- Combination Products
- Electromagnetic Compatibility
- Environmental Impact Considerations
- Expiration Dating
- In Vitro Diagnostic (IVD) Products
- Master Files
- Radiation Emitting Products
Biological evaluation of medical devices is performed to determine if there is a potential adverse biological response resulting from contact of the device’s component materials with the body and whether the associated risks are unacceptable. Evaluation of any new medical device requires information from systematic evaluation of the benefits provided by the final device and the potential risks produced by the device. The analysis should show that contact with the device does not produce unacceptable risk associated with adverse local or systemic effects, either directly or through the release of the device’s material constituents.
FDA recognizes the standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process,” which provides information on evaluating the biological response to medical devices, such as considering the physical and chemical characteristics of device materials and the nature, degree, frequency, and duration of device exposure to the body.
The intended use and the materials used in the manufacture of the new or modified device determines the nature of the biocompatibility information needed. Some devices are made of materials that have been well characterized both chemically and physically and have a long history of safe use. Therefore, it may not be necessary to conduct testing for all endpoints outlined in ISO 10993-,1 provided that materials and manufacturing information demonstrate that there are no new biocompatibility concerns.
Additional information about how to use the ISO 10993-1 standard can be found in the following guidance document:
A submission for a device that comes into direct or indirect contact with a patient or user should include information about all of the materials with direct or indirect contact, and should state if the materials, manufacturing processes, and intended use are identical to those in legally marketed device(s).
If the materials, manufacturing processes, and intended use are not identical to those in legally marketed device(s), or if manufacturing information is not available for a comparator device, additional biocompatibility information should be provided.
Any biocompatibility information, including any testing, should be well organized, complete, and included in a separate, identified biocompatibility section.
For current information regarding color additives, please refer to the following: Color Additives For Medical Devices
A combination product is a product comprised of two or more regulated components (drug/device or biologic/device) that are combined as a single entity or is a product labeled for use with a specified drug, device, or biologic where both are required to achieve the intended use, indication, or effect.
To ease the regulatory burden of industry, FDA has established Intercenter agreements which establishes the lead FDA Center for review and oversight of certain categories of products. Intercenter agreements with CDRH are referenced below.
Some combination products involve cutting edge, novel technologies that raise not only unique scientific and technical questions, but also regulatory challenges related to where and how they should be regulated in order to ensure adequate and consistent regulatory oversight. The Office of Combination Products assigns review responsibility for combination products. The Office is also responsible for designating the component of FDA with primary jurisdiction for the premarket review and regulation of any product requiring a jurisdictional designation.
Additional information regarding combination products can be found at the following website:
PMA applicants must demonstrate that the device is electrically safe and does not interfere with other devices used in the same environment. Electromagnetic compatibility, or EMC, means that the device is compatible with (i.e., no interference caused by) its electromagnetic environment, and that it does not emit levels of electromagnetic energy that cause electromagnetic interference (EMI) in other devices in the vicinity. The wide variation of medical devices and use environments makes them vulnerable to different forms of electromagnetic energy which can cause electromagnetic interference. Additional guidance and information CDRH activities in this area is available on the “CDRH Medical Device Electromagnetic Compatibility Program” website.
21 CFR 814.20(b)(11) states that an environmental assessment in accordance with 21 CFR 25 must be included in the PMA application. However, PMA applications do not ordinarily require an environmental assessment (EA) or environmental impact statement (EIS). Devices of the same type and for the same use as a previously approved device are categorically excluded from an EA or an EIS [§25.34(d)]. These devices compete for the same market with already approved devices of the same type and use, and therefore, there is no increased environmental impact resulting from the introduction of the device into commercial distribution. A statement requesting a categorical exclusion under sections 25.15 and 25.34(d) is required in the PMA application.
If the device causes environmental hazards in the manufacture, use, or disposal of the device, an environmental assessment must be submitted in the PMA.
Under 21 CFR 809, In Vitro Diagnostic Products for Human Use, the labeling must provide an expiration date based upon the stated storage instructions. Other devices are not required to have expiration dating, but may be appropriate. If expiration dating is provided in the labeling, it must be based upon the storage instructions provided in the labeling and substantiated through stability testing. Data to support the expiration date must be provided in the PMA and maintained as part of Quality System records under 21 CFR 820. Information about shelf life may be found:
21 CFR 211.166 Stability testing
In vitro diagnostics are medical devices that analyze human body fluids, such as blood or urine, to provide information for the diagnosis, prevention, or treatment of a disease. The device classification for these devices can be found under 21 CFR 862, 21 CFR 864, and 21 CFR 866.
In Vitro Diagnostic Products have special labeling requirements and distribution restrictions under 21 CFR 809, In Vitro Diagnostic Products for Human Use. Additional guidance can be found under "Device Advice Labeling Requirements for In Vitro Diagnostic Devices."
Clinical Laboratory Improvement Amendments (CLIA) of 1988
In addition to FDA regulation under the Food, Drug, and Cosmetic Act, in vitro diagnostic (IVD) devices are also subject to the Clinical Laboratory Improvement Amendments (CLIA) of 1988. This law established quality standards for laboratory testing and an accreditation program for clinical laboratories.
The requirements that apply 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: waived tests, tests of moderate complexity, and tests of high complexity. Laboratories performing moderate- or high-complexity testing or both must meet requirements for proficiency testing, patient test management, quality control, quality assurance, and personnel. These specific requirements do not apply to tests in the waived category.
In January 2000, the categorization of commercially marketed in vitro diagnostic tests under CLIA was transferred from the Center for Disease Control and Prevention (CDC) to FDA. CDRH's Office of Health Technology 7: Office of In Vitro Diagnostics and Radiological Health (OHT7) determines the appropriate complexity categories for clinical laboratory devices as they evaluate premarket submissions. Waived products, devices exempt from premarket notification, and devices under premarket review by other FDA Centers are also processed by OHT7. Responsibilities currently assigned to CDC, including review of test systems, assays, or examinations not commercially marketed as IVD products, remain with CDC.
Below is a list of CLIA Program Information Resources:
FDA CLIA Website (complexity categorizations, waiver)
CMS CLIA Website (program information, statistics, etc.)
CDC CLIA Website (regulations, CLIAC)
Additional information on assignment of CLIA categories by FDA can be found on the Internet.
Additional IVD Guidance
Additional information regarding in vitro diagnostics devices is available from the Office of Health Technology 7: Office of In Vitro Diagnostics and Radiological Health.
A PMA applicant often utilizes another party's product (e.g., material, ingredient, subassembly, or accessory) or facility in the manufacture of the device. Although information regarding the third party’s product is pertinent to the review of the PMA, the third party may not want to divulge confidential or trade secret information to the PMA applicant. To preserve the trade secrets of the ancillary medical device industry and at the same time facilitate the sound scientific evaluation of medical devices, FDA allows the third party to submit the confidential information directly to FDA in a device master file. A master file may also be considered when several applications may be submitted for different products which may use a common material or process. However, different uses of the medical device may require additional testing or information to support the evaluation of that particular product.
Please note that a master file is NOT a marketing application. It is not independently reviewed or approved. A master file is only reviewed when a premarket submission [PMA or Premarket Notification 510(k)] under review contains an authorization letter from the third party that permits FDA to review the master file to support the premarket submission. Since the master file may contain additional information than required for the review of the submission, the authorization letter should specify the appropriate sections or pages for review.
Additional guidance on master files can be found in the following guidance document.
If your medical device also emits electronic product radiation, additional requirements apply under the Electronic Product Radiation Control Provisions of the Food, Drug and Cosmetic Act. Electronic product radiation means:
- any ionizing or non-ionizing electromagnetic or particulate radiation,
- or any sonic, infrasonic, or ultrasonic wave,
- which is emitted from an electronic product as the result of the operation of an electronic circuit in such product.
Examples of products that emit electronic radiation include lasers, ultraviolet lamps, microwave ovens, ultrasound therapy devices and medical diagnostic x-ray equipment.
Regulatory requirements for these products are in place to protect the public from hazardous or unnecessary radiation exposure emitted by these products. Requirements may include submission of reports to FDA, compliance with applicable radiation safety performance standards, retention of certain records, and reporting of accidental radiation occurrences or product defects to FDA. Additional information on requirements for radiation emitting products is available on the Radiological Health Program website.
If the device contains software or is controlled by a computer, the submission should contain documentation of software development and validation appropriate to the level of risk of the software. The submission should include any information, prompts, and cautions displayed by the system. The software documentation should support all performance and safety claims.
The following guidance documents provide guidance on the recommended software documentation for a premarket submission and on software validation.
- Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices
- Guidance for Off-the-Shelf Software Use in Medical Devices
- Cybersecurity for Networked Medical Devices Containing Off-the-Shelf (OTS) Software
Conformance with recognized consensus standards can provide a reasonable assurance of safety and/or effectiveness for many aspects of medical devices. Information submitted on conformance with such standards will have a direct bearing on safety and effectiveness determinations made during the review of premarket submissions. If any premarket submission contains a declaration of conformity to the recognized consensus standards, this will, in some cases, eliminate the need for FDA to review the actual test data for those aspects of the device addressed by the standards.
Conformance with recognized consensus standards alone, however, may not be sufficient for FDA to make a regulatory decision. For example, a specific device may raise a safety or effectiveness issue not addressed by any recognized consensus standard, or a specific FDA regulation may require additional information beyond what conformity to the recognized consensus standards provides, such as summary data. Under such circumstances, conformity with recognized standards will not satisfy all requirements for marketing the product in the United States.
FDA recognizes certain consensus standards. If the device conforms to an FDA recognized standard, the applicant may provide a declaration of conformity to an FDA recognized standard, the applicant may elect to provide a declaration of conformity, if applicable, or may provide a declaration of conformity and use any type of submiss ion method. Conformance to FDA recognized standards are voluntary and may be used to demonstrate performance or safety of a device.
Additional information on FDAs standard program including a database of FDA recognized standards is located in the CDRH Standards Program section of Device Advice.
The sterilization method (e.g., steam heat, ethylene oxide, radiation), sterility assurance level (SAL), description of the packaging to maintain the device’s sterility, and method of validation must be provided in the PMA. The manufacturer may use an FDA recognized validation method or an equivalent method. Additional information on sterilization can be found here:
- FDA Guidance on Sterility: Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile Guidance for Industry and Food and Drug Administration Staff
- Although this guidance document refers to 510(k) Submissions, the information may also be used for PMA submissions.
- CDRH Standards Database
- For a list of sterility-related standards, go to the field "Specialty Task Group Area" and select "Sterility"