Please note: As of October 1, 2002, FDA charges a fee for review of Premarket Approvals
- Color Additives
- Combination Products
- Electromagnetic Compatibility
- Electronic Submissions
- Environmental Impact Considerations
- Expedited Review
- Expiration Dating
- In Vitro Diagnostic (IVD) Products
- Master Files
- Radiation Emitting Products
Biological evaluation of medical devices is performed to determine the potential toxicity resulting from contact of the component materials of the device with the body. The device materials should not, either directly or through the release of their material constituents: (i) produce adverse local or systemic effects; (ii) be carcinogenic; or, (iii) produce adverse reproductive and developmental effects. Therefore, evaluation of any new device intended for human use requires data from systematic testing to ensure that the benefits provided by the final product will exceed any potential risks produced by device materials.
FDA recognizes the standard ISO 10993 (International Standards Organization) for biological evaluation of medical devices. This standard provides guidance for selecting the tests to evaluate the biological response to medical devices. When selecting the appropriate tests for biological evaluation of a medical device, the chemical characteristics of device materials and the nature, degree, frequency and duration of its exposure to the body must be considered.
The specific clinical application and the materials used in the manufacture of the new device determines which tests are appropriate. Some devices are made of materials that have been well characterized chemically and physically in the published literature and have a long history of safe use. Therefore, it may not be necessary to conduct all the tests suggested in the FDA’s testing guidance matrix.
Additional information on biocompatibility can be found in the following guidance document:
Required Biocompatibility Training and Toxicology Profiles for Evaluation of Medical Devices, Blue Book Memo, G95-1
Color additives in medical devices are subject to the same provisions that apply to color additives in foods, drugs, and cosmetics. A color additive is a dye, pigment, or other substance, whether synthetic or derived from a vegetable, animal, mineral, or other source, which imparts a color when added or applied to a food, drug, cosmetic, or the human body. The Food, Drug and Cosmetic (FD&C) Act states that devices containing a color additive are considered unsafe, and thereby adulterated, unless a regulation is in effect listing the color additive for such use. The FD&C Act limits applicability of these provisions to color additives for devices that directly contact the body for a significant period of time. At the present time, the term a "significant period of time" is not defined by FDA regulation.
The color listing regulation may permit use of the color additive in a generic type of device, such as contact lenses, or may place limitations on its use, such as polypropylene nonabsorbable sutures for general surgical use but not for ophthalmic surgical use.
PMA applicants must demonstrate color additives remaining in and on the device are safe. Manufacturers may choose an appropriate color additive approved for medical devices in accordance with its use and restrictions. Color additives listed for use in medical devices are provided in 21 CFR 73 and 21 CFR 74.
- Part 73, Subpart D: Color additives exempt from batch certification
- Part 74, Subpart D: Color additives subject to batch certification
If a color additive has not been previously listed, the manufacturer must submit a color additive petition to FDA. If the PMA is submitted before the color additive petition is approved, the PMA approval will be delayed.
In searching for an appropriate color additive for use in its device, manufacturers should consider color additives listed for use in foods, drugs, or cosmetics as a starting point. However, the safety data of the color additive for a food, drug, or cosmetic may not be relevant to devices. That is, the color additive may be used in a different part of the body or for a longer duration than that approved.
The following provides additional guidance on color additives.
Color Additives - Center for Food Safey and Applied Nutrition
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.
CDRH accepts medical device applications in electronic form. PMA applicants should notify the reviewing division of CDRH of their desire to submit an application in electronic form prior to submission. This lead time is needed to discuss any special considerations with the submitter prior to development of the documents.
The application should be submitted in a PDF (Portable Document Format) format as the PMA review staff will use Acrobat Exchange to review the submission. This will assure that what a reviewer sees on the screen is the same as what would have been seen on paper. Applications may be submitted on floppy diskettes or CD-ROM. At least one paper copy of the submission is also required.
An electronic application does not change the order in which submissions are reviewed. No preferential treatment will be given to manufacturers who submit an electronic application. Additional copies of some reports may be requested in order to help facilitate the review.
Additional information on electronic copies can be found the Internet.
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.
Expedited review of devices subject to PMA will generally be considered when a device offers a potential for clinically meaningful benefit as compared to the existing alternatives (preventative, diagnostic, or therapeutic) or when the new medical device promises to provide a revolutionary advance (not incremental advantage) over currently available alternative modalities.
FDA considers a device appropriate for expedited review if the device:
- is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition, and
- addresses an unmet medical need, as demonstrated by one of the following:
- The device represents a breakthrough technology that provides a clinically meaningful advantage over existing technology; or
- No approved alternative treatment or means of diagnosis exists; or
- The device offers significant, clinically meaningful advantages over existing approved alternative treatments; or
- The availability of the device is in the best interest of patients.
Granting expedited review status means that a marketing application that is determined to be appropriate for expedited review is placed at the beginning of the appropriate review queue and receives additional review resources, as needed.
Additional information on the criteria and procedure for expedited review are provided in the following guidance document:
Under 21 CFR 809, In Vitro Diagnostic Products for Human Use, the labeling must provide an expiration date based upon the stated storage instuctions. 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. Guidance on shelf life protocols can be found in the following guidance documents.
21 CFR 211.166 Stability testing
Guidance for Industry: Q1A Stability Testing of New Drug Substances and Products
Evaluation of Stability Data
Guideline for Submitting Documentation for the Stability for Human Drugs and Biologics
Stability Testing of Drug Substances and Drug Products
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 tranferred from the Center for Disease Control and Prevention (CDC) to FDA. CDRH's Office of of In Vitro Diagnostic Device Evaluation and Safety (OIVD) 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 OIVD. Responsibilities currently assigned to CDC, including review of test systems, assays, or examinations not commercially marketed as IVD products, will 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
For additional information on in vitro diagnostics devices, please visit the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) website.
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
- General Principles of Software Validation
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 most cases, eliminate the need to review the actual test data for those aspects of the device addressed by the standards.
Conformance with recognized consensus standards in and of itself, however, may not always be a sufficient basis for regulatory decisions. 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. 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 complies to an FDA recognized standard, the applicant may need only submit a declaration of conformity to the standard without submitting test data. Conformance to FDA recognized standards are voluntary and may be used to demonstrate performance or safety of a device.
Information on FDA’s standard program including a database of FDA recognized standards can be found on the following website:
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 manufacture may use an FDA recognized validation method or an equivalent method. Additional information on sterilization can be found in the following documents:
Blue book memo: Updated 510(k) Sterility Review Guidance K90-1
Please note that although this guidance document is specific to the Premarket Notification 510(k) process, the information is also relevant to PMAs.
FDA recognized consensus standards for sterilization validation can be found by searching the CDRH standards database at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm