Submitting risk management plans draft guidance document: Opioid products

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• Objective for opioid products
• Canadian opioid-specific content for compliant RMPs
• Examples of opioid products that require Canadian opioid-specific content

Objective for opioid products

Opioid products need to include specific content within their RMP to address:

• the risk and uncertainties of opioid-related harms in Canada
• other risks and uncertainties posed by the product, where warranted

The objective of establishing Canadian-specific content for RMPs for opioid products is to:

• standardize and strengthen the rigour of the post-market surveillance of prescription opioids
• better quantify and characterize the risks associated with opioid-related harms in Canadian patients
• put targeted risk minimization measures in place to prevent or decrease prescription opioid-related harms in Canada

Sponsors/MAHs are encouraged to work together, where possible, to develop a common approach for pharmacovigilance studies and for risk minimization measures for opioids that share the same active ingredient or therapeutic use or indication. This would support consistency among the various measures and minimize duplication.

When developing an RMP for an opioid product, the sponsor/MAH should seek early dialogue with Health Canada's Marketed Health Products Directorate regarding the applicability, feasibility and design of the proposed measures.

Canadian opioid-specific content for compliant RMPs

Specific content related to opioid harms and uncertainties was previously included in the Canadian Specific Opioid targeted Risk Management Plan (CSO-tRMP) for Class B opioids, which was required as a term and condition. RMP requirements for opioids are now subsumed under the RMP regulations.

In order for an RMP for an opioid product to address opioid-related harms in Canada, Canadian-specific elements should be included in:

• a core RMP or
• the Canadian-specific addendum

This is part of the Canadian context, which must be taken into account in the RMP. It is insufficient to leverage only international data and measures to fulfil these requirements for opioid-related harms in Canada.

Opioid-specific content should be included in addition to the standard RMP elements described in this guidance document, and in other referenced acceptable formats (such as the EU), when preparing an RMP for an opioid product. Health Canada expects that the content of the opioid RMP will cover:

• opioid-related harms within the detailed description of the risks associated with the drug and the uncertainties related to those risks
• other important risks and missing information associated with the opioid drug in Canada

The update requirements of an RMP for opioids are as specified elsewhere in this guidance document.

Safety specification

Include the following Canadian opioid-specific content within the safety specification of the RMP prepared for the opioid product:

• the Canadian epidemiology of the indication and trends of opioid-related harms in Canada
• a description, quantitatively and qualitatively, of the occurrence of opioid-related risks associated with the use of the opioid drug in Canada
• detailed information on the evidence gaps and uncertainties related to opioid-related risks that are associated with the use of the opioid drug in Canada
• an analysis and characterization of opioid-related harms and other important safety concerns
• a summary table of safety concerns and proposed changes

Epidemiology of the indications and the target populations in Canada

Provide a breakdown, according to the formulation, regarding opioid-related harms collected from active surveillance (such as a completed post-authorization safety study) when:

• discussing the epidemiology of the indications and target populations and
• when more than 1 formulation is covered in the same opioid RMP (for example, ER/IR)

Include the Canadian trends of opioid-related harms relevant to the product, relating to, for example:

• region
• indication
• time
• age, sex or gender
• concomitant use of other substances known to interact with opioids
• underrepresented or marginalized populations

Post-authorization experience

When discussing the post-authorization experience, provide an analysis of opioid-related harms based on both crude numbers and reporting/incidence rates of events in the context of worldwide and Canadian post-market exposure (if applicable).

Update this information as new quantitative or qualitative evidence related to opioid-related harms or uncertainties is generated through the risk-monitoring/characterizing measures conducted in Canada or internationally. These measures may include pharmacoepidemiological studies or clinical trials undertaken to investigate the drug.

Pharmacovigilance measures

Include the following Canadian opioid-specific content within the pharmacovigilance measures of the RMP prepared for the opioid product:

• routine (passive surveillance) and additional (active surveillance) measures in place or to be put in place to monitor and characterize risks and uncertainties associated with the use of the drug in Canada
• the timelines for conducting the activities and reporting
• a summary table of pharmacovigilance measures and milestones

Routine pharmacovigilance measures

When discussing the Canadian-specific monitoring of adverse events for routine pharmacovigilance measures for opioid products, clearly document:

• a search strategy (including the data lock point)
• the most recent Adverse Reaction Terms (MedDRA Preferred Terms) used for spontaneous data extraction

Additional pharmacovigilance measures

Because of well-recognized limitations related to adverse reaction reporting, passive adverse event surveillance alone is insufficient to monitor opioid-related harms in Canada. An RMP for an opioid product should describe additional pharmacovigilance measures to monitor opioid-related harms and address current knowledge gaps in Canada. Examples of these measures include:

• a retrospective non-interventional post-authorization safety study (PASS) in high-risk populations
• a well-designed prospective non-interventional PASS estimating the incidence of opioid–related harms in the indicated patient population
• a surveillance system capable of monitoring (longitudinal or cross-sectional), opioid-related harms discussed associated outcomes, among diverse populations in Canada

Prepare study protocols before initiating studies, with input from qualified methodologists and statisticians. Make the choice of risk factors beforehand, and with the anticipated direction of effect to reduce the risk of spurious findings. Include factors that have already been established by the literature. When possible present significant associations for risk factors as both relative and absolute effects.

The sponsor/MAH's role should be restricted to:

• sponsoring
• reviewing of the protocol
• provision of non-binding feedback

Do not let parties that stand to benefit financially from the results unduly influence study design, implementation or interpretation. Non-profit organizations should conduct post-marketing studies.

Submit pharmacovigilance measure progress reports either in a follow-up report or in an updated RMP.

Risk minimization measures in Canada and evaluation of their effectiveness

Include the following Canadian opioid-specific content within the risk minimization measures of the RMP prepared for the opioid product:

• a description of routine and additional risk minimization measures (beyond the approved product label) that are designed to reduce or prevent:
• the occurrence of opioid–related risks
• other product-specific risks in people in Canada using the drug
• the timelines for conducting the activities and reporting
• all materials that are or will be communicated and/or disseminated by the MAH to healthcare professionals with respect to the drug
• a summary table of risk minimization measures and their evaluation

Additional risk minimization measures

An RMP for an opioid product should describe additional risk minimization measures designed to reduce or prevent the occurrence of opioid-related harms in people in Canada using the drug.

For additional risk minimization measures, it is recognized that the risk minimization approach may evolve throughout the therapeutic product life cycle and a variety of tools could be implemented in the future. Moreover, this approach may be required for some products depending on their unique benefit/risk profile. Such additional measures could include, for example:

• implementation of restricted access
• establishment of performance-linked access programs/registries as defined by CIOMS IX

When assessing whether the proposed measures prevent or reduce the opioid related risks, Health Canada will consider:

• the added positive effects of the product's benefit-risk balance
• unintended consequences on the existing workflow and standard of care in various health care settings

Include in the appendix copies of any tools or materials used in risk minimization measures.

Evaluation of the effectiveness of the risk minimization measures

The sponsor/MAH is expected to provide a detailed section on the evaluation of the effectiveness of risk minimization measures for Canadian opioid-specific content that:

• describes the measures that the manufacturer will carry out to assess the effectiveness of the risk minimization measures on health outcomes in Canadians who are using the opioid product
• provides the timelines for the conducting of the activities

Overall, the strategies to assess the effectiveness of the risk minimization aim to determine whether:

• the risk minimization measures achieve the desired level of risk management
• objective (quantifiable) measures that aim to determine this success are considered as outcome indicators
• the risk minimization has been successfully implemented
• objective (quantifiable) measures that aim to evaluate the success of the implementation of these measure are considered as process indicators

Since the ultimate goal of a risk minimization measure is to reduce or prevent risks, the sponsor/MAH must provide outcome indicators.

Acceptable examples of outcome indicators include:

• frequencies or rates of opioid-related harms (before and after implementing risk minimization)
• any metrics related to changes in hospitalizations or deaths related to opioid-related harms (before and after implementing risk minimization)

Evaluating the effectiveness of risk minimization generally uses:

• drug utilization studies
• prescriber and patient surveys
• surveillance studies of key safety outcomes

Examples of opioid products that require Canadian opioid-specific content within their RMP

The following list of products are examples of opioid products for which the Minister has required RMPs with specific content. The Food and Drug Regulations give the Minister the authority to require RMPs for any drug that meets the thresholds prescribed in the regulations.