Guidance for Industry and FDA Staff

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.
Document issued on: July 27, 2011

For questions regarding the use or interpretation of this guidance in the review of submissions to the Center for Devices and Radiological Health, contact Michael J. Ryan at 301-796-6283 or by email at [email protected].

For questions regarding the use or interpretation of this guidance in the review of submissions to the Center for Biologics Evaluation and Research, contact the Office of Communication, Outreach and Development at 1-800-335-4709 or 301-827-1800 or by email at [email protected].

When final, this document will supersede Deciding When to Submit a 510(k) for a Change to an Existing Device, dated January 10, 1997.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health

Center for Biologics Evaluation and Research

Preface

Public Comment

Written comments and suggestions may be submitted at any time for FDA (Agency) consideration to the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD, 20852. When submitting comments, refer to Docket No. 2007D-0201. Comments may not be acted upon by the Agency until the document is next revised or updated.

Additional Copies

Additional copies are available from the Internet. You may also send an e-mail request to [email protected] to receive an electronic copy of the guidance or send a fax request to 240-276-3151 to receive a hard copy. Use the document number (1793) to identify the guidance you are requesting.

Or, contact:

Office of Communication, Outreach and Development, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
Internet: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm
Tel: 800-835-4709 or 301-827-1800
E-mail: [email protected]

Table of Contents

1. INTRODUCTION
2. BACKGROUND
   • 21 CFR 807.81(A)(3)
   • CHANGES THAT “COULD SIGNIFICANTLY AFFECT” SAFETY OR EFFECTIVENESS
   • “A MAJOR CHANGE OR MODIFICATION IN THE INTENDED USE” OF A DEVICE
3. SCOPE
4. BASIC PRINCIPLES
   • IMPORTANT NOTE ON 510(K) DEVICES THAT CONTAIN NANOMATERIALS OR OTHERWISE INVOLVE THE APPLICATION OF NANOTECHNOLOGY
5. MANUFACTURING PROCESS CHANGES
6. LABELING CHANGES
7. TECHNOLOGY, ENGINEERING, AND PERFORMANCE CHANGES
8. MATERIALS CHANGES
9. IS CLINICAL DATA NECESSARY TO DETERMINE SUBSTANTIAL EQUIVALENCE?

Guidance for Industry and FDA Staff

510(k) Device Modifications: Deciding When to Submit a 510(k) for a Change to an Existing Device

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

¹ previously cleared medical device. The underlying principles that FDA uses to determine when a 510(k) is necessary for a modified device are explained here, and examples are provided for additional clarity. When final, this guidance will supersede the 1997 version of the guidance document, Deciding When to Submit a 510(k) for a Change to an Existing Device.

In 2010, FDA initiated a review of its process for premarket review of medical devices and undertook two significant initiatives to improve the Agency’s medical device premarket review programs. In August 2010, FDA released two reports, including the analyses and recommendations that suggested changes were needed to improve the predictability, consistency, and transparency of these programs. After receiving input from industry, stakeholders and the public, in January 2011, FDA announced 25 specific actions that the Agency will take to improve the premarket review programs. Updating the 1997 version of the guidance document, Deciding When to Submit a 510(k) for a Change to an Existing Device, is one of these actions.

The recommendations in this draft guidance document are consistent with FDA policy for when a modification to a device does – and does not – require the submission of a 510(k). The guidance has been updated, however, to address issues associated with software and other rapidly changing technologies, and to provide greater clarity about changes that do not trigger the need for a new premarket submission. This guidance uses examples of modifications to devices involving such technologies to illustrate changes that require a new 510(k), and changes that may simply be documented in accordance with a manufacturer’s existing Quality System without prompting the need for a new 510(k) submission. FDA believes increased certainty about the regulatory consequences of device modifications is critical to facilitating advancements in device technology.

FDA’s guidance documents, including this one, do not establish legally enforceable responsibilities. Instead, guidance documents describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word “should” in Agency guidance documents means that something is suggested or recommended, but not required.

II. Background

21 CFR 807.81(a)(3)

Almost from the 1976 enactment of the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act (the FDC Act), FDA has attempted to define with greater clarity when a modification to an existing medical device would – or would not – trigger the requirement that a new 510(k) be submitted to the Agency and cleared prior to marketing of the modified device. FDA regulations (21 CFR 807.81(a)(3)) state that a 510(k) must be submitted when:

(3) The device is one that the person currently has in commercial distribution or is reintroducing into commercial distribution, but that is about to be significantly changed or modified in design, components, method of manufacture, or intended use. The following constitute significant changes that require a premarket notification:

(i) A change or modification in the device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemical composition, energy source, or manufacturing process.

(ii) A major change or modification in the intended use of the device.

FDA issued the original guidance document Deciding When to Submit a 510(k) for a Change to an Existing 510(k) in 1997 to clarify the language used in this regulation, particularly the phrase “could significantly affect the safety or effectiveness” and use of the adjectives “major” and “significant.” Since then, regulatory changes such as the implementation of the Quality System regulation (21 CFR part 820) have occurred, and medical device technology has evolved. Accordingly, FDA is issuing this draft, updated guidance to reflect the Agency’s current thinking and emphasize the most important factors in determining whether to submit a 510(k) for a device modification.

Changes that “Could Significantly Affect” Safety or Effectiveness

The regulation, 21 CFR 807.81(a)(3), requires a new 510(k) for any change or modification that “could significantly affect” either the safety or the effectiveness of a device. Whether a change could significantly affect the safety or effectiveness of a device is the key issue this guidance tries to address. It is important to note that device changes intended as improvements to a device’s safety or effectiveness could significantly affect the safety or effectiveness and require a new 510(k).

It is also important to note that the question addressed by this guidance is a different question from whether a change does significantly affect the safety or effectiveness of a device. Whether a change does affect safety and effectiveness is typically demonstrated by testing submitted in a 510(k) application. In most cases testing cannot, however, conclusively show that a change could not affect safety or effectiveness. We have developed this draft guidance to categorize the types of changes likely to require new 510(k) submissions, the types of changes that generally do not require new submissions, and to identify gray areas where we recommend sponsors speak to the agency before determining whether a new 510(k) should be submitted.

“A Major Change or Modification in the Intended Use” of a Device

Section 513(i) of the FDC Act provides that a device may only be found substantially equivalent to a legally marketed predicate device if, among other things, the device has the same intended use as the predicate device. Thus, if a device modification results in a new intended use for the device, the Agency must find the device to be not substantially equivalent (NSE) and the device will require premarket approval. Changes to the indications for use, however, do not necessarily constitute a new intended use that would render the device NSE and trigger the requirement for a PMA. However, because changes to the indications for use are generally “major” changes to the intended use under 807.81(a)(3), they generally will require submission of a new 510(k). To clarify this principle, this guidance identifies several specific labeling changes or device modifications that affect the indications for use in a way that they have a major impact on intended use and thus require the submission of a 510(k).

[email protected]. Furthermore, this guidance is not intended to address the need for submitting 510(k)s by remanufacturers² of devices for which they do not hold the 510(k).³

The types of modifications addressed in this draft guidance include manufacturing process changes, labeling changes, technology or performance specification changes, and materials changes. This guidance is intended to assist industry in determining whether a new 510(k) is submission is necessary whenever a manufacturer makes a change to its own legally marketed device. This guidance may be used to determine whether device modifications made as corrective actions in recall situations warrant a new 510(k) submission. (See the Blue Book Memorandum K95-1, 510(k) Requirements During Firm-Initiated Recalls; if a correction alters a device rather than simply restoring it to its original specifications, a new 510(k) may be necessary. This guidance may be useful in determining whether one is warranted in cases where the correction does alter the device.)

This draft guidance document incorporates existing guidance and policy⁴ regarding when 510(k)s are necessary for modifications to legally marketed devices. In some cases, the existing guidance derives from advice given to only a few manufacturers for a limited number of devices. In such instances, we have attempted to generalize the concepts to apply to a broader range of devices. However, special cases exist where both manufacturers and FDA have worked to establish guidance for modifications to specific devices, e.g., daily wear contact lenses (see Premarket Notification (510(k)) Guidance Document for Daily Wear Contact Lenses). This draft guidance is not intended to supplant such existing device-specific guidance but may cover areas not addressed in those device-specific guidances. This draft guidance is also not meant to supersede the Office of In Vitro Diagnostic Device Evaluation and Safety’s (OIVD) Guidance for Industry and FDA Staff; Replacement Reagent and Instrument Family Policy.

The questions and answers in the following sections are provided as guidance to help manufacturers in determining whether a new 510(k) is necessary for a change or modification to an existing device. Manufacturers make the initial determination of whether a device modification requires a new 510(k), while FDA staff may review these decisions during post-market inspections. These questions should not be considered to be all-inclusive, as it is not possible for a single document to cover all possible device changes. The question and answer sections cover the following types of changes:

• Manufacturing changes
• Labeling changes
• Technology or performance specification changes
• Materials changes

⁵

To determine whether a device modification is significant and thus requires a new 510(k), a manufacturer should compare the modified device to the most recently cleared version of that device and decide whether the modification could significantly affect the safety or effectiveness of the device. It follows from this basic principle that a number of comparisons are not relevant to the decision about submitting a new 510(k):

• The modified device should not be compared to multiple devices, only to the most recently cleared version of that device, as described in that 510(k) submission.⁶
• The modified device should not be compared to a version of the device that has not received clearance. In cases where a manufacturer has made several modifications to a device and judged that they do not require submission of a new 510(k), the modified device should be compared to the most recent version of the device that received 510(k) clearance, as it was described in that 510(k) submission.
• The modified device should not be compared to any other device produced by the same manufacturer or another manufacturer, even if the other device could serve as a predicate to the modified device. The decision whether to submit a new 510(k) for a modified device is not based on whether the modified device is substantially equivalent to another device, it is based on whether the modification could significantly affect safety or effectiveness and whether it is a major change in the intended use of the device.
  For example: A manufacturer produces two legally marketed devices; Device A has design A and is made of material A, Device B has design B and is made of material B. If the manufacturer modifies Device A to be made of material B, it would be inappropriate to assume that because material B is part of a different 510(k)-cleared device the modification does not require a new 510(k). It would also be inappropriate to compare the modified Device A with material B to any other legally marketed device to decide whether a new 510(k) is necessary, even if the other marketed device would be an obvious predicate device for purposes of determining substantial equivalence of the modified device.

A manufacturer should answer the questions posed below, in Sections V-IX, for each individual change to its device until a decision is made either to submit a 510(k) or to document the change and the basis for concluding that it does not require a 510(k). For instance, if a manufacturer changes the length of a device, the thickness of the device, and the material of the device, each of these three changes should be considered individually.

Individual changes that do not require a new 510(k) may require one when evaluated collectively if those changes, taken as a whole, could significantly affect safety or effectiveness. After assessing each change individually, manufacturers should assess all changes made since the last 510(k) clearance collectively to determine whether the collective sum of all changes triggers the requirement for a new 510(k) submission.

Whenever manufacturers change their device, they must comply with the Quality System (QS) regulation (21 CFR Part 820) unless the device in question is exempt from the QS regulation. This regulation requires that specification changes be documented, validated or, where appropriate, verified prior to their implementation.

Manufacturers should have a mechanism or standard operating procedures in place for evaluating whether a proposed change meets the regulatory threshold for a new 510(k). Once a manufacturer has fully considered the device modifications:

• If there are multiple changes and analysis of any one of the changes results in a determination that submission of a new 510(k) is required, then the manufacturer should submit a 510(k) that incorporates all of the planned changes as well as a comparison of the changed device to the device as it was described in the most recently cleared 510(k). All changes to the device since its most recent 510(k) clearance should be identified, even those that did not trigger the need for a new 510(k); the specific change(s) that triggered the 510(k) should be distinguished. Note that a table is often helpful for such comparisons.
• If a manufacturer determines that its device modification(s) could not significantly affect safety or effectiveness and therefore decides not to submit a new 510(k), it should document the basis for concluding that it does not require a 510(k). Manufacturers should scientifically justify their conclusions that modifications, individually and collectively, could not affect safety or effectiveness. A copy of this documentation should be maintained. It is recommended that manufacturers answer each question below to satisfy basic Quality System requirements for documenting device modifications. See 21 CFR 820.30 and 820.70(b).

This guidance does not address every type of change to every type of device, and there will still be decisions in a “gray area” that manufacturers will have to make. For those circumstances where the proposed change is not addressed in this guidance or in a device-specific guidance document, manufacturers are encouraged to contact the appropriate review divisions to obtain advice.⁷

Important Note on 510(k) Devices that Contain Nanomaterials or Otherwise Involve the Application of Nanotechnology⁸ :

Nanotechnology is a new and evolving field for both the medical device industry and the Agency. At this time, FDA has not adopted nanotechnology-specific criteria to assist manufacturers in determining when a change to a device that contains nanomaterials or otherwise involves the application of nanotechnology rises to the level of significance that requires submission of a new 510(k). For this reason, FDA recommends that manufacturers consult with the agency for any nanotechnology-related changes to devices to determine whether and how the change may affect the safety or effectiveness of the device. FDA plans on developing additional guidance to further explain the Agency’s thinking on this matter. Contact the appropriate review division with any questions on devices that contain nanomaterials or otherwise involve the application of nanotechnology.

⁹ Other devices may include manufacturing process information in the 510(k) in order to address specific concerns, and some devices may undergo a pre-clearance inspection (e.g., infusion pumps – see Draft Guidance for Industry and FDA Staff – Total Product Life Cycle: Infusion Pump – Premarket Notification (510(k)) Submissions). In cases such as these, where manufacturing processes factor into the original clearance decision, the Agency has indicated that there is a higher likelihood that manufacturing process changes could significantly affect safety or effectiveness. Therefore, in cases where review of an original 510(k) submission includes a review of manufacturing process information, changes to manufacturing processes that could affect device specifications will likely require submission of a new 510(k). (Manufacturers should be aware of these requirements as they apply to their device type. Contact the appropriate review division with any questions.)

Device specifications include performance specifications (such as measurement accuracy), or physical or material characteristics (such as tensile strength). Changes to device specifications can significantly affect the performance of a device, and thus significantly affect a device’s safety and effectiveness. Changes to these specifications may be unintended collateral changes. For example, a new manufacturing process might leave a residue on an implant and change the surface chemistry of the device, causing it to react differently to the in vivo environment, or a change in heat treatment of an alloy might significantly affect the alloy’s physical properties, causing it to fail early.

2. Is there a change in packaging or expiration dating?

Generally, changes in device packaging or changes in the expiration date for use of a device do not result in the need to submit a new 510(k). Such changes are properly within the scope of the Quality System regulation. This conclusion is true whether the manufacturer applies an expiration date because of package integrity considerations, e.g., sterility, or because of a finite shelf-life of the device. However, where methods or protocols not described in the original 510(k) are used to support new package integrity or shelf-life claims, submission of a new 510(k) may be necessary. When such methods or protocols are described in the original 510(k), FDA reviewers should evaluate them with possible future use of the method or protocol in extended testing in mind.

3. Has there been a change in sterilization?

Changes in sterilization have the potential for changing the performance characteristics of a device. If these changes could significantly affect the safety or effectiveness of the device, the changes in sterilization methods trigger the requirements for a 510(k) submission. When manufacturers make changes in sterilization methods, they should document that the important properties and specifications of the device remain unaffected as part of their compliance with the QS regulations. In addition, if the sterility assurance level (SAL) is changed, manufacturers should consider whether device safety or effectiveness may have been compromised by the new level. If the SAL remains better than 10^-6, a new 510(k) submission is not necessary; only if the SAL is less than 10^-6 should a 510(k) be submitted. Changes to the sterilization method, such as changing from moist heat sterilization to e-beam radiation, require a new 510(k). Changes that result in a device being provided non-sterile when it was previously provided sterile, or vice-versa, also warrant a new 510(k).

¹⁰ Labeling can therefore include things such as instructions that are displayed on a screen by software, stickers or text placed on a control unit, and promotional materials.

We recommend that manufacturers consider the following questions to determine whether a labeling change requires submission of a new 510(k):

1. Does the change affect the indications for use?

For the purposes of this discussion, “indications for use” refers to a description of the disease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the patient for which the device is intended.¹¹ FDA views most labeling changes that affect the indications for use, as just described, whether made to a specific indications section of the labeling or not, as major changes to the intended use of a device that warrant the submission of a 510(k).

FDA would not consider a change in the indications for use that removes certain indications or limits use within the currently cleared indication due strictly to marketing reasons to be a major change in intended use under 21 CFR 807.81(a)(3) that requires submission of a new 510(k). For example, if a device was cleared for use with three indications and the firm decides to market the device for only two of those indications due to changes in market demand, FDA generally would not consider this to be a “major change” under the rule that would require submission of a new 510(k). However, if a firm decides to market the device for only two of those indications due to other reasons, for example, changes that have been made to the device that affect the removed indication or because of complaints or corrective actions, FDA would generally consider the removal of the indications for use to be a “major change” that requires a new 510(k).

Four other common labeling changes that affect the indications for use and that FDA believes would usually require submission of a 510(k) are:

• Changes that allow reuse of devices previously labeled “single use only”
• Changes from prescription to over-the-counter (OTC) use
• Changes from prescription use in a clinical setting to prescription use in a home setting (home use devices¹²)
• Changes from general patient populations to specific patient populations (e.g., changes from an undefined patient age group to a pediatric population)

2. Does the change affect the contraindications for use?¹³

a. Does the change add a contraindication?

While all changes in the labeled contraindications for device use should be reviewed by the Agency, FDA recognizes that, in general, the addition of a contraindication based on new information is important to public health and should be implemented immediately. To facilitate the timely implementation of such changes, manufacturers are encouraged to add new contraindications to labeling of cleared devices and to notify existing device users of such contraindications as expeditiously as possible whenever a pressing public health need arises. The new labeling should be submitted to FDA as part of a new 510(k) that is prominently labeled “change being effected” (CBE). Manufacturers may market the device with the modified labeling unless otherwise notified by FDA (FDA may ask for revisions during review of the 510(k)).¹⁴ Manufacturers should be thoroughly familiar with what constitutes a true contraindication to make a change effective before clearance; if there are any questions, contact the Agency before proceeding.

b. Does the change delete a contraindication?

Manufacturers planning to delete a contraindication should submit a new 510(k) prior to effecting the change because this type of labeling change expands the indications for use. For example, if a physical restraint was contraindicated for use with individuals weighing less than 100 pounds and the manufacturer subsequently wishes to remove this contraindication, a 510(k) should be submitted and cleared prior to marketing the device with the new labeling.

3. Is it a change in instructions for use?

If the labeling change instructs the user to use the device in a different fashion from that originally cleared, then this could lead to new significant safety risks or less effective use of the device. FDA views changes of this nature as major changes in intended use that require submission of a 510(k). Such changes are likely to significantly affect safety or effectiveness and therefore should generally be reviewed by the Agency in a 510(k) prior to marketing. Note that changes in instructions may or may not also constitute changes in indications for use.

Examples:

• Labeling for a device that provides diagnostic information is modified to include additional or new instructions on how to interpret data from the device. FDA considers this change a major change in intended use that could significantly affect the treatment of the patient and that requires submission of a 510(k).
• Labeling for a cutting instrument or laser is modified to include additional or new instructions about incision procedures. FDA considers this change a major change in intended use that could significantly affect the safety and effectiveness of the device’s treatment of the patient and that requires submission of a 510(k) prior to marketing.

4. Is it a change in warnings¹⁵ or precautions?¹⁶

Manufacturers should monitor device usage to facilitate continuous upgrades of device labeling and promptly revise the warnings and precautions sections based on use experience. Events that precipitate changes of this type should be reported under the Medical Device Reporting regulation (MDR), 21 CFR Part 803. Submission of a new 510(k) for labeling changes that add warnings or precautions is generally unnecessary; however, manufacturers are encouraged to discuss these situations with FDA. Labeling changes that delete warnings or precautions, however, could be changes in intended use that affect how a device is used and could therefore have a significant effect on safety or effectiveness. These changes are likely to warrant new 510(k) submissions.

5. Is it some other labeling change?

Other types of labeling changes might include clarifications to language that do not change the meaning, aesthetic or organizational changes to the way information is displayed, or logo or name changes. These types of changes are not usually considered major changes to the intended use and will not typically require a new 510(k). For example, the instructions for use of an automated clinical chemistry analyzer may be modified to clarify how routine batch testing operation may be temporarily interrupted to allow efficient processing of high priority samples.

¹⁷

While such changes may seem innocuous, most changes of this nature have the potential to significantly impact safety or effectiveness by altering data communication quality and therefore should result in a new 510(k) submission. Also see Deciding When to Submit a 510(k) for a Change to an Existing Wireless Telemetry Medical Device.

Examples:

• Diagnostic software that typically displays images on a monitor in a clinical setting is modified to output the image to a portable hand-held device that can be used to view the images from any location. This change could result in new risks, such as the inability to discern certain data due to a smaller hand-held screen, lower picture resolution, or loss of data during transmission, that could significantly affect the safety and effectiveness of the software. Therefore, this change should result in a new 510(k) submission.
• An infusion pump that was cleared with a hard-wired connection to a keyboard to input treatment parameters is modified to include wireless capability to allow for remote input of treatment parameters. This change could significantly affect safety or effectiveness by altering data communication quality, which could affect the input of treatment parameters, and should therefore result in a new 510(k).

8. Is the modification intended to add an aspect of autonomous or semi-autonomous control to the existing device?

Any device modification that takes control of the device away from the user or is used to assist or take away decision-making from a user likely introduces new risks that could significantly affect safety or effectiveness, and should be reviewed in a new 510(k) submission prior to marketing.

Examples:

• A colon imaging software package is modified to include computer assisted detection to assist the physician in determining potentially malignant tissue. As a new feature, this change could significantly affect the safety or effectiveness of the device by introducing the possibility of false positives or negatives that could adversely affect the course of treatment. This change requires a new 510(k).
• A dental handpiece is modified to automatically increase or decrease the revolutions per minute (rpm) of a drill bit based on treatment selected or the type of bone encountered. Automating this treatment parameter introduces several new risks, such as an inappropriate automatic increase to an unsafe rpm or an inappropriate automatic decrease to an ineffective rpm. These risks constitute significant effects on safety and effectiveness. This change requires a new 510(k) prior to marketing.
• A device that acquires nerve conduction waveforms and extracts multiple parameters from those waveforms is modified to include software that automatically compares the parameters to a reference database to provide a diagnosis. An automated diagnosis can influence patient treatment and could significantly affect the safety and effectiveness of the device. This change requires a new 510(k).

9. Is the change being implemented to address a specific risk or failure mode for your device?

Changes that are implemented to address either known or newly identified safety risks or failure modes of a device, including those intended to address a known device- or user- related adverse event or complaint, are by definition likely to significantly affect safety or effectiveness, even if the modification is intended to make the device more safe than the previous version. These modifications may include the implementation of new alarms or new alarm setpoints, modifications to the user interface to display new information that may be used to manage device settings, or design modifications that are intended to eliminate known failure modes. These changes should usually result in new 510(k) submissions.

These situations may also call for a device recall. You should contact the CDRH Office of Compliance or the Office of Compliance and Biologics Quality in these cases, and if a recall is initiated, consult the Blue Book Memorandum K95-1, 510(k) Requirements During Firm-Initiated Recalls .

Examples:

• A manufacturer of a fluid warming device wants to add a protective mechanism (either hardware or software) to cut off power to the device should the fluid temperature increase past a certain setpoint. This change also addresses a specific risk, and could significantly affect safety or effectiveness. This change should result in the submission of a new 510(k).
• A manufacturer wants to add a color-coded luer or proprietary connector to address the risk of misconnections for a feeding tube. A change of this type should result in the submission of a new 510(k).

10. Does the change affect how the device is likely to be used in practice?

Technological or design changes may affect how a device is used in practice, and therefore affect the safety or effectiveness of the device, even if no change in the Indications for Use statement accompanies the change. Such changes may create the need for new directions for use or a limitation in the device labeling to address the potential that an off label use could cause harm.¹⁸ Particularly when the modification could create a reasonable likelihood of off-label use that could cause harm, a new 510(k) should be submitted to allow FDA to determine whether a change to the labeling is necessary, even if the manufacturer does not intend a change to the indications for use in the labeling. The questions below are intended to guide manufacturers in determining whether changes to device technology, engineering, or performance constitute significant changes that trigger the need for a new 510(k) to enable FDA to evaluate whether “appropriate information” in the labeling about a use not currently identified in the labeling is necessary.

1. Is the modification to the device likely to alter or expand the use of the device?
   If an existing device is being modified to allow for its use in a different or modified type of medical procedure, or to treat or diagnose a disease or medical condition apart from what has been previously cleared, the potential to significantly affect safety or effectiveness will be high, and therefore, these changes should result in a new 510(k) submission.
    
   Examples:  
   • A manual surgical instrument is modified so that it can be connected to an electrical stimulator and conduct current (i.e., is now both a surgical instrument and an electrode). This change should be submitted in a 510(k) prior to marketing.
   • The length of a surgical scissor is modified such that an existing device previously intended for only open surgical procedures can now be used for closed, endoscopically-controlled procedures. This change should be submitted in a 510(k) prior to marketing. (Note that while a typical surgical scissor is exempt from submitting a 510(k) by regulation, 21 CFR 878.4800, a 510(k) submission may be necessary in this instance because the change may alter the intended use of the device or may involve a different fundamental scientific technology than the generic type of device (21 CFR 878.9(a), (b)).)
   • An in vitro diagnostic test is modified such that the processing utilizes frozen biopsy tissue samples rather than paraffin embedded tissue samples, so that users have more flexibility in tissue processing. This change could significantly affect the device performance and therefore should be submitted in a 510(k) prior to marketing.
2. Does the modification allow for the use of the device in a new, expanded, or more specific patient population?
   Design changes that allow use in a new, expanded, or more specific patient population also carry a high potential to significantly affect safety or effectiveness, and therefore, these changes should result in a new 510(k) submission.

   Examples:

   • New features of a ventilator allow the device to be used for the treatment of pediatric patients, whereas previously it was only cleared for use by patients who had a tidal volume in the adult range. This is an example of an expanded patient population that should result in a new 510(k).
   • The dimensional specifications of a feeding tube are reduced to facilitate use of the device in an infant by making the implanted portion shorter and the tubing diameter smaller and thus more appropriate for the slower flow rate and volume necessary for use of the device in an infant. This is an example of a more specific patient population which should result in a new 510(k).
   • An evoked response auditory stimulator intended to aid in the detection of lesions in the auditory pathway for the general population is modified in order to detect lesions in a specific patient population, e.g., persons identified as having a higher level cognitive dysfunction thought to be related to hearing. This is an example of a device being modified for a more specific patient population. This modified device should be reviewed in a 510(k) prior to marketing.
3. Does the modification significantly change or alter an established medical procedure associated with the device?
   Changes that result in an alteration to an established medical procedure should be reviewed in a new 510(k) prior to marketing because the new use of a device may introduce new safety risks or lead to less effective use of the device.
    
   Example:
   • Components of a surgical kit are combined with a surgical handpiece to allow cricothyroidotomy to be performed with one device. This device modification and its corresponding modified procedure could significantly affect the safety or effectiveness of the device and therefore should result in a new 510(k).
4. Is a specific modification intended to allow for the use of the device in a new environment in which there may be new risks affecting safety and effectiveness?
   In general, modifications to allow a device to be used in a new environment are associated with new risks. Therefore, in most cases, changing a device to fit a new environment should result in a new 510(k) submission.
    
   Examples:
   • A stationary electrocardiogram (ECG) device originally cleared and intended for use in hospitals is modified to reduce lead sets or incorporate modular electrodes, which may allow use in pre-hospital settings such as ambulance transport. This change should result in a new 510(k) submission prior to marketing.
   • If an electroencephalograph (EEG) seizure detection device originally intended for use in post hoc review of EEG data from epilepsy monitoring units is modified to add a real-time alarm, it may allow use in an intensive care setting. Similarly, if an EEG device originally intended for general use is modified to reduce the number of electrodes, it may allow use in emergency settings. These changes would introduce new risks and therefore should be reviewed under 510(k) prior to marketing.
5. Is the change intended to allow the device to be used by a lay person outside of a clinical setting?
   These changes may include those that change the indication of the device from prescription to over-the-counter, as well as those that allow the device to be used by a lay person outside of a clinical setting as prescribed by a physician (home use). Both types of changes introduce new risks that could significantly affect safety or effectiveness, and therefore should result in the submission of a new 510(k).
    
   Examples:
   • An ECG device is modified to reduce the number of leads or simplify electrode placement to allow for home use or over-the-counter use. This change should result in a new 510(k) submission prior to marketing.
   • A hemodialysis machine is modified to incorporate additional safety features, a more friendly user interface, and a special user’s manual so that it may be operated by a lay person. The potential for use by a lay person outside the clinical setting introduces new risks. This change should be reviewed in a new 510(k) submission prior to marketing.
6. Does the modification allow for the device to provide new information or data to the user that could be used for patient assessment or diagnostic purposes?¹⁹
   New technological characteristics that allow use for patient assessment or diagnostic purposes could significantly affect the safety or effectiveness of a device and may necessitate a new 510(k). This principle applies even if the new patient assessment information is used as an aid or adjunct to other measures or is only considered additional information.
    
   Examples:
   • A device that previously only qualitatively displayed blood flow or stenosis by displaying an image is modified to output quantitative or semi-quantitative data for these assessments. This change from qualitative, or informational, data to quantitative data would introduce new risks for the device and significantly impact safety and effectiveness. A new 510(k) should be provided.
   • A device that previously only derived four parameters from an EEG waveform is modified to derive two additional parameters from the waveform. This change should result in a new 510(k).
   • A device that previously calculated four parameters from a waveform is modified to calculate a standard deviation or variance of those parameters to aid in detecting abnormalities of the waveform as a diagnostic tool. This change should be reviewed in a 510(k) prior to marketing.
   • A device cleared only to acquire and display raw physiological data is modified to include software that automatically analyzes, interprets, highlights or extracts parameters from the physiological data. This change should result in a new 510(k) prior to marketing

Guidance for Industry and FDA Reviewers – Reprocessing and Reuse of Single-Use Devices and Frequently-Asked-Questions about the Reprocessing and Reuse of Single-Use Devices by Third-Party and Hospital Reprocessors

^{K86-3, K90-1, etc., as well as device-specific guidance documents.}

⁵ FDA’s regulations also contain exemptions from premarket notification requirements in 21 CFR 807.85. No premarket submissions is required for a device modification that falls within these exemptions.

⁶ Cleared 510(k) premarket notifications are listed in FDA’s 510(k) database.

^{CDRH Management Directory or CBER Key Staff Directory}

^{Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology.”}

⁹ See device-specific guidances for contact lenses and wound dressing devices, e.g., Premarket Notification Document (510(k)) for Daily Wear Contact Lenses and Guidance for Industry and FDA Staff – Class II Special Controls Guidance Document: Wound Dressing with Poly(diallyl dimethyl ammonium chloride) (pDADMAC) Additive.

¹⁰ §201(m): “The term ‘labeling’ means all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.”

¹¹ The term indications for use is defined in the PMA regulation at 21 CFR 814.20(3)(i). We have applied the definition in the same way in the 510(k) context.

¹² For purposes of this guidance, FDA considers a home use device to be a medical device intended for users in a non-clinical environment that is managed partly or wholly by the user. These devices require adequate labeling for the user and may require training for the user by a licensed health care provider. Please see Home Use Devices.

^{Device Labeling Guidance.}

^{Device Labeling Guidance.}

^{Device Labeling Guidance.}

¹⁷ Note that Medical Device Data Systems (MDDS) are exempt from 510(k) requirements, see 21 CFR 880.6310, and are outside the scope of this draft guidance. For more information on MDDS, see Medical Device Data Systems.

¹⁸ The FDC Act provides in section 513(i)(1)(E)(i) that:

Any determination by the Secretary of the intended use of a device shall be based upon the proposed labeling submitted in a report for the device under section 510(k). However, when determining that a device can be found substantially equivalent to a legally marketed device, the director of the organizational unit responsible for regulating devices (in this subparagraph referred to as the “Director”) may require a statement in labeling that provides appropriate information regarding a use of the device not identified in the proposed labeling if, after providing an opportunity for consultation with the person who submitted such report, the Director determines and states in writing—

(I) that there is a reasonable likelihood that the device will be used for an intended use not identified in the proposed labeling for the device; and

(II) that such use could cause harm.

FDA would make such a finding in writing where it determines that such a change is reasonably likely to result in an off-label use that could cause harm.

¹⁹ For the purposes of this guidance, any device that provides data or information used to assess a patient’s condition or treatment can be considered diagnostic. A device need not be indicated solely for screening or providing diagnoses to be considered diagnostic.