Medical Devices

Special Considerations


510(k)s for Biologic Products

The Center for Biologics, Evaluation, and Research (CBER) has expertise in blood, blood products, cellular therapies, and other biologics as well as the integral association of certain medical devices with these products. To utilize this expertise, CBER reviews marketing and investigational device submissions (Premarket Notification 510(k), Premarket Approval, and Investigational Device Exemption) for medical devices associated with blood collection and processing procedures as well as those associated with cellular therapies and vaccines. Although these products are reviewed by CBER, the medical device laws and regulations still apply.

Center for Biologics Evaluation and Research
Office of Communication, Training and Manufacturers Assistance (HFM-43)
1401 Rockville Pike, Room 200N
Rockville, MD 20852-1448 U.S.A.
Telephone Number: 301-827-2000 or 800-835-4709
Fax Number: 301-827-3843
Email: matt@cber.fda.gov
 

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Biocompatibility

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 FDAs testing guidance matrix.

Additional information on how to use the the ISO 10993 standard can be found in the following guidance document:

In a 510(k) submission for devices which come into direct contact with the patient or user, an exact identification and composition of all materials that contact the patient should be provided and a statement regarding any material differences from the legally marketed device(s) should be explicitly stated. If the materials are identical to the legally marketed device(s) and are identically processed and sterilized, then this should be stated. If the materials and manufacturing processes and intended use are not identical, or this information is not available for a predicate device, biocompatibility testing should be performed.

Therefore, manufacturers will need to provide biocompatibility test results for any new materials when the new device is compared to a legally marketed device made of different materials. The results should be in a separate, identified biocompatibility section, be well organized, and be complete.

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Class III Certification and Summary

A preamendment device is one that was legally in commercial distribution before May 28, 1976, the date the Medical Device Amendments were signed into law. After the Medical Device Amendments became law, FDA was required to classify all preamendment type devices. All known devices were classified into Class I, Class II, or Class III. It was intended that all preamendment Class III devices would eventually require Premarket Approval (PMA) for marketing approval. Preamendment Class III devices require a PMA only after FDA publishes a final regulation calling for PMA. After FDA publishes the requirement for PMA, the classification regulation in the Code of Federal Regulations (CFR) will state the effective date that a PMA is required.

If FDA has not required a PMA for the type of device, a Class III device that enters the market after May 28, 1976 must have a cleared Premarket Notification 510(k) prior to marketing. Class III devices for which we have not called for PMAs and require a 510(k) are identified in the CFR as Class III and include the statement "Date premarket approval application (PMA) or notice of completion of product development protocol (PDP) is required. No effective date has been established of the requirement for premarket approval." Examples include intra-aortic balloon and control system (21 CFR 870. 3535), ventricular bypass (assist) device (21 CFR 870.3545), and topical oxygen chamber for extremities (21 CFR 878.5650).

510(k)s for Class III devices must contain a Class III Certification and Summary. The certification states that you have conducted a search for information about your device type. The Class III Summary is a summary of the types of safety and effectiveness problems associated with the type of device being compared and a citation to the information upon which the summary is based. The summary must be comprehensive and describe the problems to which the type of device is susceptible and the causes of such problems. The certification should be signed by the 510(k) submitter, NOT a consultant to the 510(k) submitter, and be clearly identified as "Class III Certification and Summary." The summary of problem data, bibliography or other citations upon which the summary is based should be immediately follow the certification statement. The Class III Certification and Summary should be identified in the table of contents of the 510(k).

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Combination Products

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.

Intercenter Agreement Between the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health.

Intercenter Agreement Between the Center for Drug Evaluation and Research and the Center for Devices and Radiological Health.

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:

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Design Controls (§ 820.30)

All manufacturers (including specification developers) of Class II and III devices and select Class I devices (listed below) are required to follow design controls (§820.30) during the development of their device. The design control requirements are basic controls needed to ensure that the device being designed will perform as intended when produced for commercial distribution.

Class I Devices Subject to Design Controls

SectionDevice
868.6810Catheter, Tracheobronchial Suction.
878.4460Glove, Surgeon's.
880.6760Restraint, Protective.
892.5650System, Applicator, Radionuclide, Manual.
892.5740Source, Radionuclide Teletherapy.

The manufacturer (including specification developer) must establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met [820.30(a)]. Design controls include establishing and maintaining plans that describe the design and development activities and also define responsibility for implementation [820.30(b)]. The plans must identify and describe the interfaces with different groups or activities that provide, or result in, input to the design and development process [820.30(b)]. The design process also includes:

  • conducting a risk analysis [820.30(g)];
  • identifying design input or requirements for the device [820.30(c)];
  • developing the design output or specifications for the device [820.30(d)];
  • verifying that the design output meets the design input [820.30(f)];
  • holding design reviews at appropriate points during the design process to identify significant problems with the design or the design process [820.30(e)];
  • validating that the design meets defined user needs and intended uses [820.30(g)];
  • validating any software used in the device [820.30(g)];
  • transferring the device design to production specifications [820.30(h)];
  • controlling changes to the design during the design process and changes in the design of products on the market [820.30(i)]; and
  • documenting design control activities in the design history file [820.30(j)].

The manufacturer must have procedures in place and must maintain documentation in the design history file to demonstrate compliance with the design control requirements of §820.30 and completion of the activities identified in the design plan. The design history file must be made available for FDA inspection. FDA will evaluate the adequacy of manufacturers' compliance with design control requirements during routine quality systems inspections for all classes of devices subject to design control.

The following documents provide additional guidance on the design control requirements under the Quality System regulation.

See Good Manufacturing Practices (GMP)/Quality Systems (QS) for additional guidance on 21 CFR 820, Quality System.

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Electronic Copies

You may submit one copy of a 510(k) submission in electronic form. An electronic copy is an exact duplicate of a paper submission, created and submitted on a CD or DVD, and must accompany the paper submission. Please indicate in your cover letter that you are submitting an electronic copy that is an exact duplicate of the paper copies submitted.

The electronic copy should be sent in an Acrobat Portable Document Format (PDF) because the 510(k) review staff will use Adobe’s Acrobat to view the submission. This will assure that what a reviewer sees on the screen is the same as what would have been seen on paper.

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. An electronic copy will provide additional navigational tools for the review staff who will be working with your document. Additional copies of some reports may be requested in order to help facilitate the review.

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Evaluation of Automatic Class III Designation (De Novo Process)

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 new type of device that was found not substantially equivalent for a reason other than performance data required a Premakert Approval (PMA) application. A device could be moved out of Class III only through a reclassification process. The De Novo process provides a possible route to market low risk device types. This process does not apply to devices that have been classified by regulation into class III, i.e., preamendment class III devices or class III devices for which a premarket approval application or a reclassification petition is appropriate.

FDAMA amended Section 513(f)(2) to provide a new mechanism for classifying new Class III devices for which there is no predicate device. The De Novo process is intended to apply to low risk products that have been classified as class III because they were found not substantially equivalent (NSE) to any identifiable 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.

An applicant of a 510(k) who receives a Not Substantially Equivalent (NSE) determination placing the device into a Class III category can request a de novo classification of the product into Class I or II. The request must be in writing and sent within 30 days from the receipt of the NSE determination. In addition, the request should include a description of the device, labeling for the device, reasons for the recommended classification (into Class I or II), and information to support the recommendation. The de novo process has a 60 day review period. If FDA classifies the device into Class I or II, the applicant will then receive an approval order to market the device. This device type can then be used as a predicate device for other firms to submit a 510(k). However, if FDA determines that the device will remain in the Class III category, the device cannot be marketed until the applicant has obtained an approved PMA.

Additional guidance on the De Novo process is provided in the guidance document below.

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Expedited Review

Expedited review of devices subject to 510(k) 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:

  1. is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition, and
  2. addresses an unmet medical need, as demonstrated by one of the following:
    1. The device represents a breakthrough technology that provides a clinically meaningful advantage over existing technology; or
    2. No approved alternative treatment or means of diagnosis exists; or
    3. The device offers significant, clinically meaningful advantages over existing approved alternative treatments; or
    4. 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.

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In Vitro Diagnostic (IVD) Devices

Definition

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.

510(k) Submissions

You may submit a traditional, special, or abbreviated 510(k) for in vitro diagnostic devices. You are encouraged to use CeSub eSubmitter software to create a 510(k) for an in vitro diagnostic device that is reviewed in Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD). The software will support single and “bundled” applications for all traditional, abbreviated, and special 510(k)s including:

  • Antimicrobial Susceptibility Testing (AST) devices
  • All other in vitro device types
  • CLIA waiver and categorization applications

The software may also be used to submit 510(k) Supplements (responses to requests by FDA for additional information to a 510(k) while it is under review). The software will help you submit a complete 510(k) and is available to the public for free.

Labeling

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 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

  • complexity categorizations
  • assignment of CLIA categories
  • waivers

Center for Medicare and Medicaid Services

  • guidelines for laboratories
  • laboratory certification

Center for Disease Control

  • Clinical Laboratory Improvement Advisory Committee (CLIAC)
  • cytology proficiency testing

Additional IVD Guidance

Addtional information regarding in vitro diagnostics devices is available from the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD).

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Kits

Convenience Kits

Two or more separate types of finished devices packaged together for the convenience of the user is considered to be a kit. Kits (or trays) are often utilized in the surgical arena. The classification of the kit is based on the highest classification of the devices that are provided in the kit. Submissions for convenience kits should identify all devices provided in the kit. Certain convenience kits that meet the criteria in the Convenience Kit Interim Regulatory Guidance are under enforcement discretion and do not require a 510(k).

Guidance documents pertaining to convenience kits are provided below.

510(k) Kit Certification

If the device is to be marketed as a kit, identify all devices in the kit and document the marketing status of each device in the kit as shown in the Kit Certification. If a 510(k) submission is required, please include the kit certification in your 510(k). If a 510(k) is not required, we recommend you maintain this information in your files.

Drugs in Kits

If the device kit contains components which are subject to regulation as drugs, a substantially equivalent determination of the included devices by CDRH does not apply to the drugs in the kit. For information on applicable FDA requirements for marketing the drugs in a kit, you should contact the Center for Drug Evaluation and Research.

Gloves in Kits

A medical device kit may include medical gloves.  Kit manufacturers and assemblers should assure that gloves in their kits are cleared for marketing and that the gloves can meet the appropriate FDA and ASTM standards (such as ASTM D3577, ASTM D3578, ASTM D5250, ASTM D6319) or an equivalent test method after the kit is sterilized. 

We recommend that you enclose natural rubber latex gloves in their own packaging within the kit to avoid possible protein contamination of other devices.  You must label the kit appropriately for any device or packaging containing natural rubber (21 CFR 801.437). 

Additional guidance and other requirements for medical gloves are available in Guidance for Medical Gloves.

Sutures in Kits

Kit manufacturers and assemblers should assure that sutures in their kits are cleared for marketing. If the kit contains sutures, you should provide evidence that the sterilant does not contact the sutures during sterilization of the kit. Some kit assemblers package the sutures separately from the main tray. After processing and sterilizing the main tray, the package of sutures is piggybacked onto the main tray. Based on the evidence, FDA can conclude if the sutures are or are not further processed. However, including sutures as a component in your kit requires you to comply with the following conditions:

  • The labeling, packaging, and method of sterilization of the sutures you have listed cannot be changed without prior notification, review, and approval by FDA; and
  • the supplier(s) of the sutures included in your kit cannot be changed without prior notification, review, and clearance by FDA.

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Radiation Emitting Products

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.

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Software

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.

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Standards

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 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 provide a declaration of conformity to the standard and use the Abbreviated 510(k) submittion method. Conformance to FDA recognized standards are voluntary and may be used to demonstrate performance or safety of a device.

Information on FDAs standard program including a database of FDA recognized standards can be found on the following website.

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Sterilants and High Level Disinfectants

The document below provides a list of 510(k) cleared devices that can be used as a predicate device for a 510(k) submission.

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Sterility

For devices that are labeled sterile, the 510(k) should include the following:

  • the sterilization method (e.g., dry heat, moist heat, ethylene oxide (EO), radiation);
  • the method used to validate the sterilization cycle, but not the validation data itself;
  • a description of the packaging to maintain the device's sterility (Do not include packaging integrity test data in the 510(k) submission.);
  • the sterility assurance level (SAL), e.g., 10-6 for all devices, except 10-3 for devices only contacting intact skin, for the device that the manufacturer intends to meet;
  • the maximum levels of residues of EO and ethylene chlorohydrin that remain on the device when ETO is used to sterilize the device (Note: The ethylene glycol residual level is no longer requested because the recognized standard, "ANSI/AAMI/ISO 10993-7:1995 Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide sterilization residuals," does not include measurement of ethylene glycol residuals);
  • for devices that are labeled "pyrogen free," a description of the method used to make that determination, e.g., limulus amebocyte lysate (LAL). Devices contacting blood or cerebrospinal fluids should be pyrogen free.; and
  • the radiation dose, if radiation sterilization will be used.

If only parts of the device are labeled sterile or non-pyrogenic, the labeling should clearly identify which parts are sterile and non-pyrogenic.

The labeling for devices intended to be sterilized by the user must identify one validated method of sterilization. The instructions should be detailed and specific enough for the user to follow and obtain the required sterility assurance level. The instructions should also adequately describe any precautions to be followed such as:

  • special cleaning methods required;
  • any changes in the physical characteristics of the device that may result from reprocessing and re-sterilization, especially those which may affect the safety, effectiveness, or performance; and
  • any limit on the number of times re-sterilization and reuse can be done without adversely affecting the safety, effectiveness, or performance of the device.

The manufacture may use an FDA-recognized validation method or an equivalent method to validate the sterilization cycle. You can find consensus standards that FDA has recognized for sterilization by searching the CDRH Standards Database.

Page Last Updated: 08/21/2014
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