Guidance on clinical evidence requirements for medical devices: Clinical data and evaluation

Date published: November 15, 2022

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Clinical data

Clinical data are the safety or effectiveness information that is generated from the clinical use of a medical device. Sources of such data include device-specific clinical investigations, published clinical literature and post-market surveillance data.

Factors that may influence the need for clinical data include:

Note: Rare adverse events could include, for example, unintended events, disease or injury, or clinical signs that occur so infrequently that they cannot be evaluated in a pre-market study. The World Health Organization uses the term "rare" when describing an adverse event that occurs between 1 in 1,000 people and 1 in 10,000 people.

For example, an application may be subject to an increased need for device-specific clinical data (such as undergoing sufficient statistical analysis to justify study endpoints and sample size, demographics) if there is a lack of safety and effectiveness evidence for:

Where safety and effectiveness have been adequately demonstrated but clinical data collection is ongoing, results from ongoing tests may need to be submitted following licensing. This requirement is set out under terms and conditions at the time of licensing. Clinical data collection may be ongoing due to the emerging nature of the technology (for example, to gather information on long-term use or on use in rare patient populations in a real-world setting or to study a specific population). The results from this ongoing clinical data collection must demonstrate that the device's continued safety and effectiveness are maintained post-market.

When analyzing clinical data, it's important to consider the quality of the data in terms of sources of uncertainty, missing data or the degree of disaggregated population data. Manufacturers should provide estimates on the amount of under-reporting, for example:

The value of the clinical data is diminished and may result in a need for higher-quality device-specific clinical data if:

It's also important that any reports or collection of data represent robust evidence. There should be sufficient information to make an objective assessment of the device's safety and effectiveness. For example, randomized, controlled clinical trials provide a higher quality of evidence. By contrast, reports of clinical experience, such as anecdotal reports, individual case reports or expert clinical opinion, are of lower quality. This type of information is generally limited to cases where it's not feasible or practical to collect high-quality clinical data (for example, in rare disease states, under-represented patient populations and emergent interventions).

Health Canada expects that clinical data referred by manufacturers adequately represent the Canadian population and clinical practice. Any clinical data used by the manufacturer to demonstrate a device's safety and effectiveness should reflect the population for whom the device is intended.

Clinical data that is representative of the population

Sex- and Gender-based analysis plus (SGBA Plus) is an analytical process used to assess how diverse groups of people may be impacted by product or federal initiatives. Diverse groups of people include women, men, girls, boys, gender-diverse people, racial and ethnic minorities, persons with disabilities, and First Nations, Inuit and Métis people. Consideration is given to biological factors related to sex, race and ethnicity, socio-cultural factors related to gender and other identity factors.

The "Plus" recognizes that people have multiple identity factors that intersect and accumulate, that privilege or disempower, impacting their lived experiences and health. In other words, SGBA Plus considers many critical identity factors (for example, race and ethnicity, religion, age, mental and physical disability, geography, income, education). The ways they intersect inherently govern their social, economic and health outcomes.

Evidence demonstrates that biological, economic and social differences between diverse groups of women and men contribute to differences in health risks, health services use, health system interaction and health outcomes. The integration of SGBA Plus throughout the life cycle of a medical device will lead to sound science that addresses the different needs of people effectively.

Given the potential for different impacts of medical devices for diverse subpopulations, clinical studies should include adequate representation in a disaggregated manner:

As a guideline, manufacturers should consider the following key questions when integrating SGBA Plus in the design of clinical trials:

Device design should take into account the unique anatomical and physiological characteristics of all sexes and genders to the extent that this is practicable. When clinical studies are not sufficiently sized or powered to draw conclusions from these subgroups, manufacturers are encouraged to consider how certain types of other clinical data (in particular real world evidence (RWE) and post-market clinical experience) can be used to demonstrate the differential impacts of a device on different sexes and genders.

Further, where feasible, the differential impacts of a device on under-represented populations, including racial and ethnic groups, should be considered in clinical trials or investigations. This might be done through clinical trial design approaches such as stratification or by requiring a minimum number of patients from these subgroups within a larger clinical trial.

For more information and guidance, please consult the following items:

Clinical data for under-represented populations

When considering clinical data for under-represented populations, including children or pregnant individuals, manufacturers may have limited clinical data. Sometimes, this data gap can be mitigated by conducting small, well-designed clinical trials or by including a group of patients from the under-represented population within a larger clinical trial. Alternately, a device might be granted a licence with terms and conditions that stipulate more follow-up to demonstrate ongoing safety and effectiveness. Labelling limitations may also be required where there is not sufficient clinical data.

Manufacturers may also consider other ways to extract the needed clinical data from existing data. This can include leveraging RWE that may reflect the device's use in sub-population groups who don't usually participate in clinical investigations. Manufacturers should also consult existing institutional research practices or guidelines on including under-represented populations in clinical trials or investigations when it's safe to do so.

Pediatric devices (neonates, infants, children and adolescents)

Biologically, children (especially 6 years and younger) and adults are different. As infants and children have smaller organs, medical devices designed for adults may not be appropriate.

Pediatric populations are under-represented in clinical trials and investigations. This is an area of concern. As such, care must be taken to evaluate the limited datasets in the pre-market evaluation stage and in the assessment of post-market signals.

Manufacturers need to consider the following factors, including:

These pediatric-related factors should be considered when designing the product, as well as during the assessment, interpretation of data, indications for use, labelling and risk mitigation phases. Intended patient age and/or patient weight should be stated in the intended use if it will affect the device's performance or safety. Consideration should also be given to different sub-groups of the pediatric population (for example, neonates, adolescents), which have different needs and risk profiles.

Pre-market applications for a product used by the pediatric population should show how the design considers this group. For example, if a device will be used by adolescents down to neonates, then the pre-market application should show how these targeted populations were considered in the design. Product testing or theoretical justification, whichever is appropriate, may be used to demonstrate this. For example:

Device usability is another important aspect to consider in all populations, including in pediatric populations, especially if the device includes a user interface and relies on patient inputs, oversight or options. The pre-market application should make it clear whether the use of the device requires adult supervision or can be operated by the pediatric patient.

Human factors and usability studies should demonstrate that the person who is to operate the device (parent/caregiver or child of the intended age) can follow the prescribed labelling or training. Intended operators should be able to operate the device without making errors that could be hazardous or undermine the device's effectiveness. Manufacturers need to analyze these studies to demonstrate that possible hazards have been identified and successfully mitigated. Note: The use of labelling to mitigate such a risk may be ineffective in pediatric populations, especially for younger patients.

Generating clinical data from clinical investigations

A clinical investigation may be used to collect information about the safety and effectiveness of a medical device. Manufacturers that conduct a properly designed device-specific clinical investigation may be highly confident in their ability to evaluate the device's safety and effectiveness.

Clinical investigations may be necessary to support a pre-market licence application, especially in devices with limited characterization of performance within a clinical setting.

In Canada, no person shall conduct a clinical investigation in respect of a medical device unless the person holds an authorization issued under Part 3 of the Regulations. In addition, clinical investigations carried out by or on behalf of the manufacturer should follow the ethical principles of the Declaration of Helsinki and the Tri-Council policy statement (2nd edition): Ethical conduct for research involving humans. They should also conform to good clinical practices outlined in ISO 14155 - Clinical investigation of medical devices for human subjects.

Health Canada does accept clinical data from other jurisdictions. However, countries that have different standard clinical practices, different patient demographics or different standards than Canada may influence how we interpret the data.

For more information on the sale and import of a medical device for investigational testing involving human subjects, please consult the Applications for medical device investigational testing authorizations guidance document.

Generating clinical data from post-market clinical experience

Once a medical device is on the market, more safety and effectiveness data can be obtained as information about the device continues to accumulate from real-world use. This clinical data, known as real-world data (RWD), can provide supporting information on the ongoing safety and effectiveness of a device. For example, the device could be used for longer durations or in patient populations that are broader compared to those studied in a pre-market clinical investigation. Devices may also be marketed for different uses in different countries.

Various types of post-market data may be included to support the product's safety and effectiveness in a new licence application or in an application for an amendment to a licence. The data may be based on the subject device or a comparable device.

Marketing history information in Canada and other jurisdictions

This includes information on the marketing history in Canada and other jurisdictions, including for:

Marketing history should include a summary of the total number of sales per year of each model of the subject device, broken down by country or regulatory jurisdiction.

Manufacturers should note that marketing history is generally associated with significant under-reporting of adverse events. Therefore, while marketing history can be helpful in identifying possible risks associated with the device, it's limited in its ability to demonstrate safety or effectiveness.

Incidents and corrective actions

A device that is the subject of a licence application in Canada may have been sold for use previously, in Canada or internationally. This could be through earlier market authorization in a foreign regulatory jurisdiction or an authorization in Canada through SAP or ITA.

As part of the post-market monitoring of the subject device, a manufacturer may have:

Information gathered by the manufacturer who handles a complaint or adverse event or recalls the device may provide valuable context as part of a licence application. However, incident reporting by consumers has limitations due to under-reporting and incomplete information. Manufacturers are also encouraged to inform consumers about incident reporting.

To submit device incident data to Health Canada, manufacturers should:

If a recall has occurred or other corrective action has been taken to address an identified problem with a device, detailed information should be submitted as part of the licence application. For more information and guidance, please consult the Guide to recall of medical devices (GUI-0054).

Real-world data (RWD) and real-world evidence (RWE)

Examples of RWD include:

RWD sources can be used as data collection and analysis infrastructure to support many types of trial designs. These include randomized trials, such as large simple trials, pragmatic clinical trials and observational studies (prospective and/or retrospective).

To inform market authorization decisions, well-designed and -planned clinical investigations are the most robust tool for providing evidence of device safety and effectiveness. Following specific patient populations in a highly controlled environment facilitates the collection of high-quality data. However, it can limit the generalizability of the device's use in real-world settings. Moreover, conducting clinical investigations is not always feasible and may not be considered ethical for certain diseases/disorders (such as rare diseases) or certain patient populations. In other situations, excessive investigation costs or small available patient populations may introduce constraints.

Expanding evidence sources to include RWD and RWE may address some of these concerns and offer opportunities to:

With the proper analysis, RWD of sufficient quality, quantity and relevance may be used to generate useful RWE. Robust RWD and RWE may be used to support Health Canada's regulatory decision-making before and after a device is available in the Canadian marketplace (pre- and post-market).

It's not the intent of this guidance document to elaborate on the methodological approaches that can be used to generate or analyze RWD. Manufacturers filing a medical device licence application or amendment application with RWD/RWE to Health Canada should:

For more information about the use of RWD and RWE, please consult Elements of real world data/evidence quality throughout the prescription drug product life cycle. Although the document focuses on pharmaceuticals, some information is also relevant to the elements of protocol development and data quality with respect to generating RWD and RWE for medical devices.

Literature reviews

Clinical data can also be obtained from sources that are already publicly available. This includes data on a subject device that has been published in the scientific literature or published clinical data from a comparator device with similar technological characteristics.

A literature review is considered the systematic identification, synthesis and analysis of the body of available scientific literature on the subject device when used for its intended purpose(s). When providing a literature review as evidence of safety or effectiveness, manufacturers should ensure that it does not rely on devices that are not comparable. Ideally, the literature review is for the subject device.

If the clinical history of a comparator device has been well established, a manufacturer may rely solely on a literature review to establish safety and effectiveness for the subject device. If a manufacturer cannot demonstrate that the comparator device is suitable, then device-specific clinical data may be required.

A literature review should include a critical analysis of all available evidence, including both favourable and unfavourable reports, as well as the validity or limitations of the study designs. Manufacturers are expected to provide a summary of each publication and an analysis of the data contained in the publication. All publications that are cited should be included in the application.

Generating clinical data from usability studies and simulations

Usability studies and simulation data sets are usually performed outside of the scope of investigational testing authorizations in Canada. However, they can also provide valuable information about the safety and effectiveness of certain medical devices.

Usability or human factors studies often involve typical users of medical devices who test the medical device in a simulated clinical environment. Outcomes from these studies often focus on indicators such as user errors and adequacy of following instructions.

The IEC 62366-1 international standard on medical devices - Part 1: Application of usability engineering to medical devices defines a usability test as a method for exploring or evaluating a user interface with intended users within a specified intended use environment. For this guidance, usability or human factors studies should include an appropriate user group and be conducted in a representative clinical setting, where the device is used in a manner consistent with the provided labelling.

For additional guidance, refer to the international standards associated with human factors engineering and usability studies.

Simulation studies generally refer to numerical simulations of real-world use of a medical device. For the purpose of this guidance, Health Canada defines simulation as:

Simulations can also provide useful information on safety and effectiveness, especially when based on validated clinical databases. Information on the databases, numerical simulation software or other tools used should be clearly described. Validation of the tools and data used should be clearly demonstrated so that the results can be applied to the actual clinical use of the proposed device.

In some cases, human factors evidence may be deemed necessary to demonstrate that all known risks have been reduced to the extent possible.

Data considerations for devices with cosmetic indications for use

Some devices may have several therapeutic applications that may either:

This includes devices with cosmetic applications or cosmetic indications for use. Examples include lasers for hair removal, lasers for corrective refractive eye surgery, wrinkle reduction devices and devices for liposuction or circumference reduction.

Benefit-risk considerations

All medical devices are reviewed to confirm that the benefit of the device outweighs the risks. In the case of devices with cosmetic indications for use, Health Canada will review the clinical evidence submitted by the manufacturer to confirm:

When applicable, information on how a device with cosmetic indications for use could affect diverse patient subpopulations may be considered in assessing the benefits or risks related to the device. Diverse patient subpopulations include various groups of females, males, women, men and gender-diverse people, racial and ethnic minorities, pediatric and elderly patients, and patients with special needs.

Providing objective clinical information

In some cases, it may be difficult to quantify the benefit of the cosmetic indication for use. Make sure that any data are gathered as objectively as possible. Manufacturers can reduce or eliminate potential bias by:

If the device is intended to improve the appearance of the patient, image comparisons from before and after treatment are often used. Data collected in the form of pictures should be taken in a controlled environment, using the same conditions before and after treatment, including location, angle, lighting, resolution and camera type/model. Data collected should also be disaggregated by sex and gender across age and racialized groups as appropriate. Note these considerations in the application.

Literature provided as evidence should include enough details to allow Health Canada to confirm that the conclusions are not biased or confounded by poor controls during the assessment. Include key journal articles in the application. Provide at least one objective measure of effectiveness (for example, count and length of wrinkles before and after, weight before and after procedure).

Supporting the effectiveness of the device

Manufacturers must provide evidence to support all parts of the indications for use of their medical device. For example, if the product is indicated for use to achieve permanent results, then the manufacturer needs to provide data from a clinical investigation that follows patients over an extended period of time. The length of follow-up should be based on scientifically grounded evidence that the results are indeed "permanent" as opposed to "long-term" or "short-term."

When the product is indicated for temporary results, the data must clarify how long the results will last. If specific areas of the body are targeted for treatment, then the clinical data provided in the application must reflect that specific target area. Manufacturers should justify that the clinical data they used was gathered in a large enough number of healthy patients to prove that the results are statistically significant. The manufacturer should use scientifically supported and validated assessment tools and methods to collect measures of patient impact, quality of life or satisfaction.

Supporting the safety of the device

Health Canada will be critical in its review of the safety evidence provided. Manufacturers must take measures to ensure that the design of the device eliminates, or reduces as much as possible, any dangers that can arise from its use, when used in accordance with the instructions for use.

For requirements to mitigate potential thermal damage of energy-based medical devices, please refer to the Risk of thermal harm from therapeutic and cosmetic energy-based medical devices: Notice to industry.

If the device is to be used by the public or non-health care professionals who have had limited training, manufacturers must demonstrate that the design of the device is safe for all users. Manufacturers are encouraged to consider usability or human factors testing to confirm that interactions between the device and its users occur as intended and are safe.

If a certain frequency of treatment is required to maintain the effectiveness of treatment, then clinical data supporting the safety of that frequency of treatment is required. As well, patient characteristics that could affect safety, such as dermatological conditions or skin pigmentation, must be clearly considered. Clinical data must also be provided to support the safety in those populations of patients.

Medical devices with cosmetic indications for use are subject to the same stringent Health Canada review as other devices to ensure the benefits outweigh the risks. Manufacturers should consider whether the clinical evidence provided to support these applications is objective and addresses all aspects of the indications for use.

Clinical evaluation

A clinical evaluation should consider all relevant information from all sources of clinical data.

Through proper clinical evaluation, it's expected that the manufacturer will have demonstrated the following:

If a comparison is being made to a licensed or marketed device, manufacturers may also provide objective evidence that the outcomes observed when using the proposed device are not inferior to the existing standard of care approaches. This comparison should include an equivalent patient population (where applicable) and contemporary outcomes from an existing equivalent intervention or for an accepted standard of care treatment. Confidence levels and uncertainties in the datasets should also be discussed.

The evaluation should also address any clinical claims made about the device, the adequacy of device labelling and product information (particularly contraindications, precautions and warnings) and the suitability of instructions for use.

When deciding upon the scope of a clinical evaluation, a manufacturer should consider:

Manufacturers may provide a Clinical Evaluation Report (CER) with their Class III or IV applications. A CER provides the conclusions of the clinical evaluation of the subject device. The CER should include all analyzed clinical data and demonstrate that the subject device achieves its intended purpose while maintaining a favourable benefit-risk profile. The CER is not mandatory in Canada.

When providing a CER with a medical device licence application, additional supporting evidence may be required to ensure the comparator device and the subject device are discussed given their Canadian regulatory status. Once provided, the CER becomes subject to the Public Release of Clinical Information.

For guidance on the CER and the Public release of clinical information, please refer to the resources provided on the Overview page.

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