Guidance on additions to the list of Nicotine Replacement Therapy dosage forms: Types of evidence

On this page

• Overview
• Evidence from observational studies
• Evidence of potential for non-therapeutic use
• Market evidence and surveillance

Overview

This section outlines general information about the types of evidence that could be submitted as part of a request to add an NRT dosage form to the List.

Evidence can include studies reported in the literature or unpublished studies you have conducted if the data are presented in a report format that includes a critical analysis of results, study limitations and generalizability. Health Canada may also request protocols to be submitted.

You should also provide a summary tabulation and critical analysis of the significance of the findings and the risk to public health.

Evidence may focus on individual products; however, the totality of the evidence must be broadly applicable to the NRT dosage form. If you submit product-specific evidence, you should include detailed product information, such as:

• Brand name
• Active ingredient(s)
• Dose
• Natural Product Number or other registration number (as applicable)
• Intended purpose (such as smoking cessation or recreational use)

Evidence from observational studies

Well-designed observational studies, such as consumer self-selection studies and longitudinal and population-based studies, can provide data to help analyze the appropriate use and choice of an NRT dosage form. These types of studies can help analyze consumer behaviour and identify patterns of use. They should include a study methodology and detailed analysis of the results as well as discussion on the limitations and steps taken to mitigate them.

Consumer self-selection studies

Self-selection studies assess whether consumers can apply the label information to their personal medical situation and correctly decide whether to use the dosage form in question. Self-selection studies can also help demonstrate that the NRT dosage form can be appropriately selected without pharmacist intervention in physical and online retail spaces.

These studies should be conducted with the intended consumers (recommended subpopulation) and unintended consumers (young people and individuals who do not smoke), who are representative of Canadian demographics.

Self-selection studies for an NRT dosage form could address the following questions:

• Can intended and unintended consumers properly identify the purpose of a product in the relevant dosage form?
• Based on their smoking status, can intended and unintended consumers determine whether they should use a product in the relevant dosage form? For example, would individuals who do not smoke want to access and use the product because of its dosage form?

Open-ended questions could be asked to assess self-selection decisions of unintended consumers.

If the protocol of a self-selection study is requested, you should include a comprehensive statistical analysis plan. You should also provide an analysis of quantitative and qualitative data to support and interpret study findings.

Longitudinal and population-based studies

Longitudinal and population-based studies can help demonstrate a history of appropriate use. These studies can be conducted to observe the use of an NRT dosage form over time in a large group of people to show whether there is a pattern of consistent, appropriate use of the NRT dosage form during that period. The observations must be sourced from populations with reasonable comparability to the Canadian context, with regards to key parameters such as socioeconomic stratification, mental health status and public health concerns. The data provided from such studies should be paired with other evidence (such as sales data) validating the appropriate use of the dosage form in the population at large.

Longitudinal and population-based studies could address many topics relevant to the safety profiles of NRT dosage forms including patterns and trends over time for both exposure and risk of potential harms to health, such as prevalence rates, incidence rates or other relevant outcome measures.

Evidence of potential for non-therapeutic use

An analysis that demonstrates the potential for use of the NRT dosage form among unintended consumers of NRTs (young people and individuals who do not smoke) when available in areas of self-selection may help evaluate the potential for that dosage form to be used inappropriately (non-therapeutic use) should it be added to the List. Evidence should demonstrate that the risk of use of the NRT form by unintended users is minimal and comparable to that of other dosage forms already on the List.

For example, studies could assess the likelihood the NRT dosage form in a self-selection setting would be used inappropriately or demonstrate how the NRT dosage form is perceived by unintended users.

Participants should be representative of Canadian demographics.

Evidence of market experience and surveillance

In the context of this guidance document, market experience is knowledge gained about an authorized product once it is being sold and used by consumers. Market experience provides additional information on the safety and effectiveness of a product given the larger and more diverse population than that in clinical trials.

Evidence of market experience will help determine whether the NRT dosage form is being marketed in a way that increases interest among unintended users, such as young people and individuals who do not smoke, or encourages unintended use, such as for purposes other than smoking cessation. The types of evidence you should submit in the evidence package include:

• Sales and utilization data
• Advertising strategies and promotional content
• Other post-market safety information

You should include information on the NRT dosage form in Canada and internationally.

This evidence should be paired with other evidence outlined in this guidance and include data from relevant comparator groups when available.

Sales and utilization data

This could include a summary of the estimate of exposure to the dosage form (cumulative and annual) derived from sales (including online sales) and other sources, such as population use prevalence, if available.

Advertising strategies and promotional content

This could include examples of marketing strategies and marketing content used to promote the NRT dosage form (not only for a specific product but including other available NRT products in this dosage form) across all media, including social media.

Other post-market safety information

This could include an analysis of post-market exposure and health outcomes in the context of potential inappropriate use and risks that might arise from that use, such as cumulative reports of adverse reactions or events related to non-therapeutic use or substance use disorders.

Other relevant data that could be provided if available include:

• data relating to diversion of products to young people or other unintended users; and
• data from sources reporting on non-therapeutic use such as:
  • poison control centres
  • medical examiners
  • addiction centres
  • public health data
  • scientific or medical literature

You could provide the following information from Canada and if applicable, other jurisdictions:

• Any risk management plans submitted to regulatory agencies
• A summary of identified and potential risks including adverse event data, if applicable, from your safety databases
• A summary of the findings from your comprehensive review of scientific literature containing safety information (including reference articles from peer-reviewed medical journals, and search methodology)
• A summary of all clinical trial safety information
• Information on all suspected reports of accidental overdose
• Information on all suspected reports of medication errors
• Information on all suspected reports of intentional misuse
• A summary of all foreign regulatory actions taken with respect to safety, including a chronological summary of available risk communications, licence suspensions, and recalls

You should also provide a critical analysis of post-market safety information submitted, with a conclusion as to whether and to what extent the risks for non-therapeutic use and potential risks to health would differ should the NRT dosage form be added to the List.

With respect to adverse event data, you should:

• Include an analysis of adverse event data from the World Health Organization's Vigibase and the Canada Vigilance Database, as well as other available international databases.
• Consider the foreign regulatory requirements and procedures by which adverse events are collected to contextualize the data. For example, you should outline whether a foreign country's adverse event reporting is voluntary or mandatory and under which circumstances.

You should contextualize all relevant foreign market experience information provided from other regulatory authorities.

The following details about the NRT dosage form and its comparators from relevant jurisdictions should be submitted:

• Foreign product information, including:
  • salt or derivative of the active ingredient and its bioavailability
  • strength(s) of active ingredient(s) per unit of the product
  • recommended single and maximum daily dose
  • duration of use
  • indications, including intended population and intended use

Note: If the evidence includes specific foreign products, they should have the same dosage form as the one proposed to be added to the List.

• Regulatory status, including:
  • whether products in the NRT dosage form have been classified as a prescription drug, a non-prescription drug product, a consumer product, or other
• Level of healthcare professional involvement and consumer access, including:
  • any conditions of authorization/sale from all levels of government that pertain to the oversight of, and access to, the NRT dosage form
    • the level of health care professional involvement required in the selection and sale of the NRT dosage form
  • the level of access of the NRT dosage form for purchase (for example, whether the public has direct access in all retail locations or in pharmacies only)
• Other risk mitigation measures, including:
  • the differences between the packaging and labelling of the foreign product and the required Canadian packaging and labelling
  • any restrictions applicable to the NRT dosage form in the foreign jurisdiction, such as flavour restrictions
    • If there are foreign restrictions, permitted elements should be indicated (for example, if there are flavour restrictions, the permitted flavours should be indicated)
  • information about any other specific risk mitigation measures in place for the NRT dosage form (such as restrictions on any form of advertising) in other relevant countries and any significant safety-related changes since the date of marketing
• Product exposure
  • when applicable, the length of time the NRT dosage form has been marketed and an estimate of the NRT dosage form exposure in other relevant jurisdictions
  • information on the use of the NRT dosage form by young people, if available