Submitting risk management plans draft guidance document: Opioid products

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Objective for opioid products

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

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

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:

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:

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:

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:

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

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 pharmacovigilance measures

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

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:

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:

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:

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:

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

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:

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

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:

Evaluating the effectiveness of risk minimization generally uses:

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.

Drugs intended for human use containing any of the following active ingredients Including (but not limited to) Qualifier
Buprenorphine Buprenorphine Hydrochloride n/a
Butorphanol Butorphanol Tartrate n/a
Codeine Codeine Phosphate Except for those products referred to in subsection 36(1) of the Narcotic Control Regulations
Diamorphine Diamorphine Hydrochloride;
Diacetylmorphine Hydrochloride
Fentanyl Fentanyl Citrate n/a
Hydrocodone Hydrocodone Bitartrate n/a
Hydromorphone Hydromorphone Hydrochloride n/a
Meperidine Meperidine Hydrochloride n/a
Methadone Methadone Hydrochloride n/a
Morphine Morphine Hydrochloride; Morphine Sulfate n/a
Normethadone Normethadone Hydrochloride n/a
Opium Opium and Belladonna n/a
Oxycodone Oxycodone Hydrochloride n/a
Oxymorphone Oxymorphone Hydrochloride n/a
Pentazocine Pentazocine Hydrochloride; Pentazocine Lactate n/a
Tapentadol Tapentadol Hydrochloride n/a
Tramadol Tramadol Hydrochloride n/a

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