Draft guidance on how to interpret ‘significant change’ of a medical device: General principles

A significant change is a change that could reasonably be expected to affect the safety or effectiveness of a Class III or IV medical device. This also applies to a change to a compatible Class II device that may affect the safety or effectiveness of a Class III or IV device with which it interacts.

For significant changes, you must submit an application to:

• amend your medical device licence as per section 34(a) of the Medical Devices Regulations (regulations) or
• amend your medical device authorization as per section 68.14 of the regulations

To determine whether a change is significant:

• consider this general principles section as well as the applicable descriptions of the types of changes
• consider the impact the change may have on the patient, practitioner or user and on the specifications of the device
• determine whether the change could reasonably be expected to affect the safety, quality or effectiveness of the device, in either a positive or negative way
• consider the results of a risk assessment
• consider whether data supporting the modified device can be interpolated from existing datasets
• consider the need for and results of verification and validation testing

When considering several simultaneous changes to a device, assess each change separately, as well as the collective impact of the changes (concomitant changes).

Health Canada considers that any change made to a device, including to the labelling and packaging, is likely significant if it:

• could affect the device’s safety or effectiveness
• was made in response to known changes in the safety or effectiveness of a medical device

We also consider the following cases to be significant changes:

• a new, previously unidentified hazard or hazardous situations
• a change in the likelihood of a hazard occurring
• a change in severity of an adverse consequence
• a change to risk control measures

In all cases, determining that a change is significant according to any section of this guidance results in a final determination that the change to the device is significant.

In general, a determination that a change is non-significant may occur when:

• the descriptions of the types of changes do not result in a determination that the change is significant and
• the risk assessment concludes that
  • any new or modified risks are negligeable and
  • the probability of introducing unintended consequences is negligeable.

Using risk assessment

A risk assessment should be incorporated throughout the process of assessing the significance of a change and as a final step.

A risk assessment is especially helpful to determine whether a change is significant in situations where the descriptions provided in this guidance:

• may not address your specific change or
• may not result in an initial determination that the change is significant  

A risk assessment should:

• identify hazards or hazardous situations that can lead to harm of the patient or operator
• estimate the probability of harm occurring
• assess the severity of that harm
• determine the acceptability of the residual risk, taking into consideration risk control measures that have been incorporated into the device’s design and
• evaluate the probability and impact of unintended consequences

It should also identify and analyze new risks as well as shifts in existing risks that result from the change. The result may be that the change is not significant if new or modified risks associated with the change are determined to be negligible.

A change intended to improve the safety of a given device may unintentionally introduce other risks that compromise the safety or effectiveness of the device. Your risk assessment should consider such unintended consequences.

Examples:

• A delivery system modified to ensure the device is not deployed prematurely may unintentionally introduce a feature or component that could damage or change the useful life of other components, or cause a failure itself (for example, the device fails to deploy or only partially deploys).
• An alarm may be introduced to warn of an adverse event, but it sounds or looks like another alarm and thus may be misinterpreted. It may also be raised too frequently, leading to alarm fatigue and failure to respond to other higher-priority alarms.

 A risk assessment may conclude that the change is likely non-significant if:

• no part of the change has been assessed as being significant and
• the probability of introducing unintended consequences is inherently negligeable by design, based on the nature of the change

Assessing changes by interpolation from existing datasets

Interpolation from existing datasets may be used to determine if a change is significant or not.

A change may be determined to be non-significant when:

• test reports for the authorized device previously submitted to and reviewed by Health Canada can be used to show the changed device is safe and effective
• the changed device design is still fully within the scope of the existing datasets for the authorized device
• existing test reports for the  authorized device can be used as evidence of the changed device performance and show the change has no impact on device risks or
• the change alters the device performance in a manner that can be predicted from within existing data sets

Examples of a change that can be determined to be non-significant based on interpolation:

• the size of the changed device is between the sizes of 2 existing devices under the same authorization
  • You must verify the change does not alter the safety and effectiveness of the device and that performance is consistent with the existing range of devices.
• the indications for use have been narrowed to a subset of previously authorized indications
  • This change must not have been made based on new data indicating the device is unsafe or ineffective over its expected useful life.

Note: A change would be significant if new safety issues have been identified and are the root cause for implementing the change.

In cases where the existing datasets do not adequately reflect the changed device, the change is likely significant. This is also true in cases where performance changes are unpredictable based on existing data sets and are very sensitive to small design changes.

Examples of such a significant change:

• the size of device is not reflected in the current range of devices covered in the authorization
• the indications for use have been expanded
• the size of the new heart valve is in between 2 existing authorized sizes
  • Such changes are significant because the performance of bioprosthetic valves cannot be adequately predicted from existing data and valve durability is very sensitive to changes in size.
• magnetic resonance (MR) conditional claims have been modified or introduced for a mid-sized cardiovascular or neurovascular electrode or lead
  • Such changes are significant because the performance of these types of devices within an MR environment cannot be adequately predicted from existing data.

Verification and validation testing

Verification testing ensures that a device performs as intended. Most changes (significant or otherwise) will need to undergo verification testing.

A change to a device is likely significant if verification testing:

• produces unexpected results
  • in this case, the risk assessment should be re-evaluated to determine if the change could affect the safety or effectiveness of the device
• is different than that conducted in a previous application, especially if the device change drives the need for new or modified testing activities
  • differences in testing include changes to test methods, protocols or acceptance criteria

Validation testing demonstrates that the clinical performance of a device is acceptable. The need for validation testing usually indicates that the change made to the device is significant. However, a lack of need for validation testing does not necessarily indicate that the change is not significant, as consideration of the change against all the other factors set out in this guidance is also required.