Submitting risk management plans draft guidance document: Introduction

Organization: Health Canada

Date published: 2022-12-16

On this page

• Policy objectives
• Purpose of a risk management plan
• Scope and application
• Background
• Note about guidance documents in general
• Definitions
• List of relevant guidance documents

Policy objectives

Health Canada has adopted and integrated the use of risk management plans (RMPs) and the International Conference on Harmonization (ICH) E2E Guideline into the regulatory review of drugs in Canada. This long-standing practice has now been incorporated into the Food and Drug Regulations. This will:

• support a life cycle approach to drug vigilance
• align drug vigilance with international best practices
• enhance the quality of Health Canada's regulatory assessments
• support Canadians' timely access to safe, efficacious and high quality drugs
• support ongoing evaluation of information that could have an impact on the benefit-risk profile of drug products

Purpose of a risk management plan

A risk management plan (RMP) is a document that:

• identifies and characterizes risks and uncertainties of a drug product, such as:
• important identified risks
• important potential risks
• missing information
• describes pharmacovigilance measures designed to monitor and address risks and uncertainties
• describes risk minimization measures, such as interventions designed to prevent or reduce risks
• assesses the effectiveness of those risk minimization measures and interventions

Health Canada may require RMPs for drug products when the Minister has reasonable grounds to believe:

• there is a significant degree of uncertainty respecting the risks associated with the drug
• the drug presents a serious risk of injury to human health that warrants measures, other than labelling, to reduce the probability or severity of such an injury

The RMP may be used to:

• identify, characterize, prevent or minimize risks or address uncertainties of that drug product
• assess the safety and effectiveness of the drug, for example, in deciding whether to issue, suspend or remove a market authorization

For specific examples, refer to when to file a risk management plan with Health Canada.

Scope and application

This document provides the sponsor/market authorization holder (MAH) with guidance on when and how to submit an RMP and RMP updates during the lifecycle of the drug product.

The document also provides clarification on:

• an acceptable RMP format
• RMP summaries and an acceptable RMP summary format
• requirements for taking into account the Canadian context, including the format for a Canadian-specific addendum
• RMP updates with Health Canada

Additionally, this document provides:

• clarification to the sponsor/MAH regarding the management of the submission of RMPs
• the sponsor/MAH with an overview of review timelines including deadlines for responding to questions
• the sponsor/MAH with information on compliance with other requirements related to RMPs

The regulatory requirements, principles and practices outlined in this document apply to "drugs," as defined by section 2 of the Food and Drugs Act, for human use and include the products within the scope of ICH E2E:

• pharmaceutical drugs, such as prescription and non-prescription drugs, including generic drugs
• biologic drugs, as set out in Schedule D to the Food and Drugs Act, including:
• vaccines
• fractionated blood products
• biotherapeutic drugs, including biosimilars
• radiopharmaceutical drugs as set out in Schedule C to the Food and Drugs Act

This document does not apply to the submission of RMPs for:

• veterinary products
• natural health products
• whole blood and blood components
• medical devices, except when they are part of a combination product submission and classified in one of the applicable product categories

Readers of this document should be familiar with those requirements of the Food and Drugs Act and Food and Drug Regulations relating to routine pharmacovigilance measures such as adverse reaction reporting and summary reporting.

Please note that elements of RMPs, such as controlled distribution programs, are not intended to restrict access to Canadian reference products (CRPs) for generic drug manufacturers for the purposes of conducting comparative testing. Any RMP elements should not delay or hinder comparative testing with generic products or hinder their ability to enter the market.

Background

Health Canada bases the decision to authorize a drug for sale in Canada on its safety, effectiveness and quality. The benefits of the drug must outweigh the risks within the conditions of use specified in the product labelling.

This decision is based on the information available at the time of authorization. The knowledge related to the safety profile of the drug can change over time through expanded use in terms of patient characteristics and the number of patients exposed. In particular, during the early post-marketing period, the drug might be used:

• in settings different from those studied in clinical trials
• by a much larger population in a relatively short timeframe

As an observer country, Canada was a signatory to the ICH Pharmacovigilance planning E2E guideline, released in 2004. The ICH E2E guideline provides instruction in cases where there are "important identified risks of a drug, important potential risks, and important missing information, including the potentially at-risk populations and situations where the product is likely to be used that have not been studied pre-approval".

Since the release of the ICH E2E Guideline, the European Medicines Agency (EMA) and other regulators have released their own guidelines to reflect the intent of the ICH E2E, and update them from time to time. Many sponsors/MAHs refer to EMA GVP Module V as their preferred approach.

In February 2009, Health Canada published the Notice regarding implementation of risk management planning. The notice advised on:

• key components of RMPs
• acceptable formats
• reasons, criteria and scope for RMP requests
• the submission process

In June 2015, Health Canada published the Guidance document – Submission of risk management plans and follow-up commitments. This document provided sponsors/MAHs with guidance on how to proceed when submitting an RMP. The regulatory amendments to the Food and Drug Regulations build on long-standing practice outlined in the 2015 guidance document. In August 2020, Health Canada published a notice of clarification specifying that RMPs are not meant to restrict access to Canadian reference products. In November 2020, Health Canada published a second notice of clarification regarding the inclusion of Canadian-specific considerations in RMPs.

In response to the growing public health crisis due to opioids, the Minister of Health announced the Federal Action on Opioids on June 17, 2016. In November 2016, Health Canada convened a Scientific Advisory Panel on Opioids (SAP-Opioids) to provide recommendations on the monitoring and managing of the risks related to opioids. Recommendations from this panel were taken into consideration for the development of this guidance document.

Note about guidance documents in general

Guidance documents provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. They also provide guidance to Health Canada staff on how mandates and objectives should be met fairly, consistently and effectively.

Guidance documents are administrative, not legal, instruments. This means that flexibility can be applied. However, to be acceptable, alternate approaches to the principles and practices described in this document must be supported by adequate justification. They should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As always, Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, to help us adequately assess the safety, efficacy or quality of a therapeutic product. We are committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read along with the relevant sections of the Regulations and other applicable guidance documents.

Sponsors/MAHs should refer to the most up-to-date versions of the guidance documents. The links included are a starting point to help sponsors/MAHs, and is not an exhaustive list of guidance documents.

Definitions

The definitions and terminology are derived from documents prepared by Heath Canada and other regulators such as the European Medicines Agency (EMA).

Additional measures :

additional pharmacovigilance measures and/or additional risk minimization measures.

Additional pharmacovigilance measures (also known as additional pharmacovigilance activities) :

measures, activities or methods designed to address products with special safety concerns, not sufficiently addressed by routine pharmacovigilance measures, such as the need for additional data to more fully characterize risks or to evaluate the effectiveness of additional risk minimization measures. Examples include safety studies or registry.

Additional risk minimization measures (also known as additional risk minimization activities) :

an intervention, in addition to the routine risk minimization measures, intended to prevent or reduce the probability of an undesirable outcome, or to reduce its severity should it occur. Examples include controlled distribution programs or educational material.

Compliant risk management plan :

a risk management plan that meets the requirements set out in section C.01.700 of the Food and Drug Regulations.

Core RMP :

a risk management plan, in an acceptable format, and which contains all of the essential elements of the EU format.

Data package :

a formal submission or application to a regulatory authority to obtain a regulatory decision or to maintain regulatory status for a drug. In Canada, this includes data as per the Food and Drug Regulations or other information filed for review by Health Canada. Examples include risk management plans filed independently of a submission, periodic safety update reports.

Foreign reviews (also referred to as foreign review reports) :

scientific safety, efficacy and/or quality reports prepared by foreign regulatory authorities, upon which foreign regulatory decisions on drugs are based. They include initial scientific assessments, regulatory correspondence with the sponsor/MAH, follow-up assessments, and the final decision (for example, positive, negative or conditional). They include, where applicable, risk management plans and on-site evaluation reports (or equivalent). They do not include the data package filed with the foreign regulatory authority.

ICH E2E :

this ICH Guidance on Pharmacovigilance Planning helps plan pharmacovigilance activities, especially in preparation for the early post-marketing period of a new drug. It focuses primarily on specific aspects of a Safety Specification and Pharmacovigilance Plan that sponsors/MAHs may submit at the time of an application for market authorization.

Important identified risks :

undesirable clinical outcomes for which there is sufficient scientific evidence to show they are caused by the drug product, and which are likely to impact the benefit-risk balance of the product or have implications for public health. Important identified risks included in the RMP usually require measures to prevent, reduce or further characterize them.

Important potential risks :

risks that if further characterized and confirmed, would impact the risk-benefit balance of the product or have implications for public health. For example, where there is a scientific rationale that an adverse clinical outcome might be associated with off-label use, use in populations not studied or the long-term use of the product, the adverse reaction should be considered a potential risk and if deemed important, should be included in the list of safety concerns as an important potential risk. Important potential risks included in the RMP would usually require further evaluation as part of the pharmacovigilance plan.

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) :

a joint regulatory-industry initiative pertaining to the international harmonization of regulatory requirements for drug products. The parties in ICH represent the regulatory bodies and research-based industry in 3 regions: North America, Europe and Japan. Most new medicines are developed in these regions.

Label :

includes any legend, word or mark attached to, included in, belonging to or accompanying any drug.

Medication error :

any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer. Medication incidents may be related to professional practice, drug products, procedures and systems, and include prescribing, order communication, product labelling/packaging/nomenclature, compounding, dispensing, distribution, administration, education, monitoring and use.

Missing information :

information on the safety of the drug product, likely to have an impact on its benefit-risk balance or have implications for public health, that is missing and needs to be collected. Such missing information may include gaps in knowledge about the safety of a drug product for certain anticipated uses (for example, long-term use) or in particular patient populations. The absence of data itself (for example, exclusion of a population from clinical studies) does not automatically constitute a safety concern. Instead, the risk management plan should focus on situations that might differ from the known safety profile. A scientific rationale is needed for the inclusion of that population as missing information in the RMP.

New active substance (NAS) :

A new drug (pharmaceutical or biologic) that contains a medicinal ingredient not previously approved in a drug in Canada and that is not a variation of a previously approved medicinal ingredient. (approved means for human use or for veterinary use, as the case may be)

Opioid-related harms :

any adverse drug reaction related to opioid use disorder or opioid induced disorders as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), resulting from therapeutic or non-therapeutic use of a drug product.

Periodic Benefit-Risk Evaluation Report (PBRER):

a pharmacovigilance document intended to provide a comprehensive, concise and critical analysis of new or emerging information on the risks of the drug product, and on its benefit in approved indications, to enable an appraisal of the product's overall benefit-risk profile. The updated ICH E2C(R2) guidance ensures that Periodic Safety Update Reports (PSURs) for marketed drugs have the role of being periodic benefit-risk evaluation reports by covering: safety evaluation, evaluation of all relevant available information accessible to sponsors/MAHs and benefit-risk evaluation.

Periodic Safety Update Report (PSUR) :

a mechanism for summarizing interval safety data, and for conducting an overall safety evaluation. It is a tool for sponsors/MAHs to conduct systematic analyses of safety data on a regular basis. In addition to covering ongoing safety issues, the PSUR should also include updates on emerging and/or urgent safety issues, and major signal detection and evaluation that are addressed in other documents.

Pharmacovigilance :

the World Health Organization (WHO) defines pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse events or any other drug-related problems.

Post-Authorization Safety Study (PASS) :

a study relating to an authorized drug product conducted with the aim of identifying, characterizing or quantifying a safety hazard, confirming the safety profile of the drug product, or of measuring the effectiveness of risk management measures. A PASS may be interventional or non-interventional.

Risk Evaluation and Mitigation Strategies (REMS) :

Risk Evaluation and Mitigation Strategies (REMS) are required by the U.S. Food and Drug Administration from the sponsor/MAH to manage known or potential serious risks associated with a medicine to ensure that the benefits outweigh its risks. REMS use risk minimization strategies beyond labelling.

Risk Management Plan (RMP) :

a document that describes a set of pharmacovigilance measures and interventions designed to identify, characterize, prevent or minimize risks and address uncertainties related to the safety and effectiveness of drug products, and the assessment of the effectiveness of those interventions (adapted from the EMA definition of a Risk Management System).

Risk Management Plan Summary (RMP Summary) :

a document within the Risk Management Plan that reflects and summarizes the content of the Risk Management Plan.

Risk minimization measures (also known as risk minimization activities) :

interventions intended to prevent or reduce the occurrence of adverse reactions associated with the exposure to a medicine, or to reduce their severity or impact on the patient should adverse reactions occur. Examples include warnings in the label or minimization measures beyond routine, such as healthcare professional educational material.

Routine pharmacovigilance measures (also known as routine pharmacovigilance activities) :

measures, activities or methods that are sufficient for post-approval safety monitoring of products for which no special concerns have arisen. Examples include monitoring of the safety profile of the product through signal detection activities and preparation of reports for regulatory authorities (for example, PSURs).

Routine risk minimization measures (also known as routine risk minimization activities) :

standard measures or activities that apply to all drug products. Examples include product labelling and limitations on drug pack size.

Safety specification :

a detailed description of the important identified risks of a drug product, important potential risks and missing information. The safety specification should also address the populations potentially at risk (where the drug is likely to be used) and outstanding safety questions which warrant further investigation to refine understanding of the benefit-risk profile during the post-authorization period.

Serious adverse drug reaction :

a noxious and unintended response to a drug that occurs at any dose and that requires in-patient hospitalization or prolongation of existing hospitalization, causes congenital malformation, results in persistent or significant disability or incapacity, is life-threatening or results in death.

List of relevant guidance documents and notices