Draft guidance on how to interpret ‘significant change’ of a medical device: Types of changes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
• 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 device or its packaging and labelling material.

Examples of a manufacturing change would be:

• changes to the component formation process
  • for example, 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 consider the impact of all manufacturing changes on the device specifications, performance and material properties. Evaluate these changes using the other applicable 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 is likely a significant change, as it may impact device performance.

Changes that are likely non-significant are as follows:

• increases to the tolerance ranges if the impact of the change can be interpolated from the verification or validation testing previously submitted and reviewed by Health Canada for the authorized device
  • Submitted information must demonstrate the safety and effectiveness of the device over the full range of allowable outputs from a new, wider tolerance range.
• changes that tighten specifications within the existing range of authorized specifications where the mean value is not changed
• 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
  • the new facility has the same manufacturing process and equipment of the same specification
  • the new facility is not a new sterilization facility or new abattoir for animal-derived materials

For more information, refer to the following sections:

• Changes to sterilization
• Changes in materials for non in vitro diagnostic devices

For combination products, there are increased sensitivities associated with the production and application of active pharmaceutical ingredients (APIs).  As changes to the manufacturing process of a combination product that involve APIs are often significant, we recommend that you contact the Medical Devices Directorate by email at meddevices-instrumentsmed@hc-sc.gc.ca for assistance.

Table of examples

Changes to manufacturing quality control procedures

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 acceptance quality limits (AQL) have not increased. On the other hand, removing or modifying these activities where the result is that specifications or criteria are loosened or the AQLs are increased is a significant change.

Changes to quality control inspections or tests used to control the quality, purity or sterility of materials and devices that affect the specifications of the finished device or its components, including its packaging, are often considered significant. However, if adding or modifying the inspection or test method provides equivalent or improved assurance of reliability, then the modification is not significant. It must be reported at annual renewal, with applicable justification made to support this modification.   

Examples include changes to the:

• test or inspection criteria
• test method
• parameter tested or inspected
• statistical rationale or sample size
• acceptance quality limits (AQL)
• validation endpoints
• sterility assurance level (SAL)

For example, changes to the manufacturer's requirements for material acceptance criteria can be considered a significant change if these changes alter the design specifications of the device.

Table of examples

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.

Significant 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 is the means by which the action of a device is directed or the output of a device is regulated. As control mechanisms can be complex, any changes to them could alter how the device works. This can impact its risk profile, as well as its safety and effectiveness and therefore changes to the control mechanisms are significant.

Examples of changes:

• pneumatic to electronic control of a mechanical ventilator
• analog to digital control of a device

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.

Examples of operating principle changes include switching:

• an energy input source from AC to DC or battery
• an output source from microwave to radiofrequency
• from wired to wireless communication (in relation to therapeutic or diagnostic features)
• between types of wireless communication, such as WIFI to Bluetooth

Examples of operating principle changes for an in vitro diagnostic device (IVDD) include:

• a change from an immunofluorescence-based assay to an enzyme-linked immunosorbent assay (ELISA)
• changes in methods such as specimen pretreatment, incubation times and temperatures, which may affect the operating principle of an IVDD
  • are considered significant changes if they result in altered performance characteristics that are reflected in the labelling

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 involve:

• a device’s physical characteristics such as the shape, size, dimension or materials, including non IVDDs and IVDDs
• performance or technical specifications
• patient or user interfaces
• software or firmware updates

For an IVDD, design specifications also include performance characteristics (for example, precision, accuracy, sensitivity, specificity, stability).

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

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

1) Indications for use/intended use

Changes to design that affect the indications for use or intended use are significant. They can impact the target patient population (for example, elderly or pediatric patients), the target anatomical areas or the target disease states.

Example of a significant change:

• changing the length or diameter of a cardiovascular stent so it can be placed in different arteries may introduce an additional indication for use (whether explicitly claimed in the labelling or not)

2) Clinical data

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

Examples of a significant change:

• making a device smaller so that a pediatric indication can be added requires clinical evidence
• introducing a change that results in a new indication or clinical use or introducing a new feature whose use is not well established for that type of device requires new clinical validation

3) Risk profile

You should conduct a risk assessment when making a design change. The risk assessment will identify any new risks. If the risk assessment finds that the change would alter the safety and effectiveness of the device, either positively or negatively, the change is significant.

Examples of a significant change:

• the design change may:
  • introduce a new hazard or hazardous situation
  • change the severity or the likelihood of the harm occurring
  • introduce new required risk mitigation actions

The change is likely not significant if:

• the risk assessment conclusions are not altered by the design change and
• the device performs the same as the original design submitted in a previous application

Components or accessories, including Class II

Adding or changing device components or accessories used with the authorized device is a significant change if it:

• affects the safety, function or compatibility profile of the device as a whole or
• could cause the device to be used in a new way

Modifying an existing 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

This is true regardless of the classification of the component or accessory, or whether all parts are on the same authorization or authorized separately.

An application to amend the associated Class III or IV device(s) would be required. You would need to:

• describe and validate the change
• verify the safety, effectiveness, compatibility and risk profile of the assembled combination of devices, components and accessories is the same

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 likely significant.

Examples are changes to:

• the display or layout of a control panel or graphical user interface (GUI)
  • for example, a blood glucose meter
• the way the device interacts with the patient or user
  • for example, the way a CPAP mask attaches to a patient’s face
• the way a surgical tool or delivery system is designed to be held or used by the surgeon

Cosmetic changes that:

• do not affect function or clinical use are likely not significant
• alter how a device functions or performs clinically are significant (could affect its safety and effectiveness)

Table of examples

Changes to sterilization

Changes that could affect the effectiveness of the sterilization process or the safety of a sterile device are significant.

The nature of sterilization is such that it is impossible to determine by inspection and testing if the device has been sterilized successfully. Medical devices are considered sterile if you can demonstrate a sterility assurance level (SAL) of 10^-6 or better. The sterilization process must be verified and validated, and its performance routinely monitored.

Examples of significant sterilization changes are those where the:

• manufacturing process, environment or device material introduces 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 most-difficult-to-sterilize location for sterilization validation
• device material is more difficult to sterilize or affects sterilant residuals
• quality control verification and validation processes are changed, such as introducing or removing parametric release or changing the sterilization dose auditing method
• sterilization method is changed
• 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, a change that triggers a new or increased risk or produces unexpected results from routine verification and validation is a significant change. 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 a non-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 (for example, in ISO 11135 or ISO 11137)

Examples:

• a contract sterilizer with multiple locations moves sterilization to a different facility using a verified equivalent sterilization process
• equipment changes (within an approved site or at a new site) do not alter the equipment that was validated previously
• minor changes to cycle parameters (for example, humidity, pressure, elevation) do not affect the delivered dose and/or sterilant residuals, set out in the approved process and validation

Using a sterilization method that does not adhere to recognized standards may have a significant impact. Consult:

• Health Canada-recognized standards

For advice on how to assess the significance of any changes you wish to make to novel sterilization methods, contact the Medical Devices Directorate at meddevices-instrumentsmed@hc-sc.gc.ca.

Note: A change in facility that introduces a new, more challenging organism or bioburden level to the sterilization process which has not been validated before would be significant. This is the case even if the cycle parameters are the same.

Changes to sterile barrier packaging

Packaging changes should also be assessed for their impact on sterilization. In general, any change in packaging characteristics (such as in materials, size, shape, seal width) or configuration (such as in the outer packaging, loading density) is likely significant if it could affect the:

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

Issues of compatibility between the packaging material and the sterilization process must also be taken into consideration.

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 been reviewed and approved in a previous application for a similar device and
• all of the following are true:
  • the device is not more difficult to sterilize than the previously authorized device
  • the interactions of the device with the proposed packaging do not present a greater risk related to the integrity of the sterile barrier
  • the devices are of identical material and similar design (no new worst case design features)
  • the proposed changes have been completely represented and approved in a previous new or significant change application

Table of examples

Changes to software

Software can be embedded within a medical device or an accessory to a medical device or exist as software as a medical device (SaMD). Software is updated easily and frequently, and thus may undergo several changes during 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 any unintended consequences
• create or necessitate a new risk control measure or a 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 authorized version of the device
• incorporate a change to the operating system in which the software is running, where the underlying software code is not changed
• are made solely to strengthen cybersecurity and do not have any other impact on the software or the device
• only introduce non-therapeutic and/or non-diagnostic features 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

As these are only examples, we recommend that you evaluate additional software changes that can, if not controlled properly, create unexpected software behaviour. Whether a change is significant or not depends on their potential impact on safety or effectiveness.

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

• a re-write in another programming language
• driver modifications
• operating system changes
  • not significant if no changes are made to the application
  • significant if driver changes are required or the kernel between operating systems is different
    • 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 known 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 authorized with a PCCP, subsequent changes made according to the authorized PCCP are not significant. Thus, they do not require the submission of a licence amendment application.

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:

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

Common software change types and 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
• cosmetic changes
  • for example, new logos, user interface fonts, colours
• refactoring
  • for example, improving efficiency, structure or maintainability
• 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 that other software components be updated so they are compatible

You should consider the consequences of the changes to assess whether the change is significant.

A software change is likely not significant if:

• a risk assessment supports this
• it can be verified using the same testing activities that were reviewed by Health Canada for the previously authorized software version and
• does not require software validation testing

Table of examples

Changes in materials for non in vitro diagnostic devices

A change in material type or formulation may affect the chemical, physical and/or electromagnetic properties of the material. A material change may also influence the device’s:

• manufacturing process
  • for example, different equipment is required
• design specifications
  • for example, device mechanical performance is altered
• biological safety and biocompatibility
  • for example, a new potentially harmful leachable
• stability
  • for example, device shelf life is reduced
• sterilization method
  • for example, ethylene oxide sterilization to replace gamma irradiation is required
• labelling
  • for example, warning for allergic reaction to device material is added

Changes related to materials may be intentional or unintentional. Changes in a manufacturing process, equipment or material storage conditions may also affect the properties of device materials.

Examples:

• E-beam/gamma sterilization dosage change may affect the material properties of a crosslinked polymer.
• Material extrusion equipment change may affect the material surface roughness.
• Changes to material reuse/recycling processes or storage conditions for raw material intended for additive manufacturing may affect the properties or performance of the finished device.

All changes should be assessed separately.

The impact of a material change on the safety and/or effectiveness of the device also depends on:

• how the device is to be used
• if the device is invasive or non-invasive
• the type and duration of contact with body tissues or fluids
• if the altered material was used in an authorized device with the same intended use

Note: Please refer to other sections of this guidance document for a material change related to changes in:

• manufacturing process
• facility
• equipment
• control procedure
• design specifications
  • for example, device mechanical performance
• sterilization process
• labelling
• compatible Class II devices
  • for example, a material change to an independently authorized Class II surgical stapler that’s compatible with  authorized Class III surgical staples

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

Text description

Figure 1 is a flowchart containing 7 boxes with yes or no questions. Each answer advances the reader through the decision-making process.

Box 1 in the flowchart shows that a change to the sourcing or processing of materials of human or animal origin is 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)

Box 2 concerns changes to the vendor or supplier. This type of change is not significant if it does not alter the material type, formulation, chemical composition or processing.

Starting from Box 3, the considerations relate to changes that altered the material type, formulation, chemical composition or processing.

First, as indicated in Box 3, you need to determine if the altered material will be in direct or indirect contact with body tissues or fluids.

• Direct contact refers to physical contact of a material with 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.

However, in terms of device safety, there is no difference between direct and indirect contact with body tissues or fluids. A change that involves either type of contact could be significant, pending further considerations.

The change is not significant if the altered material does not have direct or indirect contact with body tissues or fluids and does not cause other changes that could be significant.

If the altered material is in contact with body tissues or fluids, then Box 4 asks if the altered material is used in an authorized device with a similar design for the same indications by the same manufacturer. The change is not significant if the 2 devices are manufactured by the same process and the material is used in the same physical configuration for the same indication in the 2 devices. In addition, there must have been no concerns about the biocompatibility of the authorized device.

The authorized device must have all of the following:

• same or greater risk classification
• same or riskier category of contact
  • for example, contact with blood is riskier than contact with intact skin
• same or longer duration of contact

Note: A material change may affect how it interacts with adjacent materials that bond together. Introducing a material used previously in an authorized device to a device where the interactions with adjacent materials are different is a significant change.

If the device doesn't meet those conditions, then Box 5 asks if the altered material is used in an invasive device that is to:

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

If a device meets these conditions, it is a significant change, unless:

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

If the device doesn't meet those conditions, then Box 6 asks about biocompatibility concerns. A material change associated with a new or increased biocompatibility concern is a significant change:

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

For example, if an altered material 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 not applicable to the sensitization potential of the leachable

Finally, according to Box 7, if a material change results in other changes such as device specifications, performance, manufacturing process or labelling, consult other sections of this guidance where appropriate.

Table of examples

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 of 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

Examples of material changes that are likely significant are changes:

• to a critical component of an IVDD
• for which a risk assessment identifies a potential impact on the safety or effectiveness of the device, such as:
  • impacts a performance claim
  • require a new stability study
• to materials in an IVDD that affect the operating principle of the device
  • for example, from immunofluorescence to ELISA
  • changes in the operating principle can affect an IVDD’s performance characteristics, including specificity or sensitivity (the impact of each change on the safety and effectiveness of the device should be considered)
  • for example, changes in reaction components or materials such as calibration materials that result in altered performance characteristics and are reflected in the labelling are likely significant

Changes to the materials of an IVDD that cause a change to the design, manufacturing process, equipment, control procedures and/or labelling, including stability, are addressed in other sections of this guidance.

Table of examples

Changes to labelling

Labelling includes:

• user manuals
• patient labelling
• instructions for use
• labels affixed on the device
• other provided documents that include information about using the device

Labelling changes are often triggered by:

• changing user requirements
• changes to a device, including changes to performance specifications and materials

You must consider each labelling change separately, as well as the total impact of the labelling changes over time.

Changes that trigger a labelling change should also be assessed against all other relevant sections of this guidance.

Changes concerning indications for use, intended use and clinical benefits

Changes to the intended use or indications for use are significant unless they are within the current scope of indications set out in the labelling. This follows the general principles where:

• interpolation is less likely to result in a significant change
• extrapolation is more likely to result in a significant change

A significant change would be to add a new subgroup of patients to the indications or intended use. This group may be considered higher risk than the more general population group identified in the previous indications or intended use.

However, this change is likely not significant if the identified subgroup of patients was added for clarification and would have been covered within the indications for use for the authorized device.

Example of a significant change:

• the change includes pediatric patients, but the previous indications associated with the labelling for the authorized device were general and did not refer to patient age

Example of a non-significant change:

• a device was indicated for use in patients who experienced a heart attack and
  • a change was made to add “adult” patients who experienced a heart attack to the indications for use and
  • the device was a well-established technology where early intervention is not associated with increased long-term or life-time risks

In general, reducing indications for use to a subset of the original population is a non-significant change.

Despite this, the following would 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 imply that more clinical evidence exists to support the claim beyond what was previously submitted and reviewed by Health Canada
  • involves new wording and new claims
• the indications for use are modified to allow for use only in cases where a medical condition exists, such as hypertension above 150 mm Hg
  • requires clinical evidence to support the claim

Examples of other significant changes to labelling:

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

Examples of changes to warnings and precautions that may not be significant:

• minor changes clarifying the existing wording of warnings and precautions for a device
• removing a warning or precaution where the same information is included and presented identically elsewhere in the labelling
• adding a warning or precaution not driven by new information pertaining to the safety and effectiveness of the device

Examples of changes to warnings and precautions that are significant:

• adding or removing a contraindication
• removing a warning or precaution unless equivalent information continues to be included elsewhere in the labelling in an equivalent manner
• adding a warning or precaution that is driven by new information on the safety and effectiveness of the device
• removing possible adverse events if listing these events is part of a required risk mitigation

Adding a clinical benefit to labelling may introduce new claims or expand existing claims made in the indications for use. This is likely to be a significant change in most cases.

Examples of a significant change:

• new claims (explicit or implied) of safety and of effectiveness that need to be supported with data 
• new representation of uncertainties about performance that require supporting data 
  • for example, stating that a total knee replacement has 80% reliability at 15 years

Example of a non-significant change:

• adding a clinical benefit where the statements are fully included within the scope of the authorized indications for use and the supportive information is in the existing authorized labelling

New labelling may be introduced that targets different populations (such as patient-specific labelling) or is created for marketing purposes.

Examples of a non-significant change:

• new labelling does not introduce new claims or statements about device safety, effectiveness, uncertainty or therapeutic mechanisms, that are beyond the scope of indications for use, intended use or the general description of use included in the labelling for the currently authorized device
• labelling changes that clarify instructions to make the device easier, safer or more effective to use

For IVDDs, the following are examples of changes that are likely significant:

• identifying a new subpopulation for which clinical data have not previously been provided  
  • The identification of this new subpopulation would not be a significant change if clinical data have already been provided and reviewed for the subpopulation.
• adding or removing limitations not captured in the intended use but that appear elsewhere in the package insert
  • This change is non-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 concerning reprocessing, sterilizing, cleaning or disinfection

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

Consult:

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

Changes to the recommended sterilizing, cleaning or disinfecting method or product as previously submitted and reviewed in relation to an authorized class III or IV device may be deemed significant. Removing a recommended method or product from the labelling or package insert may not be a significant change if alternate, validated options authorized in Canada are still included in the labelling.

Changes concerning other regulatory jurisdictions

For information on adding a clinical benefit to labelling, please refer to the subsection on Changes concerning indications for use, intended use and clinical benefits. Including additional languages required in other regulatory jurisdictions is not a significant change.

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

• include articles that relate specifically to off-label use of the medical device in relation to the currently authorized labelling  
• add references related to off-label usage
• add new claims to the labelling associated with referenced materials if the claims have not been previously reviewed and incorporated into labelling authorized by Health Canada

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

• introducing new references to data housed in third-party databases that may be required for other regulatory approvals if this database indicates the data are available for non-Canadian audiences
• including references to publicly available information, such as journal articles

You should also remove references to obsolete devices from the instructions for use once a device is no longer available for sale and use in Canada. This is not considered a significant change.

Changes concerning the useful life of a product

The following are examples of a significant change:

• introducing a new statement about the projected useful life of a device that adds a specific timeframe (for example, 90% freedom from device failure at 3 years) which has not been included in the currently authorized labelling
• making claims for shelf-life extension if the:
  • protocols and methods for determining shelf life have been changed or were not reviewed in a previous application
  • results or acceptance criteria are significantly different from previously reviewed data
• reducing shelf life if a change has affected the safety or effectiveness of the device or other considerations have changed the risk/benefit ratio

Examples of a non-significant change:

• adding broad statements without specific claims, such as:
  • knee implants have a finite life and future revision or replacement may be required
  • the projected useful life depends on use and patient characteristics
• adding statements associated with simulated bench testing that demonstrate a minimum life based on non-clinical testing models, with a clear disclaimer that patient factors may increase or decrease the expected lifetime of the device if Health Canada has previously reviewed the data
  • This would be significant if the simulated bench testing had not previously been submitted to Health Canada as part of the submission supporting the authorization.
• making claims for shelf-life extension, including for IVDDs, if the new claims were validated by you, with similar findings based on using the same protocols and methods as the initial validation submitted to Health Canada at the time of authorization (the same protocol including the same acceptance criteria previously accepted by Health Canada)
  • If any of the parameters change during the validation of the shelf-life extensions, the change becomes significant.

Changes concerning compatible devices

You should clearly communicate within the labelling what devices are available in Canada. Information should clearly indicate how the device can be used safely and effectively with authorized compatible devices that are available in Canada. Be sure to remove references to obsolete devices from the instructions for use once a device is no longer available for sale and use in Canada (not a significant change).

Adding references in the instructions for use to unauthorized devices or to devices that were previously authorized but are no longer available in Canada due to obsolescence are not significant changes as long as:

• the labelling does not include language that is promotional or is being used to advertise the unauthorized device for sale
• there is no claimed interoperability between the unauthorized device and your device that is not substantiated, for example:
  • labelling for a proposed bone plate references unauthorized screws and you have evidence the device is safe and effective if used with those screws, then it is acceptable to include a reference to the unauthorized screws
    • non-significant change
  • labelling for a patient monitor references an unauthorized diagnostic probe manufactured by another manufacturer for which you do not have evidence of safety and effectiveness
    • significant change, as this would require evidence be submitted to demonstrate safety and effectiveness

• the primary indication for use does not depend on this unauthorized device
  • for example, whether the unauthorized device is mentioned in the indications for use
• use of the unauthorized device is not required for your device to meet the requirements of sections 10 to 20 of the regulations
• use of the unauthorized device is not required for your device to meet the requirements of paragraph 68.11(2)(g) of the regulations
• including the reference to unauthorized devices is not misleading to the user, as the instructions for use for the unauthorized device may be ignored and still allow the device to be used safely and effectively

Adding compatibility claims to labelling of a Class III or IV device with a separately authorized Class III or IV device is often a significant change. This applies to both of the following situations:

• adding the claim to both Class III and IV devices, where both devices are from the same manufacturer
• adding the claim to the Class 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 authorized femoral head

Adding a compatibility claim with an authorized device that’s similar to a currently listed compatible device is not necessarily a significant change.

Adding a compatibility claim would not be significant if:

• the differences between the proposed and current compatible device are considered non-significant according to this guidance and
• the currently listed compatible device and the new proposed compatible device (which is also authorized in Canada) are manufactured by the same manufacturer

However, adding a new compatible device is likely significant if:

• the manufacturer of the new proposed compatible device has not previously been listed as a manufacturer of a compatible device
• the new compatible device impacts the indications for use of either device

If you made a compatibility claim with a device from a different manufacturer, you should monitor for possible changes that would render the compatibility invalid. A significant change made by a third-party manufacturer to a compatible device could impact the safety and effectiveness of your device. This would be a significant change.

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

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
• the concerns are about how the devices interact with each other and how the system will perform as a result

Changes concerning magnetic resonance

In general, a change to the magnetic resonance (MR) safety claim of an authorized medical device, in terms of scan conditions under which a scan may be safely performed, is significant.

A non-significant change would be where:

• an implantable device contains no ferro-magnetic or para-magnetic materials (for example, a polymer implant) and new MR labelling claims are being added
• MR conditional claims are reduced to a subset of previously authorized conditions

Table of examples

Class III and IV amendments for compatible Class II devices

“Compatibility” is the ability of a device, when used with 1 or more other devices, to achieve the overall clinical purpose without the user having to modify or adapt any part of the combined devices.

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

• be compatible with every other medical device with which it interacts and
• not adversely affect the performance of the medical devices used together

This requirement applies to compatible devices that reside on the same authorization and those that are authorized separately.

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

• Licensing requirements for inter-dependent medical devices

When a change is made to 1 or more of the compatible devices, you must ensure that the combination of medical devices continues to meet section 18 requirements. As well, as per item (d) of the definition of “significant change”, a change to the intended use of the device includes new or extended use.

This section of this guidance applies to the following 2 scenarios:

1. the labelling of a Class III or Class IV device is being changed to indicate compatibility with a Class II device, even if the formal “intended use and/or indications for use” statement stays the same
2. a change is being made to an authorized Class II device that is already indicated as compatible with an authorized Class III or IV device

To evaluate whether either of these 2 scenarios are significant changes for the Class III or IV authorization, 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 would typically be significant changes:
    • longer duration of use
    • new clinical indications beyond or more specific compared to those on the Class III or IV claims
    • different patient population
    • change that necessitates new clinical studies
    • change to the therapy delivered
    • new operating workflow or user interface
• Differences in key design specifications between the Class II device(s), which are previously indicated as compatible with the device, 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 such factors as compatibility, performance and risk mitigations.

Table of examples

Changes to diagnostic ultrasound systems

Health Canada recognizes there are a number of diagnostic ultrasound systems authorized in Canada that have an established safety profile in Canada and in other regulatory jurisdictions. Consequently, a change made to a diagnostic ultrasound system is not significant if all of the following apply:

• intended use of the system has not changed and 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: A-mode, B-mode, M-mode, Doppler (CW, Color, PW, Power, Combination), speckle-tracking, tissue harmonic imaging and combination
  • not well established modes: shear wave elastography, acoustic attenuation mapping, transmission based imaging, sound speed measurement
• modifications do not lead to acoustic outputs that exceed the recommended maximum acoustic output levels (consult Device licence applications for ultrasound diagnostic systems and transducers)
  • I_SPTA.3 < 720 mW/cm² for most applications, <430 mW/cm² for cardiac, <17 mW/cm² for ophthalmic
  • I_SPPA.3 < 190 W/cm² for most applications, <28 W/cm² for ophthalmic
  • MI < 1.9 for most applications, <0.23 for ophthalmic
• modifications do not result in any ultrasound interrogation parameters outside each of the following ranges:
  • 1 to 20 MHz centre frequency
  • 0 to 7 MPa peak rarefactional pressure
  • 1 to 100 cycles in a pulse (except for CW Doppler)
  • 100 to 20,000 Hz pulse repetition frequency
• modifications do not use novel mechanical or thermal effects for imaging or measurements
• measurements and analyses are clearly described and the user can adjust 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 possible, 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 validated cleaning/disinfecting instructions and identifies appropriate probe covers

Table of examples