices
How does FDA Look at Quality Control?
- 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.
See also:
Internal Quality Control Testing; Principles and Definitions, NCCLS C24-A
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.
- No registration fee is required.
- 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.
See also:
Device Advice: Establishment Registration
Registration and Listing for Firms
What is Medical Device Listing?
- 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.
- No listing fee is required.
- 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.
See also:
Device Advice: Medical Device Listing
Registration and Listing for Firms
What are Good Manufacturing Practices (GMPs) and Quality System Regulations (QSRs)?
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.
See also:
Good Manufacturing Practice / Quality Systems
Device Advice: Good Manufacturing Practices (GMP) / Quality System (QS) Regulation
What is Medical Device Reporting?
- 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.
See also:
Medical Device Reporting (MDR)
Device Advice: Medical Device Reporting (MDR)
What happens to products that are in violation of laws administered by 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, 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.
See also:
Device Advice: Medical Device Recalls and Corrections and Removals
How does OIVD ensure compliance with the Federal Food, Drug, and Cosmetic Act?
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.
What is the Medical Device User Fee and Modernization Act of 2002 (MDUFMA)?
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.
See also:
Medical Device User Fee and Modernization Act (MDUFMA) of 2002
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