Guidance on how to interpret "significant change" of a medical device: Types of changes

On this page

• Changes to manufacturing processes, facilities or equipment
• Changes to manufacturing quality control procedures
• Changes in design
• Changes to sterilization and sterile barrier packaging
• Changes to software
• Changes in materials for non in vitro diagnostic devices
• Changes in materials for in vitro diagnostic devices
• Changes to labelling
• Class III and IV amendments for compatible Class II devices
• Changes to diagnostic ultrasound systems

Changes to manufacturing processes, facilities or equipment

For the purposes of this section, a manufacturing change impacts how a device is made but does not intentionally change the design of the device, its packaging or labelling material.

Examples of manufacturing changes include:

• changes to the component formation process
  • for example, switching from an extruded to a machined component
• altering manufacturing machine tolerances
• replacing equipment used to perform a manufacturing function
• moving manufacturing to a new facility

A change to the manufacturing process, facility or equipment can impact the safety or effectiveness of a device. You should assess the impact of all manufacturing changes on the device specifications, performance and material properties. These changes should also be evaluated using other relevant sections of this guidance document.

If a change to the manufacturing process, facility or equipment involves changes to the sterilization process, refer to the section on changes to sterilization.

Tolerances that have been increased to allow for more variation in the end product likely represent a significant change, as this may impact device performance.

Examples of changes that are likely non-significant include:

• changes that tighten specifications within the existing range of licensed specifications for the same device, model or component on the licence where the mean value is not substantially altered
• increases to the tolerance ranges, if the impact of the change is fully verified and validated from the information previously submitted and reviewed by Health Canada for the same licensed device
• changes to the manufacturing process, facility or equipment that do not impact the device specifications, performance or materials and for which incoming inspections to evaluate the material provided by the supplier have not been changed
• the addition of a new manufacturing facility when the:
  • manufacturer's name and address on the device labelling stays the same and
  • new facility has the same manufacturing process and equipment of the same specifications and
  • new facility is not a new sterilization facility or new abattoir for animal-derived materials
    • For more information, refer to the section on changes to sterilization and the section on changes in materials for non in vitro diagnostic devices

For combination products regulated as medical devices, changes involving active pharmaceutical ingredients (APIs) require special consideration due to increased sensitivities associated with API production and application.

Changes to the manufacturing process of a combination product that involve APIs are often significant. For this reason, we recommend that you contact the Medical Devices Directorate by email at meddevices-instrumentsmed@hc-sc.gc.ca for specific guidance on all changes to manufacturing process, site or specifications for the API of a combination product.

Changes to manufacturing quality control procedures

For the purposes of this section, a manufacturing quality control change impacts oversight of the manufacturing steps, but does not intentionally change the design of the device, its packaging or labelling material.

Examples of manufacturing quality procedure changes include:

• changes to test or inspection criteria
• alterations to test methods
• adding or deleting a tested or inspected parameter
• changes to statistical rationale or sample size
• changes to acceptance quality limits (AQL)
• changes to validation endpoints
• increasing or decreasing required sterility assurance level (SAL)

Changing or adding new testing or inspection activities for incoming materials, in-process materials and final products is not a significant change if the specifications or acceptance criteria have not been loosened and AQLs have not increased. On the other hand, removing or modifying these activities where the result is that specifications or criteria are loosened or AQLs are increased is a significant change.

The following changes are often considered significant:

• changes to quality control inspections or tests used to control the quality, purity or sterility of materials
• changes that could affect the specifications of the finished device or its components, including its packaging

However, if adding or modifying the inspection or test method results in equivalent or improved assurance of reliability, then the modification would not be deemed a significant change.

Changes in design

Changes in design range from minor design specification or engineering changes to major changes in operating principles. All design changes must be evaluated, verified and validated according to the accepted procedures recorded in the quality management system.

Examples of design changes can include modifications to the:

• device's control mechanism
• device's operating principles
• device's design specifications
• device's components or accessories
• human factors of the patient or user interface

Control mechanism

A control mechanism refers to the means by which a device's actions are directed or its output is regulated. Control mechanisms can be complex. Any modification to them has the potential to alter how the device functions. Such changes may affect the device's risk profile, safety or effectiveness. Therefore, changes to the device's control mechanisms are considered significant.

Operating principles

Operating principles are the means by which a device produces or brings about an intended or appropriate effect. Changes to operating principles are considered significant.

For more information on operating principle changes that include software, refer to the section on changes to software.

Design specifications

Changes to design specifications can include modifications to the:

• physical characteristics such as shape, size, dimensions or materials, including non IVDDs and IVDDs
• performance or technical specifications
• patient or user interfaces
• software or firmware updates
  • for more information, refer to the section on changes to software
• precision, accuracy, sensitivity, specificity or stability for IVDDs

A change to design specifications may be significant if it affects at least 1 of the following 3 factors:

1. indications for use or intended use
2. requirements to have clinical data
3. risk profile of the device

1. Indications for use or intended use

Changes to design that affect the indications for use or intended use are considered significant. Such changes may impact the:

• target patient population
  • for example, elderly or pediatric patients
• target anatomical site or area
• target disease, disease state or condition

2. Clinical data

Changes to the design specifications that require new clinical data to demonstrate and validate the safety and/or effectiveness of the device are significant.

3. Risk profile

A design change may introduce new hazards or hazardous situations, alter the severity or probability of harm, or require new risk-mitigation measures. A new risk assessment should be conducted for any design change. The risk assessment should identify any new risks.

If the risk assessment finds that the change could alter the safety or effectiveness of the device, the change is significant. However, a change is not significant if the risk assessment and its conclusions remain unchanged by the design change and the device performance is unchanged compared to the design that underwent pre-market review.

Components or accessories, including Class II devices

A change in device design may result from modifications to accessories or devices intended to be compatible with a licensed Class III or IV device, regardless of if they are licensed together or separately. This includes those listed under a Class II licence.

Adding new components or changing the design of device components or accessories used with a Class III or IV device are considered significant changes if they:

• affect the safety or function of the device as a whole or
• substantially alter how the user interacts with the Class III or IV device through the operation of the modified or newly added design of the components or accessories or
• could cause the device to be used in a new way
  • for example, new workflow, new patient population, new indication

Modifying an existing component or accessory or adding a new component or accessory that is intended to be, or labelled to be, compatible with a Class III or IV device is a significant change if:

• this addition or modification may impact the safety or effectiveness of the assembled combination of devices, components or accessories when used as intended.

This applies regardless of the classification of the component or accessory, or whether all parts are on the same licence or licensed separately. An application to amend the associated Class III or IV device is required. The application must include a clear description of the change, as well as evidence verifying the safety, effectiveness and compatibility of the modified or added components or accessories with the Class III or IV device.

For more information, refer to the section on Class III and IV amendments for compatible Class II devices.

Human factors of the patient or user interface

A design change that affects how the device is used or how it interacts or interfaces with the patient or user is generally considered significant.

Examples of such changes include:

• changes to the display or layout of a control panel or graphical user interface (GUI) if used for device control or risk mitigation
• changes to how the device interacts with the patient or user, particularly when the information exchanged is necessary for monitoring device performance or function
• changes to the design of a surgical tool or delivery system that modify how the surgeon operates or manipulates the device

Cosmetic or aesthetic modifications, such as those made solely for appearance or user comfort, are generally not significant if they do not affect device function, use, clinical performance, safety or effectiveness.

Changes to sterilization and sterile barrier packaging

Changes that could affect the effectiveness of the sterilization process or the safety or effectiveness of the sterilized device are considered significant. This is regardless of whether the sterilization process is during manufacturing or by the end user. The same considerations should also be applied if a device requires disinfection for safe use. Given that it's impossible to determine by inspection if a device is sterile or adequately disinfected, this must be confirmed through a validated process.

Medical devices are considered sterile when the sterility assurance level (SAL) of 10-6 or better is demonstrated. The sterilization process must be verified and validated, and its ongoing performance routinely monitored.

Examples of significant sterilization changes are where the:

• manufacturing process, environment or device material may introduce an organism that is more difficult to kill compared to the challenge organism previously used in sterilization validation testing
• manufacturing process, environment or device material increases the bioburden above the maximum bioburden level previously validated in sterilization validation testing
• device design introduces a feature or alters existing features that result in a new worst case more-difficult-to-sterilize location for existing sterilization validation
• device material is more difficult to sterilize or increases sterilant residuals
• quality control verification and validation processes are changed, such as introducing or removing parametric release or changing the sterilization dose auditing method
• type of sterilization method is changed during manufacturing or recommended to end user in labelling
• critical cycle parameters (such as ethylene oxide gas concentration or radiation dose) are changed
• dose delivery is changed (such as changes in loading density or configuration)

In general, any change that could trigger a new or increased risk is a significant change.

Non-significant changes would be those limited to adding a new facility, chamber or equipment that uses the same sterilization method and critical cycle parameters. For example, EO gas concentration or radiation dose and validating to a SAL of 10-6 using a Health Canada-recognized standard, such as:

• ISO 11135 or ISO 11137 or
• an identical international version of these standards like BS EN ISO 11135 or BS EN ISO 11137

Adding a new test acceptance criteria or test method to the existing process to provide the same or better assurance of sterility, reliability or similar safety aspects is generally considered a non-significant change.

Using a sterilization method that does not adhere to recognized standards (refer to Health Canada-recognized standards) may impact the expected sterility assurance level of the device. For changes involving novel sterilization technologies, you should contact the Medical Devices Directorate for guidance at meddevices-instrumentsmed@hc-sc.gc.ca.

A change in manufacturing facility is considered significant if it introduces a new or more challenging organism or results in a higher bioburden level that was not previously validated in the sterilization process. This applies even when the sterilization cycle parameters remain unchanged, as the validated worst-case conditions are no longer assured.

Changes to sterile barrier packaging

Packaging changes must be assessed for their potential impact on sterilization. In general, any modifications to packaging characteristics (for example, material type, size, shape, seal width or configuration, such as in the outer packaging, loading density) is likely significant if it could affect:

• absorption or penetration of the sterilant
• sterilant residual levels (where applicable)
• the overall effectiveness of the sterilization process
• the safety or integrity of the sterile device
• package seal strength and sealing process parameters

Compatibility between the packaging material and the sterilization process must also be assessed, as changes may alter the performance or reliability of the packaging.

Changes to previously approved cycles or configurations

A change to the sterilization method or packaging of a sterile medical device is likely not significant if:

• it has already undergone successful pre-market review in a previous new or amendment application for a similar device by the same manufacturer and
• all of these conditions are met:
  • the device is not more difficult to sterilize than the previously licensed comparator device
  • the interaction between the device and the proposed packaging does not introduce greater risk to the integrity of the sterile barrier
  • the devices are made of identical materials and have similar designs, with no new features that would create a new worst-case scenario for sterilization
  • the proposed changes were explicitly represented, requested and approved in a previous new or significant change application

Changes to software

For the purpose of this section, medical device software can either be integrated into the hardware of a medical device or distributed separately. Our recommendations in this section apply to both software and firmware.

Software can be updated easily and frequently, and thus may undergo multiple changes throughout its lifecycle. Health Canada considers some of these changes to be significant.

Examples of significant software changes are those that:

• affect the function or performance specifications associated with the intended use of the device or the intended use of a compatible device whose function is controlled by the software
• introduce a new risk or modify an existing risk that could result in significant harm, including harms from unintended consequences
• create or necessitate a new risk control measure or modification of an existing risk control measure for a hazardous situation that could result in significant harm

Examples of non-significant changes, if none of the previous changes apply, are those that:

• are made solely to return the system into specification of the most recently licensed version of the device
• incorporate changes to the operating system on which the software runs, without changing the underlying software code
• are made solely to strengthen cybersecurity and do not have any other impact on the software's or the device's safety or effectiveness
• only introduce features with no medical purpose such as printing, faxing, improved image clarity, reporting format or additional language support
• only modify the appearance of the user interface, with little risk of affecting the usability, diagnosis or therapy delivered to the patient
• disable a feature that does not affect the safety or effectiveness of the device

These examples are only illustrations. All software changes should be evaluated for their potential to create unexpected software behaviour. Whether a change is significant depends on its potential impact on device safety or effectiveness. A risk assessment is recommended following any software modification.

Other examples of software changes that may or may not be significant:

• rewriting the software in another programming language is likely to be significant
• driver modifications are likely to be significant
• changes to the operating system may be:
  • non-significant if no changes are made to the application
  • significant if driver changes are required or the kernel differs between operating systems
    • for example, a change in operating system family from Windows to Linux or a major Windows change from XP to Windows 10

Medical devices that use machine learning (ML), in part or in whole, to achieve their intended medical purpose are referred to as machine learning-enabled medical devices (MLMD). A predetermined change control plan (PCCP) provides a mechanism to address cases where pre-authorization of planned significant changes is needed to address a known risk. This approach can be beneficial in managing certain known risks with MLMD, such as ML system performance degradation over time due to ML model drift.

For medical devices that have been licensed with a PCCP, any significant changes made according to the authorized PCCP have already undergone review. Thus, an amendment application is not required.

For amendments to a device that are outside of an authorized PCCP, including changes to the PCCP itself, consult:

• the Medical Devices Regulations
• other relevant guidance documents in addition to this one

For more information on submission requirements for MLMDs and PCCPs, consult:

• Pre-market guidance for machine learning-enabled medical devices

Common software change types and potential unintended consequences

Software changes can come in several different forms, such as:

• infrastructure changes
  • for example, changing compilers, programming languages, software drivers
• architectural changes
  • for example, new operating system compatibility, software changes to support modified or new hardware
• algorithm changes
  • for example, modifications to the logic or calculations performed by the software
• cosmetic changes
  • for example, new logos, user interface fonts, colours
• refactoring
  • for example, improving software efficiency, structure or maintainability without changing the software behavior or functionality
• re-engineering
  • for example, reconstituting the software in a new form, replacing aging software

Cosmetic changes are often non-significant. However, the changes listed here may be deemed significant as there may be unintended consequences when executing software code in often complex software environments. For example, an operating system (OS) upgrade may:

• trigger unintended effects through the use of different drivers or kernels
• require updates to other software components to maintain compatibility

You should carefully evaluate the potential consequences of software changes to determine whether the change is significant, considering its potential impact on the safety or effectiveness of the device.

Changes in materials for non in vitro diagnostic devices

Changes in materials include any changes in the material source, supplier, processing methods, type, formulation and chemical, physical or electromagnetic properties. Each material change should be assessed on its own and together to determine its impact on the safety and effectiveness of the device.

This section focuses on the impact of material changes on the device. For example:

• biological safety and biocompatibility of the device
• bonding or adhesion to adjacent materials
• mechanical or physical properties

In general, a change to materials of human or animal origin is considered significant. For more information, consult:

• Guidance on the regulation of medical devices manufactured from or incorporating viable or non-viable animal tissue or their derivative(s)

The impact of a material change on the safety or effectiveness of the device also depends on factors such as:

• the origin of the material
• if the material type, formulation, composition or processing has changed
• if the device is invasive or non-invasive
• the type and duration of the material's contact with body tissues or fluids

Changes to the materials of a medical device may also directly or indirectly impact several other aspects of the overall medical device or its function, for example:

• device specifications, resulting in altered mechanical performance
• device stability and shelf life
• a material change may require a change to labelling content
• sterilization process effectiveness, including interactions with sterilant

The impact of altering the materials of a Class II device that's compatible with a Class III or Class IV device, whether licensed together or separately, should also be considered. This change to the Class II device may impact the safety or effectiveness of the higher-risk device and require a licence amendment before the Class II material changes are made. For example, changes to the materials of a surgical stapler may have an impact on the safety or effectiveness of the compatible surgical staples.

Likewise, changes to other aspects of the design, manufacturing or storage and transportation should be assessed for potential intended or unintended impacts on the device or packaging materials. Examples of such changes include:

• changes in a manufacturing process or equipment could impact the properties of 1 or more device materials
• changes in storage conditions may influence material characteristics or stability of the device material or packaging materials

Change in the source or supplier of the material

A change in the source of a material refers to switching from 1 supplier or manufacturer of a raw material, component or substance used in the device to another.

In general, changes to the supplier or vendor are not considered significant when the change does not alter the material type, formulation, chemical composition or processing. This is regardless of whether the device comes into direct contact with a patient.

However, changes that affect the material type, formulation, chemical composition or processing are likely significant. This is especially the case when the material is implanted, has direct patient contact or is essential to the safety or effectiveness of the device.

Change in material processing

A change in material processing is to any modification in how a material used in a medical device is manufactured, treated or handled during production.

The impact of such a change should be assessed by comparing the modified material specifications against the original specifications. A material-related change that results in an alteration to the device specifications should also be evaluated as a design change.

When only the material specifications are affected and all other device specifications remain unchanged, the change is likely significant if it could reasonably be expected to impact the safety or effectiveness of the device.

Examples of material processing changes that may affect device safety or effectiveness include:

• changes to material extrusion equipment that could modify surface roughness
• adjustments to E-beam or gamma sterilization dosage that may alter the properties of a crosslinked polymer

Change in type of material

A change in the type of material refers to the substitution of one material for another that differs in chemical composition, biological origin, or physical properties. This is distinct from changes related to supplier or processing methods.

A change in the type of material is likely significant if the altered material may:

• have different biocompatibility characteristics
• change the performance or function characteristics of the device
• alter electromagnetic properties such as magnetic resonance imaging (MRI) compatibility or susceptibility to radiofrequency (RF) interference
• introduce new risks or change the device's benefit-risk profile
• affect the stability or durability of the device component
• affect the effectiveness or safety of the sterilization process or packaging system

Change in the formulation or chemical composition of the material

A change in the formulation and chemical composition is any change to the ingredients, ratios or chemical structure of a material used in the device. This includes:

• substituting 1 chemical compound for another
• altering the concentration or proportion of components within a mixture
• adding or removing additives, stabilizers or fillers
• changing the polymerization method or cross-linking agents

A change in the formulation or chemical composition of the material is likely significant if the:

• altered material is in direct or indirect contact with body tissues or fluids
• change affects the biocompatibility of the device
• modifications alter the mechanical, chemical or thermal properties of the device
• change in material has the potential to modify the overall benefit-risk profile of the device

The following flowchart and explanation outline the assessment you must undertake to determine if your change is significant.

Text description

The figure is a flowchart with several boxes that contain different questions. Each box is numbered 1 to 7.

Box 1 asks if the altered material of human or animal origin? If the answer is yes, then the flowchart indicates this is a significant change. If the answer is no, the flowchart indicates to proceed to box 2.

Box 2 asks if there is a change in material type, formulation, composition or processing. If the answer is no, the next box indicates it is not a significant change. If the answer is yes, the flowchart indicates to proceed to Box 3.

Box 3 asks if the altered material will be in direct or indirect contact with body tissues or fluids. If the answer is yes, the flowchart indicates to proceed to box 4. If the answer is no, then skip to box 7. Box 7 asks if the altered material has resulted in other changes. If the answer to box 7 is no, then this is not a significant change. If the answer to box 7 is yes, then consult other sections of this guidance.

Box 4 asks if the altered material is identical to that used in a licensed device by the same manufacturer with a similar design for the same indications. If the answer is no, then proceed to box 5. If the answer is yes, then proceed to box 7. Box 7 asks if the altered material has resulted in other changes. If the answer to box 7 is no, then this is not a significant change. If the answer to box 7 is yes, then consult other sections of this guidance.

Box 5 asks if the altered material is used in an invasive device intended to be absorbed by the body, remain in the body for at least thirty days or in contact with the central cardiovascular system or central nervous system. If the answer is yes, then this is a significant change. If the answer is no, then proceed to box 6.

Box 6 asks if there are any new or increased biocompatibility concerns identified with the altered material. If the answer is yes, then this is a significant change. If the answer is no, then proceed to box 7.

Box 7 asks if the altered material has resulted in other changes. If the answer to box 7 is no, then this is not a significant change. If the answer to box 7 is yes, then consult other sections of this guidance.

Additional considerations

Changes to reuse or recycling processes or to storage conditions for raw materials intended for additive manufacturing such as 3D printing are likely significant if the properties or performance of the finished device are affected.

If the altered material will be in direct or indirect contact with body tissues or fluids, it is likely significant.

• Direct contact refers to physical contact between the material and body tissues or fluids.
• Indirect contact refers to a material through which a fluid or gas passes before the fluid or gas comes into physical contact with body tissues or fluids. In other words, the material itself does not physically contact body tissues or fluids.

For device safety, direct and indirect contact with body tissues or fluids should be assessed using the same considerations. Any change involving either type of contact may be significant, pending the full assessment.

If the material has neither direct nor indirect contact with body tissues or fluids, no further biological or biocompatibility considerations need to be assessed in terms of significant change.

If the altered material is in contact with body tissues or fluids, but the altered material is used in a Canadian-licensed device with a similar design for the same indications by the same manufacturer, the material change may not require an amendment. This is the case if:

• both devices are manufactured by the same process and
• for the same indication and
• the material interacts with the same adjacent materials in both devices

The licensed device must also have all of the following:

• same or greater risk classification
• same or higher risk nature of contact
  • for example, blood is considered worst-case or higher risk compared to intact skin
• same or longer duration of contact

Biocompatibility concerns reported in a post-market clinical follow-up or surveillance and part of the corrective action or mitigation includes a change to the materials would be considered a significant change.

A change is likely significant if there's a change made to materials used in an invasive device that's intended to:

• be absorbed by the body
• remain in the body for at least 30 days or
• be in contact with the central cardiovascular system or central nervous system

The material change is likely not considered significant if:

• it is a colourant change using an altered dye that complies with List 7 of the FDA's Colour Additive Status List and
• no other changes are introduced

If the device doesn't meet these conditions, then biocompatibility assessment should be performed. A material change that could introduce a new or increased biocompatibility concern is considered a significant change.

• A new biocompatibility concern refers to the scenario where a new type of biocompatibility testing is required.
• An increased biocompatibility concern refers to the scenario where the original biocompatibility testing for the device no longer applies.

For example, if a material change introduces a new leachable that needs to be tested:

• a new biocompatibility concern would result if the leachable is suspected to be genotoxic and no previous genotoxicity testing of the original device was conducted
• an increased biocompatibility concern would result if sensitization testing of the original device is no longer applicable due to sensitization potential of the leachable

A material change is likely not significant if it:

• does not introduce new or increased biocompatibility concerns and
• is not used in a device intended to be absorbed by the body and
• is not intended to be retained in the body for 30 days or more and
• is not intended to be in contact with the central cardiovascular or central nervous system and
• does not result in any other modifications to the device's design, specifications, performance or overall safety

Changes in materials for in vitro diagnostic devices

There is a distinction between in vitro diagnostic devices (IVDDs) and other devices regarding material changes.

Material changes to an IVDD include those made to:

• critical components
  • such as antigens, antibodies, primers, conjugates
• other reagents
  • such as buffers
• materials that are in direct contact with device reagents
  • such as cassettes, solution bottles

A material change to a critical component of an IVDD is likely significant when the risk assessment identifies a potential impact on the safety or effectiveness of the device, such as:

• impact on a performance claim
• impact on the approved shelf-life or stability claim
• affects the operating principle of the device (for example, from immunofluorescence to ELISA)
• changes the operating principle and thus IVDD performance characteristics, including specificity or sensitivity
  • The impact of each change on the safety and effectiveness of the device should be considered.
• changes reaction components or materials such as calibration materials resulting in altered performance characteristics reflected in the labelling

Material changes to an IVDD may also lead to changes in the design, manufacturing process, equipment, control procedures or labelling, including stability claims. You should consult all relevant sections of this guidance to determine if your proposed change is significant.

Changes to labelling

The labelling of a device contains important information about its safe and effective use. Some labelling changes are considered significant. Each labelling change should be assessed individually, as well as in the context of the cumulative impact of all labelling changes made over time.

Changes to labelling can include changes to:

• user manuals
• patient labelling
• electronic labelling
• instructions for use
• labels affixed on the device
• manufacturers marketing materials including websites intended for Canada
• any other documents that provide information related to the use of the device

Changes that trigger an update to the labelling should also be evaluated against all other relevant sections of this guidance. For example, labelling changes are often triggered by changes to:

• user requirements
• performance specifications or materials
• the design of the user interface

Labelling changes related to indications for use, intended use and clinical benefits

In general, changes to the intended use or indications for use are considered significant. The exception is if they are a subset of the intended use or indications for use. The revised subset of the statement must be based on the currently licensed intended use or indication for use that was previously reviewed under a medical device licence application. In this case, be sure to:

• still include the same text for the majority of the intended use or indications for use and
• remove previously approved text to create the subset of the intended use or indications for use

The following general principles apply:

• clarifying terminology that is clinically equivalent is less likely to result in a significant change
• generalizing or broadening claims is likely to constitute a significant change

The addition of a new patient subgroup to the indications or intended use is typically a significant change. This is especially true if the:

• subgroup may be considered higher risk or more vulnerable than the population previously identified
• change introduces usage of the device that is not widely accepted medical practice in Canada for that type of device

The following situations would also likely be considered a significant change:

• a limitation to the indications for use is introduced because of concerns associated with the safe or effective use of the device
  • note that a contraindication or a warning should also be added to the labelling in this case
• wording is modified to state or imply that new clinical evidence exists to support the claim beyond what was previously submitted and reviewed by Health Canada
  • involves new wording and new stated or implied claims
• the indications for use are modified to allow use only in cases where an explicit medical condition exists
  • requires clinical evidence to support the claim

Adding a patient subgroup may not be significant if the identified subgroup:

• is added for clarification
• is not considered higher risk or more vulnerable than the patient population identified in the previous indications or intended use and
• would have been clinically assumed within the indications for use for the licensed device

Example of a non-significant change involving a patient subgroup:

• A device previously indicated for people with heart failure is revised to indicate for adults with heart failure. Although this clarifies a specific patient subgroup, but does not introduce a vulnerable population, as adults would reasonably be assumed to be included in the general previous indication.

Examples of a significant change involving a patient subgroup:

• The change includes adding pediatric patients, the previous indications were general and did not refer to patient age. Pediatric use is not widely accepted medical practice in Canada for this type of device.
• The change includes adding patients with diabetes, expanding the indication beyond the previously general population and altering the benefit-risk considerations.

Reducing indications for use to a subset of the original population is often a non-significant change.

Example of a non-significant change involving a patient subgroup:

• A device indicated for patients who experienced a heart attack is revised to specify "adult" patients who experienced a heart attack. This is a clarification, does not introduce a higher-risk population and follows the widely accepted medical practice for the use of the device in Canada.

Other types of significant labelling changes

Examples of other significant changes to labelling include:

• changes that alter label content about when, where or by whom the device is used
• new claims associated with earlier interventions in the disease progression compared to current labelling claims for the licensed device
• new claims that may change the environment in which the device is used
  • such as a change from a hospital setting to an office or home setting
• new claims that alter who can use the device
  • such as changing from a health care practitioner to a technician, patient, caregiver or the public

Examples of changes to warnings, precautions or possible adverse events that may not be significant include:

• minor changes that clarify the existing wording of warnings and precautions
• relocating a warning or precaution when the same information is already included, labelled as a warning or precaution and presented identically elsewhere in the labelling
• adding a warning or precaution for health care professionals that reflects a well-established standard of practice in Canadian clinical settings for using the type of device
  • for example, "do not implant the device in patients with sepsis"

Examples of changes to warnings, precautions and possible adverse events that are significant include:

• adding or removing a contraindication
• removing a warning or precaution from the labelling
• adding a warning or precaution driven by new information related to a previously unidentified or identified hazard affecting safety or effectiveness of the device
  • Information may arise from incident trending, user feedback, scientific literature or national registry data regardless of hazard type.
  • For more information on definitions of precautions and warnings, refer to Guidance for the labelling of medical devices, not including in vitro diagnostic devices - Appendices for the labelling of soft, decorative, contact lenses and menstrual tampons.
• removing possible adverse events when they formed part of the device's risk mitigation plan previously reviewed or required by Health Canada
• adding a new possible adverse event due a newly identified safety concern

Adding a clinical benefit to the labelling may introduce new claims or expand existing claims made in the indications for use. In most cases, this constitutes a significant change.

Examples of a significant change involving the addition of a claim include:

• new claims (explicit or implied) related to safety or effectiveness that require supporting data
• new representation of uncertainties about performance that require supporting data

Example of a non-significant change involving the addition of a claim include:

• adding a clinical benefit where the statements are fully within the scope of the licenced indications for use and the supportive information already appears in the existing licensed labelling

New labelling, including for marketing purposes, that targets new populations may not be significant. The change must stay within the scope of the claims that Health Canada reviewed for the licensed device. Any labelling that goes beyond those claims may be considered significant.

Examples of a non-significant change involving a change in population:

• new labelling that does not introduce new claims or statements about device safety, effectiveness, uncertainty or therapeutic mechanisms, beyond the scope of licensed indications for use, intended use or the general description of use included in the labelling which underwent pre-market review for the licensed device

For IVDDs, examples of changes that are likely significant include:

• identifying a new subpopulation for which clinical data were not previously been provided
  • This change would not be significant if clinical data for the subpopulation were already submitted and reviewed.
• adding or removing limitations that do not appear in the intended use but appear elsewhere in the package insert
  • This change is not significant if it does not impact the correct use, performance or interpretation of correct results, supported by usability assessment or clinical experience.
• removing a warning or a precaution
  • Adding a warning or precaution is likely not a significant change, unless it also impacts the intended use.

Changes in labelling concerning reprocessing, sterilizing, cleaning or disinfection

Medical devices that are reprocessed, sterilized, cleaned or disinfected by the end user must include manufacturer-validated instructions for the cleaning, disinfection and sterilization process.

For more information, consult:

• Information to be provided by manufacturers for the reprocessing and sterilization of reusable medical devices

Changes to the recommended reprocessing, sterilizing, cleaning or disinfecting method of a product compared to the previously submitted and reviewed method for a licensed Class III or IV device may be considered significant. Removing a recommended reprocessing method or product from the labelling or package insert may not be a significant change if alternate, validated options licensed in Canada are still included in the labelling.

Labelling changes concerning other regulatory jurisdictions

For information on adding a clinical benefit to labelling, refer to the subsection on changes concerning indications for use, intended use and clinical benefits.

Modifications to the labelling made solely to include additional languages (other than French or English) required in other regulatory jurisdictions is not considered a significant change.

Changes related to references in the labelling are significant if they:

• add or modify wording related to references for articles that relate specifically to off-label use of the medical device compared to the currently licensed Canadian labelling
• add references related to off-label usage compared to Canadian-licensed claims
• add or imply new claims for the device compared to those that underwent successful premarket review to obtain a medical device licence for the Canadian market

When it comes to references, the following are not considered significant changes:

• introducing new references to data from third-party databases required for other regulatory approvals, where the database content is clearly intended for non-Canadian audiences
• including references to publicly available information, such as journal articles, provided these do not introduce or imply new claims or promote off-label use relative to Canadian-licensed labelling

It is not considered a significant change to remove references to obsolete devices from the instructions for use when those devices are no longer available for sale in Canada.

Labelling changes concerning the useful life of a product or shelf-life

The benefit-risk profile, safety or effectiveness of a medical device may be impacted by the date of manufacturing or packaging. Evidence supporting compliance with the regulations is based on both the recommended or predicted duration of safe device use and the duration of protection provided by the product's packaging.

Examples of a significant change include:

• introducing a new statement about the projected useful life of a device that specifies a timeframe (for example, 90% freedom from device failure at 3 years) that was not included in the currently licensed labelling
• making claims for shelf-life extension when the:
  • protocols and methods used to determine shelf-life have changed or were not previously reviewed as part of a pre-market application
  • results or acceptance criteria differ significantly from data previously reviewed by Health Canada
• reducing the shelf-life when a change has affected the safety or effectiveness of the device or when other considerations have changed the benefit-risk profile

Examples of a non-significant change include:

• adding broad statements without specific claims, such as adding a statement that the device may need to be replaced in the future, without adding a defined useful life claim
• making shelf-life extension claims, including for IVDDs, if the new claims were validated, using the same protocols, methods and acceptance criteria previously reviewed and accepted by Health Canada when the licence was issued
  • If any of the parameters change during the validation of the shelf-life extensions, the change becomes significant.

Labelling changes to include unlicensed devices

It is illegal to advertise or market for sale an unlicensed device in Canada.

It may be acceptable to include model numbers or device listings within the labelling provided no detailed content or instructions related to the unlicensed devices are included.

Changes to international labelling made solely for the purpose of listing devices not intended for sale or no longer for sale in Canada may be considered non-significant if all of the following conditions are met:

• the labelling does not include promotional language or otherwise advertise the unlicensed device for sale and
• there is no claimed interoperability between the unlicensed device and your device that is unsubstantiated and
• the indication for use or intended use of your device does not depend on the unlicensed device and
• the reference to the unlicensed device is not misleading to the Canadian user and can be disregarded without affecting the safety and effectiveness of the licensed device and
• use of the unlicensed device is not required for your device to meet the requirements of sections 10 to 20 of the regulations

Labelling changes to include compatible devices

"Compatibility" refers to the ability of a device, when used with another device or devices, to achieve the intended overall clinical purpose without the user having to modify or adapt any part of the combined devices.

Changing the labelling of a Class II, III or IV device to claim compatibility with a separately licensed Class III or IV device is often considered a significant change for the Class III or IV licence. This applies to:

• adding a compatibility claim to both devices, where both devices are from the same manufacturer
• adding a compatibility claim to a Class II, III or IV device, where the manufacturer of the second device is different
  • for example, adding a compatibility claim between a polyethylene liner and a separately licensed femoral head

To illustrate:

• Licence 1 has Device A, with a list of compatible devices that includes Device B
• Licence 2 has Device B, which is currently intended to be used with Device A
• Licence 3 has Device C, which currently has no compatibility claim

Adding a compatibility claim to Licence 1 (Device A) may not be significant if:

• Device C is equivalent to Device B, which is currently listed as compatible devices and
• adding the compatibility claim to Device A or C does not introduce a significant change under any other section of this guidance and
• Device C is not significantly different from Device B based on all relevant criteria in this guidance, and is manufactured by the same manufacturer as Device B

However, adding Device C as a compatible device to Licence 1 is likely a significant change if the:

• manufacturer of Device C and B are different or
• addition of compatibility between Device A and C impacts the indications for use of either device

If you have a compatibility claim involving a device from a different manufacturer, you should monitor for changes to that device that could invalidate a compatibility claim with your device. A significant change made by the third-party manufacturer that affects safety or effectiveness of the paired use would constitute a significant change for your device.

Removing an approved compatibility claim may be considered a significant change if the:

• removal is due to concerns with the safe or effective use of the assembled compatible devices and
• change impacts how the devices interact with each other or how the system will perform

For changes to compatibility claims involving a compatible Class II device, refer to the section on Class III or IV amendments concerning separate compatible Class II devices.

Labelling changes concerning magnetic resonance

In general, any change to the magnetic resonance (MR) safety claim of an licensed medical device, including changes to the scan conditions under which an MR scan may be safely performed, is considered a significant change.

Examples of non-significant changes:

• The device is implantable and composed of non-magnetic materials (for example, a polymer implant), and an MR-safe claim is being explicitly added to the labelling.
• MR conditional claims are reduced to a subset of previously licensed MR conditions.

Class III and IV amendments for compatible Class II devices

"Compatibility" refers to the ability of a device, when used with 1 or more other devices, to achieve the intended overall clinical purpose without the user needing to modify or adapt any part of the combined devices.

An important requirement in demonstrating the safety and effectiveness of medical devices that are to be used together is compliance with section 18 of the regulations. Under section 18, a medical device intended to be used together with other medical devices must:

• be compatible with each medical device it is intended to be used with and
• not adversely affect the performance of the medical devices used together

Refer to the following notice for the situation when the devices are licensed separately:

• Licensing requirements for inter-dependent medical devices

As noted in the section on general principles, Class II amendments are not within the scope of this guidance document.

However, changes made to a Class II device that is compatible with a Class III or IV device may alter the safety and effectiveness of the Class III or IV device. This is the case even if the design of the Class III or IV device remains unchanged.

Such changes may represent a significant change for the Class III or IV licence and could therefore require a Class III or IV amendment before the modified Class II device can be marketed.

Some devices are compatible with multiple devices. If changes are made to 1 or more of the compatible devices, you must ensure that the combination of medical devices continues to meet the requirements of section 18 of the regulations. Note that under item (d) of the significant change definition, new or extended uses resulting from these modifications are considered changes to the intended use.

This section applies to the following 2 scenarios:

• The labelling of a Class III or Class IV device is being changed to indicate compatibility with a new or licensed Class II device, even if the formal "intended use and/or indications for use" statement of the Class III or IV is unchanged.
• A change is being made to a licensed Class II device that is already indicated as compatible with a licensed Class III or IV device.

To evaluate whether either of these 2 scenarios are significant changes for the Class III or IV licence, you must assess if they may affect the safety or effectiveness of the Class III or IV device. Consider the following factors:

• critical nature of the Class II device
  • the more critical the Class II device is to overall system function (including safety or effectiveness), the more likely the compatibility change could affect the safety or effectiveness of the Class III or IV device
  • the following changes would be considered significant:
    • indicating the device can perform a task or treat a condition for a different duration of time
    • the Class II has or introduces new clinical indications or intended uses beyond or more specific to those of the licensed Class III or IV claims
    • the Class II has a different target patient population
    • changes that necessitate new clinical studies or usability studies
    • changes to the therapy delivered
    • introducing a new operating workflow or user interface
• differences in key design specifications between the Class II device previously indicated as compatible and the new or modified Class II device

You should identify and analyze how such differences could impact safety and effectiveness of the overall system. This includes assessing whether the change may affect factors such as compatibility, performance and risk mitigations.

An amendment for both the Class II licences and the Class III or Class IV licences would be required if a change is deemed significant for compatible devices on different authorizations.

Changes to diagnostic ultrasound systems

Health Canada recognizes that there are a number of licensed diagnostic ultrasound systems that have a well-established safety profile in Canada and in other regulatory jurisdictions.

A change made to a diagnostic ultrasound system will not be considered significant if all of the following apply:

• intended use or indications for use remains unchanged and the modifications do not introduce intracardiac or intravascular imaging through catheter-based transducers
• modifications do not introduce sterile use or sterilization where previously not indicated and do not affect previously indicated sterile use
• modes of operation for the modified device are well established:
  • well established modes include A-mode, B-mode, M-mode, Doppler (CW, Color, PW, Power, Combination), speckle-tracking, tissue harmonic imaging and combination
  • not well-established modes include shear wave elastography, acoustic attenuation mapping, transmission-based imaging and sound speed measurement
• modifications do not lead to acoustic outputs that exceed the recommended maximum acoustic output levels
• refer to Device licence applications for diagnostic ultrasound systems and transducers: Notice to industry
  • ISPTA.3
    • < 720 mW/cm2 (most applications)
    • <430 mW/cm2 (cardiac)
    • <17 mW/cm2 (ophthalmic)
  • ISPPA.3
    • < 190 W/cm2 (for most applications)
    • <28 W/cm2 (ophthalmic)
  • MI
    • < 1.9 (most applications)
    • <0.23 (for ophthalmic)
• modifications do not result in any ultrasound interrogation parameters outside each of the following ranges:
  • centre frequency: 1 to 20 MHz
  • rarefactional pressure: 0 to 7 MPa peak
  • pulse length: 1 to 100 cycles (except for CW Doppler)
  • pulse repetition frequency: 100 to 20,000 Hz
• modifications do not use novel mechanical or thermal effects for imaging or measurements
• modifications do not introduce diagnostic or diagnostic support functions developed by the same manufacturer that represent previously unlicensed capabilities
• measurements and analyses are clearly described and the user can adjust the following associated control parameters
  • image processing should be reversible or the original image should be available to the user
  • user is able to edit or adjust user-activated post-processing applications used for measurements (for example, segmentation and registration)
  • where applicable, user should be able to edit assumed values, parameters or thresholds in equations or algorithms used to generate additional outputs based on measurements of anatomical dimensions, tissue velocity or pixel intensity
  • labelling provides complete information about the processing or compression algorithms used by the device, when appropriate
• integrated transducer element check is performed each time a transducer is connected to the main system or activated to help ensure appropriate transducer performance
  • for example, an impedance check of each element may provide a preliminary evaluation of the element integrity and function
• transducer surface temperature falls within the requirements of IEC 60601-2-37
• if the device is for endocavity use, labelling includes clear, manufacturer-validated cleaning and disinfecting instructions using products licensed for sale in Canada and identifies appropriate probe covers