Submitting risk management plans draft guidance document: Procedures to submit

On this page

• When to file a risk management plan with Health Canada
• Acceptable risk management plan format
• General considerations
• Submission
• Use of foreign reviews
• Cover letter and note to reviewer
• How to prepare a Canadian-specific addendum
• RMP summaries
• Risk management plan updates
• Review of risk management plans
• Compliance and implementation
• Contact information for submitting an RMP or related documents
• Status requests
• Record-keeping requirements

When to file a risk management plan with Health Canada

As required by the Food and Drug Regulations, sponsors/MAHs must submit RMPs to Health Canada if:

• there is a significant degree of uncertainty respecting the risks associated with the drug or
• 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

A sponsor/MAH must submit an RMP:

• as part of a new drug submission (NDS), abbreviated new drug submission (ANDS), extraordinary use new drug submission (EUNDS) or abbreviated extraordinary use new drug submission (AEUNDS) when required or upon request from Health Canada
• upon request from Health Canada following the submission of an application seeking a drug identification number (DIN)
• as part of a supplemental new drug submission (SNDS) when a new RMP or an RMP update is required to assess the safety and effectiveness of the drug in relation to the matters that are the subject of the SNDS
• when requested by Health Canada post-authorization
• when an update is required due to significant differences in risks or uncertainties, or to the measures the sponsor/MAH intends to take, as described in the existing plan

Here are some further explanations and some examples of when to file an RMP with Health Canada.

As part of a drug submission or application

Examples of when to file an RMP with Health Canada include:

• new drug submissions that include new active substances (NAS)
• generic and biosimilar drugs whose reference product has an RMP with additional measures
• drug products where one of the components of a drug-drug kit has a separate DIN with an RMP that includes additional measures

Sponsors/MAHs must also include an RMP in a drug submission seeking issuance of a notice of compliance (NOC) for drugs with the designation "extraordinary use".

The RMP assists the Minister in assessing the safety and effectiveness of the drug as part of drug submissions.

Health Canada may also require, in writing, an RMP following the submission of an application for a DIN where:

• there is a significant degree of uncertainty respecting the risks associated with the drug or
• 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

Health Canada may consider that there is a significant degree of uncertainty respecting the risks associated with the drug when:

• there are significant outstanding uncertainties regarding the safety and effectiveness of the drug that cannot be resolved based on the data reviewed to grant market authorization of the product
• For example, this could be in the form of missing information for particular populations, or for anticipated uses, such as long-term use or specific populations, not studied prior to the drug submission application. There may also be missing information related to the use of a drug product, such as in situations where the clinical trials supporting the market authorization included a small number of patients.
• Missing information (such as, exclusion of a population from clinical studies) does not always constitute a safety concern. A scientific rationale is needed to determine whether exclusion of that population is missing information for the purposes of an RMP.
• the anticipated use of the drug includes settings that differ from clinical trials, such as in a larger population when there are concerns about its use in those larger settings or the drug is expected to be highly used in a population with additional risk factors compared to the studied population.
• An RMP may be required to identify and further characterize the uncertainties to prevent or mitigate risks associated with such uncertainties.
• the significance of uncertainty may vary between drug categories
• For example, vaccines are given to large, generally healthy populations, where benefit-risk calculation may differ from that of some therapeutic drugs. For that reason, RMPs may be requested for some vaccines that do not contain new active substances.
• risks have either been identified or there are potential risks associated with the drug, but more information is required to characterize those risks and their impact on the safety and effectiveness of the drug
• Examples of risks or uncertainties that may not be fully characterized could include the potential for off-label use, long-term use or use in patients with comorbidities. An RMP may be required due to the uncertainty surrounding these risks to further study, characterize and manage the risks.
• a product produced by innovative technologies may merit greater scrutiny than one that is made using established, well-characterized ones
• Examples could include certain gene therapies or cell therapies.

Health Canada may consider that 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 when:

• the risk would not only be serious, but may have an impact on the balance of benefits and risks of the product
• An RMP may be required when a serious risk has already been identified and characterized and where additional measures or interventions may need to be either considered, or required, to prevent or minimize the risk.
• An RMP may also be required to provide an assessment and evaluation of the effectiveness of any additional measures or interventions proposed.
• Examples could include relevant risks identified from reports of adverse reactions in clinical trials, epidemiological studies and so on, including issues emerging from post-market use (for example, off-label use, medication errors).
• the drug is a member of a class of drugs with known safety concerns and uncertainties for which additional measures may already be in place
• Additional risk minimization measures could include physician or patient educational materials, restricted access and so on.
• An example could include products known to present opioid-related harms.

For a discussion of "serious risk", refer to annex A of the Amendments to the Food and Drugs Act: Guide to new authorities.

If sponsors/MAHs have questions about whether they are required to submit an RMP to Health Canada, we encourage them to begin communicating early with the Regulatory Project Management Office of the Marketed Health Products Directorate. They should do this well in advance of their application or the submission process.

Generic and biosimilar drugs

An example of when to file an RMP with Health Canada is a generic or biosimilar drug whose reference product has an RMP with additional measures, such as:

• certain types of designated laboratory tests
• restricted distribution programs
• distribution of educational materials, patient alert cards
• post-market safety studies
• registries

Sponsors of a generic or biosimilar drug should consider the risk profile in comparison to the reference product and consider additional measures, such as risk minimization measures and pharmacovigilance measures, accordingly. Health Canada may also require an RMP for generic or biosimilar drugs when there are unique safety issues associated with the generic or biosimilar drug.

Sponsors/MAHs of generic and biosimilar drugs are encouraged to review posted RMP summaries of the reference product, when available, to determine whether the innovator product has additional measures in advance of the submission process. If a posted RMP summary is not available, sponsors/MAHs of generic and biosimilar drugs should refer to the Drug Product Database or the Canadian Product Monograph to identify if additional measures have been implemented for the reference product.

If sponsors/MAHs have questions regarding the need for additional measures, we encourage them to contact the Regulatory Project Management Office at the Marketed Health Products Directorate (MHPD).

The sponsor/MAH, as part of their RMP, would be expected to consider the need of similar additional measures for their product, and describe those measures as appropriate. If the additional measures in the generic or biosimilar RMP differ from the reference product RMP, the sponsor/MAH should provide a rationale.

Not as part of a drug submission or application

Health Canada may also require an RMP not linked to a drug submission or application when no RMP has been submitted to Health Canada in the past.

The decision to exercise this requirement would be made on a product-by-product basis, depending on information available at the time. Such a request may be part of an ongoing review to support informed regulatory decision making about the drug, including to assess its safety and effectiveness.

Health Canada may request an RMP for drugs that have already been assigned a DIN, when the Minister has reasonable grounds to believe that there is a significant degree of uncertainty respecting the risks associated with the drug.

• A drug associated with actions subsequent to authorization, such as cancellation of a DIN, discontinuation of sale, suspension of an NOC or stop sale, may also be subject to a request for an RMP either at the point of market re-entry or subsequently, especially if the action was associated with a serious safety issue or significant uncertainty.
• An RMP may be required when an emerging serious safety issue of significant potential risk is confirmed from a signal that requires further characterization to identify how the risk will impact the safety and effectiveness of the drug
• For example, a major new safety concern found in a product from the same class.

Health Canada may also request an RMP for drugs that have already been assigned a DIN, when the Minister has reasonable grounds to believe that 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.

• An RMP may be required when an emergent serious risk has been identified and where additional measures or interventions may be required to prevent or minimize the risk. This could occur when a serious safety signal or a significant change, in what is known about the risks of the drug, is identified through an Annual Summary Report, Periodic Safety Update Report (PSUR) or Periodic Benefit-Risk Evaluation Report (PBRER) or report of a foreign regulatory action.

The time frame for RMP submissions that are not part of a drug submission or drug application would be established by Health Canada after discussion with the sponsor/MAH. In general, a 30-day timeline is sufficient for most RMP requests. If the sponsor/MAH fails to provide the RMP within the time specified and an extension has not been provided or the request has not been withdrawn, the sponsor/MAH must not sell the drug until an RMP compliant with section C.01.700 of the Food and Drug Regulations has been provided.

Updates on what is meant by "significantly different"

Sponsors/MAHs are required to submit an update to the RMP for a drug for which a DIN has been assigned, if the currently known risks associated with the drug, or uncertainties relating to those risks, are significantly different from those that are described in the existing plan.

When the risks and uncertainties are significantly different, the existing RMP may no longer be sufficient to meet its purpose of identifying, characterizing, preventing or minimizing the risks or addressing uncertainties of the drug.

Examples of risks and uncertainties being significantly different include:

• a new or heightened risk or uncertainty
• a new or expanded target population, for example as a result of a new indication
• increased potential for medication error or accidental exposure

Examples of how these may be identified include:

• an annual summary report under section C.01.018 of the Food and Drug Regulations
• an assessment ordered under section 21.31 of the Food and Drugs Act
• an issue-related summary report under section C.01.019 of the Food and Drug Regulations
• a foreign regulatory action (for example, reported under section C.01.050 of the Food and Drug Regulations)

An RMP update is also required when the measures that the sponsor/MAH intends to take to address and monitor the uncertainties relating to the drug's risks or to prevent or reduce those risks are significantly different than those that are described in the existing plan, including:

• new additional measures
• the removal of additional measures
• the significant alteration of additional measures
• changes to the evaluation of the effectiveness of the additional measures in Canada

You can find more information on risk management plan updates further on this page, including examples of a significant difference.

The following changes are not considered significant:

• changes made to an RMP in a foreign jurisdiction relate to an indication not authorized in Canada
• changes that do not relate to the conditions of use outlined in the Canadian product monograph, or the risks, uncertainties or additional measures described in the existing RMP submitted to Health Canada

However, if the changes made to an RMP in a foreign jurisdiction relate to the safety specification or the additional measures that are applicable to Canada or previously included in the RMP submitted to Health Canada, the sponsor/MAH must assess:

• whether the detailed description of the risks in the RMP is still sufficient
• if the pharmacovigilance plan is still sufficient to address and monitor the uncertainties related to risks associated with the drug
• if the risk management plan is still sufficient to prevent or reduce the risks associated with the drug

An updated RMP must be provided if the results of the assessment show a significant difference to the safety specification or the additional measures.

If sponsors/MAHs have questions regarding whether there is a significant difference in information, or whether they are required to submit an updated RMP to Health Canada, we encourage them to contact the Regulatory Project Management Office at MHPD.

Health Canada may require an updated RMP from the sponsor/MAH when the Minister has reasonable grounds to believe that

• the risks associated with the drug, or the uncertainties relating to those risks, are significantly different than those that are described in the existing plan
• the drug presents a serious risk of injury to human health that warrants measures to reduce the probability or severity of such an injury that are significantly different than those described in the existing plan

Examples of measures to reduce the probability or severity of a serious injury can include:

• controlled distribution programs
• educational tools or materials
• risk communications
• prescriber checklists
• patient wallet cards
• pregnancy prevention programs
• patient testing and monitoring

Generally, such updates to an RMP would be required by the Minister when the existing RMP is no longer sufficient to identify, characterize, prevent or minimize the risks or address uncertainties of the drug, or to assess the safety and effectiveness of the drug.

Supplemental New Drug Submission

When submitting a supplemental new drug submission (SNDS) or a supplemental abbreviated new drug submission (SANDS), an RMP or an RMP update may be needed to assess the safety or effectiveness of the drug when the risks or uncertainties are significantly different from those contained in the new drug submission or abbreviated new drug submission.

For example, an RMP or an RMP update may be requested, in writing, when an SNDS (or SANDS) is submitted for any of the following matters:

• the labels used in connection with the new drug
• the packages of the new drug
• the representations made with regard to the new drug respecting
• the recommended route of administration of the new drug
• the dosage of the new drug
• the claims made for the new drug, including changes in indication
• the contra-indications and side effects of the new drug
• the withdrawal period of the new drug
• the dosage form in which it is proposed that the new drug be sold

Some examples for an SNDS (or SANDS) when an RMP or RMP update may be required include:

• there is a change in indication or the extension of an existing indication to a vulnerable population
• there are new conditions of use (for example, from administration by a health care professional to self-administration in the home setting, or vice-versa)

For requests made following an SNDS (or SANDS) to assess the safety and effectiveness of the drug in relation to the matters that are the subject of the SNDS (or SANDS), the applicable timelines apply.

Acceptable risk management plan format

All RMPs submitted to Health Canada must meet the requirements established in section C.01.700 of the Food and Drug Regulations. Health Canada will determine if the RMP submitted is a compliant RMP under the Regulations.

To meet the requirements of the Food and Drug Regulations, a compliant RMP must take into account the Canadian context and must include the following:

• product overview
• a description of the drug and what it is used for
• safety specification
• a detailed description of the risks and uncertainties of the drug (important identified risks, important potential risks and missing information)
• pharmacovigilance plan
• a detailed description of the measures the sponsor/MAH intends to take to address and monitor the uncertainties (routine pharmacovigilance measures and additional pharmacovigilance measures)
• risk minimization measures
• a detailed description of the measures that the sponsor/MAH intends to take to prevent or reduce the risks (routine risk minimization measures and additional risk minimization measures)
• evaluation of the effectiveness of risk minimization measures
• a detailed description of how the sponsor/MAH intends to evaluate the effectiveness of the measures that the sponsor/MAH intends to take to prevent or reduce the risks
• summary of the RMP
• a summary of the plan's contents, in English and in French

Health Canada will accept RMPs in the following acceptable formats to meet the requirements of a compliant RMP:

• the EU format
• other formats if they include all the required elements outlined above

A compliant RMP must take into account the Canadian context. Where warranted, sponsors/MAHs must include a Canadian-specific addendum containing information specific to the Canadian context, unless the sponsor/MAH has prepared the RMP specifically for Canada and has taken into account the Canadian context throughout the Canadian RMP.

General considerations

An RMP reflects safety data that is both clinical and non-clinical. It should be updated throughout the drug's life cycle as discussed and agreed upon with Health Canada and the sponsors/MAHs. When submitting RMPs, Health Canada encourages sponsors/MAHs to:

• submit one RMP per brand name product (not per indication)
• submit the most recent version of the RMP available
• notify Health Canada if a revised RMP becomes available later during the regulatory review process
• provide a foreign RMP review and an attestation form (if available)
• include available post-market data if marketed in Canada or elsewhere
• For example, if there is a submission in Canada for a drug that is already marketed elsewhere (for example, Europe), there will be value in including the market experience of that drug in the RMP.
• examine the potential for new or heightened safety concerns for combination drugs relative to the individual products
• provide a rationale, supported by scientific evidence, for the change, addition or removal of any safety concern, additional pharmacovigilance measure or additional risk minimization measures from the previous RMP version submitted to Health Canada
• If referencing changes that have been implemented or planned in another jurisdiction/country, provide the evidence to support such a change and an evaluation of any relevant Canadian data that supports a similar change in Canada.
• submit both clean and track change versions of the RMP and addendum to the RMP (if revised) and clearly outline the major changes made since the last version was submitted to Health Canada
• provide a rationale in situations where additional pharmacovigilance measures (for example, a drug utilization study, registry) or risk minimization measures (for example, contraindication, restricted distribution, educational material) are proposed or implemented in major jurisdictions (for example, Europe or the U.S.) but not in Canada
• This information can be included in an appendix to the RMP or Canadian addendum.
• reference the most recent version of the Canadian product monograph
• refer to EMA's Guidance on the format of the risk management plan (RMP) in the EU - in integrated format

For more information on submission requirements, refer to:

• Guidance document: The management of drug submissions and applications (new drug submissions including NDS, SNDS, ANDS and SANDS, and DIN applications)
• information and submission requirements for biosimilar biologic drugs (biosimilars)

Sponsors/MAHs should have an adequate system in place to manage RMPs. An adequate system should:

• adapt to scientific and technical progress throughout the lifetime of the drug
• include proper documentation of all measures taken
• ensure that all persons involved in the procedures and processes of the quality systems be appropriately qualified and trained
• include in any subcontracts a description of the process in place to ensure third parties are in compliance with the subcontracted pharmacovigilance measures

For more information on adequacy of a pharmacovigilance system refer to:

• Good pharmacovigilance practices (GVP) guidelines (GUI-0102)

Submission

There are currently 2 acceptable filing formats for RMPs or related documents:

• Electronic Common Technical Document (eCTD) format
• Non-eCTD Electronic-Only format

For submissions in the eCTD format, refer to:

• Guidance document: Preparation of drug regulatory activities in the Electronic Common Technical Document format

For submissions in Non-eCTD Electronic-Only format, refer to the structure template recommended in:

• Guidance document: Preparation of regulatory activities in the "Non-eCTD Electronic-Only" format

For general procedures on how to file submissions, refer to:

• Guidance document: Management of drug submissions and applications

Use of foreign reviews

Sponsors/MAHs should provide reviews from regulatory authorities in the U.S. (FDA) and from the EU's centralized procedure (EMA) if they are available at the time of initial submission of the data package. For RMPs attached to a submission, if the foreign RMP review is not available at the time of initial submission but becomes available later during the regulatory review period, sponsors/MAHs can submit it as "unsolicited information."

Health Canada may also consider reviews from other foreign regulatory authorities.

In situations where more than 1 foreign review is available, submit all that are available.

For more information on the use of foreign reviews, refer to:

• Draft guidance document: The use of foreign reviews by Health Canada

Cover letter and note to reviewer

A cover letter and a note to reviewer should accompany all RMPs, updates and other related documents to reviewers. If the RMP is included with a submission, the cover letter should reference the RMP.

The cover letter should indicate:

• the submission type, for example, RMP update
• information requested by Health Canada, if any
• whether the submission relates to an existing RMP

The note to reviewer can refer to:

• if an RMP update, a clear outline of the changes that have been made subsequent to the previous submission
• scientific information related to the reason for submission
• unsolicited information, which can include:
• new safety concerns identified by the sponsor/MAH
• proposed changes to existing risk minimization or pharmacovigilance measures
• other (please specify)

For more information on the cover letter and the note to reviewer, refer to:

• Guidance document: Preparation of drug regulatory activities in the Electronic Common Technical Document format

How to prepare a Canadian-specific addendum

A Canadian-specific addendum is not required if the RMP has been prepared specifically for Canada, using an acceptable RMP format, and has taken into account the Canadian context throughout the Canadian RMP.

Sponsors/MAHs must include any Canadian-specific considerations, as well as a detailed description of how the information and measures apply to Canada, in the RMP or in a Canadian-specific addendum.

Examples of special considerations for the Canadian context and related to medical practice or populations in Canada when submitting an RMP or related documents include:

• information related to Canadian patient exposure
• genetic or extrinsic factors that are specific to the Canadian population
• the epidemiology of the medical condition(s) or risk factors that reflect the authorized indication(s) in Canada
• for example, Canadian epidemiology data such as incidence rate and prevalence in Canada for the proposed indicated population
• post-authorization experience in Canada and worldwide
• for example, if a drug has been marketed outside of Canada for a period of time, there would be knowledge about emerging risks not identified in clinical trials (sponsors/MAHs should submit a summary of this information to Health Canada)
• important public health issues specific to Canada and specific measures needed to address, monitor, reduce or prevent them
• for example, opioid-related harms

The Canadian-specific addendum should also include:

• RMP submission history in Canada
• safety issues specific to Canada
• pharmacovigilance measures in the Canadian context/setting
• this could involve monitoring Canadian adverse events from sponsor/MAH's database and reconciliation of such event(s) with adverse reactions in Health Canada's Canada Vigilance Database
• risk minimization measures and evaluation of their effectiveness in the Canadian context/setting
• appropriate milestones and timelines for reporting on additional pharmacovigilance and risk minimization measures that are applicable to Canada

Find more information on preparing a Canadian-specific addendum.

RMP summaries

Sponsors/MAHs must submit an RMP summary as part of their submission, including for RMP updates, as part of the requirements under section C.01.700. The summary should be written in plain language, and must be submitted in both English and French. The plain language should be clear and concise and should be accessible for a wide audience, including:

• industry
• academia
• health professionals
• interested members of the public
• health technology assessment bodies
• patient safety and other stakeholder associations
• government agencies or departments and regulatory licencing bodies

The format of the RMP summary should mirror the EU RMP summary format and include all the following essential elements:

• an overview of the drug and what it is used for
• a summary of the risks and how they are managed
• a summary of any missing safety information to be collected
• any additional measures, including:
• additional risk minimization measures
• additional pharmacovigilance measures
• a list of planned studies to provide more information on the safety of the drug

The RMP summary must include Canadian-specific considerations and reflect and summarize the content of the Core RMP. The Canadian-specific considerations can either be included:

• throughout the summary
• in a Canadian-specific section included within the RMP summary

Health Canada will consider the RMP summary as part of the overall RMP review. The sponsor/MAH is expected to incorporate proposed changes to the RMP into the RMP summary during the course of the review.

To support transparency and to increase access to information on drugs, Health Canada intends on publishing RMP summaries, in both official languages, in a publicly accessible web location and format. As such, it is the sponsor/MAH's responsibility to verify that the RMP summary contains no confidential business information that they do not want made public.

Find more information on preparing an RMP summary.

Risk management plan updates

An RMP update is required when:

• requested by Health Canada when, on the basis of new information obtained after the existing plan was provided to the Minister, the Minister has reasonable grounds to believe that:
• the risks associated with the drug, or the uncertainties relating to those risks, are significantly different than those that are described in the existing plan
• the drug presents a serious risk of injury to human health that warrants measures to reduce the probability or severity of such an injury that are significantly different than those described in the existing plan
• the MAH concludes that what is known about the risks or uncertainties associated with the drug is significantly different than when the drug was authorized or when the existing plan was submitted:
• the risk management measures are modified after the sponsor/MAH learns about new information that may lead to a significant difference in the risks or uncertainties of a drug in the Canadian context, for example:
• identification of serious safety concerns which require additional pharmacovigilance measures or changes to the risk minimization measures
• significant changes to the Safety Specification section due to the addition of new evidence (quantitative or qualitative) related to risks or uncertainties concerning opioid-related harms or other risks and uncertainties generated through risk-monitoring/characterizing activities conducted in Canada or internationally to investigate the drug
• the final study results confirm a safety risk that requires changes to various parts of the RMP
• the summary of safety concerns changes, including when another regulator such as the EMA has approved the addition, removal or reclassification of safety concerns
• the measures that the MAH intends to take are significantly different than the existing RMP, previously submitted to Health Canada, including:
• an additional pharmacovigilance or risk minimization measure is ceased, added or substantially altered
• any changes to the objectives, population or due date of final results for any of the studies listed in the RMP

The sponsor/MAH must provide the RMP update as soon as feasible, or if the update has been requested by Health Canada, within the time specified in the request.

If the sponsor/MAH fails to provide an updated RMP when requested by Health Canada, within the time specified, and an extension has not been provided or the request has not been withdrawn, the sponsor/MAH must not sell the drug until a compliant updated RMP has been provided.

Sponsors/MAHs of generic and biosimilar drugs are encouraged to review posted RMP summaries of the reference product, when available, to determine whether the reference product has made significant updates to their RMP. An updated generic or biosimilar product RMP may be required, as appropriate.

Each RMP update should have a distinct version number and date. When sponsors/MAHs revise any part of the RMP:

• a new RMP version number should be assigned each time
• the revision date should be reflected as the "last revised" date, which is when the RMP is considered final

Review of risk management plans

Review bureaus at the MHPD conduct the review of RMPs, updates and other related document. Review bureaus include the:

• Bureau of Biologics, Radiopharmaceuticals and Self-Care Products (BBRS)
• Marketed Pharmaceuticals Bureau (MPB)
• Office of Policy, Risk Advisory and Advertising (OPRAA)

The RMP review time may vary from product to product. If the RMP is part of a submission, the applicable timelines for those submissions apply.

Pre-submission meetings for RMPs that are intended to be part of a drug submission

Sponsors wishing to file a submission with Health Canada are encouraged to determine whether an RMP is required. If needed, sponsors can also request a pre-submission meeting to discuss all aspects of their submission including RMPs.

When an RMP is required, or if requested by Health Canada prior to submission, the RMP must be included with the submission package in accordance with the relevant submission requirements.

Sponsors should:

• refer to the Guidance document: Management of drug submissions and applications for instructions on how to request pre-submission meetings
• request their pre-submission meeting, if needed, and indicate in the request that the sponsor will have discussion points related to the RMP, if applicable

During a pre-submission meeting, MHPD representatives will aim to provide appropriate guidance on the content and format of the RMP, based on the information provided in the meeting package. Sponsors may include a draft RMP in the data package for a pre-submission meeting. Alternatively, sponsors may provide an outline of the RMP or any potential questions related to the RMP.

Correspondence, screening and review of RMPs that are part of a drug submission

Regulatory correspondence for RMPs attached to a submission should include reference to the control number.

Health Canada will screen the submission. If the sponsor/MAH does not provide an RMP for a product where one is required, Health Canada will request one.

After Health Canada considers the submission acceptable to enter review, the RMP will be forwarded to the MHPD. The MHPD conducts the RMP review in parallel with the review of other submission components by the pre-market bureaus.

Health Canada may communicate with the sponsor to clarify RMP-related issues during the review. Health Canada may also share with the sponsor:

• comments stemming from the RMP review
• the RMP review report, upon request

Review of RMPs not included in a submission

This process describes how Health Canada manages RMPs not included in a submission.

Health Canada may send a letter to the sponsor/MAH at any time, requiring an RMP or an update to an existing RMP.

Examples of RMPs submitted to Health Canada outside of a drug submission can include:

• an RMP update for a Canadian marketed drug for which a new emerging or serious post-market safety issue is identified
• an RMP for a Canadian marketed drug for which there are significant uncertainties relating to the risks associated with the product
• an RMP update for a Canadian marketed drug for which a new serious safety risk is identified for a similar product in the class
• an RMP update when measures included in the existing RMP are no longer sufficient to identify, characterize, prevent or minimize risks or address uncertainties of that drug

The MHPD may communicate with the sponsor/MAH to clarify RMP-related issues during the review. Sponsor/MAHs should send responses to these clarification requests to the attention of the MHPD. The MHPD will communicate with the sponsor/MAH on the compliance of the document or on deficiencies identified by the MHPD.

If the MHPD has identified deficiencies in the RMP, it sends a feedback letter to the sponsor/MAH including the timelines for response. The timeline to respond should be between 15 to 30 calendar days. These are guidelines and can be adjusted due to the nature of the request.

Health Canada will share the RMP review report with the sponsor/MAH upon request.

Compliance and implementation

Health Canada will communicate with the sponsor/MAH to confirm the compliance of the RMP following review. For an RMP to be compliant, it must meet the requirements of section C.01.700 of the Food and Drug Regulations.

As part of the review, Health Canada will evaluate the RMP based on the requirements in the Food and Drug Regulations, and will make a determination on compliance based on the:

• sufficient reflection of the Canadian context within the RMP
• accuracy of the description of the drug compared to the information already known to the Minister
• risks and uncertainties being described in sufficient detail
• the measures that the manufacturer intends to take being sufficient to address and monitor the uncertainties related to the risks associated with the drug and to prevent or reduce the risks associated with the drug
• pharmacovigilance plan and the risk minimization measures being described in sufficient detail
• plan to evaluate the effectiveness of the measures to prevent or reduce the risks being described in sufficient detail and being sufficient to evaluate those measures
• accuracy of the summary in reflecting and summarizing the content of the RMP, in English and in French

The compliance of the RMP will also take into consideration whether the plan, including the proposed measures are feasible and reasonable.

When an RMP is required as part of a submission, Health Canada will consider the RMP in making its decision regarding the issuance of the market authorization. As such, if the RMP is non-compliant with the regulations or deficient, this has an impact on the authorization decision.

Sponsors/MAHs are expected to implement and perform the pharmacovigilance and risk minimization measures in accordance with the descriptions and timelines detailed in the compliant RMP. They are also expected to implement and perform any agreed-upon measures detailed in subsequent compliant RMP updates.

Health Canada may request follow-up actions from the sponsor/MAH, as needed.

Health Canada may impose Terms and Conditions on a product's DIN in relation to an element or measure related to, or within, the RMP. Namely, terms and conditions may be imposed where they are necessary to ensure the management of risks and resolution of uncertainties. Examples could include:

• the required implementation of a specific pharmacovigilance or risk minimization measure
• a requirement to submit significant milestones outlined as reportable outcomes regarding a pharmacovigilance or risk minimization measure

For more information on Terms and Conditions, refer to:

• Draft guidance document on terms and conditions (T&Cs) for human and veterinary drugs

Contact information for submitting an RMP or other related documents

Sponsors/MAHs should submit RMPs or other related documents to the Office of Submissions and Intellectual Property (OSIP) via the Common Electronic Submissions Gateway (CESG) using the regulatory enrolment process (REP).

For transactions in e-CTD format, please consult the following guidance documents:

• Preparation of regulatory activities in the eCTD format
• The regulatory enrolment process (REP): Drugs for human/veterinary use and disinfectants

For transactions in non-eCTD format, please consult the following guidance documents:

• Preparation of regulatory activities in the Non-eCTD format
• The regulatory enrolment process (REP): Drugs for human/veterinary use and disinfectants

Status requests

In an effort to streamline administrative processes and expedite drug submission reviews:

• senior regulatory affairs officers are assigned to each submission in BRDD
• regulatory project managers are assigned to each review bureau in PDD, NNHPD and MHPD

The regulatory project managers and officers will serve as the primary points of contact between the review bureaus and the sponsor/MAH.

Sponsors/MAHs with questions regarding the RMP component of their submissions should contact the regulatory project manager in MHPD.

Record-keeping requirements

Sponsors/MAHs should retain a copy of the compliant RMP and maintain records of the decisions they made in the creation of the plan, together with the information relied on in making those decisions.

All decisions relating to creating or updating the RMP should be documented, including the decisions made relating to:

• the submission of an updated RMP
• the feasibility of the measures outlined in the RMP
• any modifications made to the RMP (for RMP updates)

Examples of information that the sponsor/MAH may rely on when making decisions could include:

• documentation of measures described in the RMP, such as:
• process approvals
• operating procedures
• information supporting a change to the measures outlined in the RMP
• data supporting the effectiveness of the measures outlined in the RMP
• information supporting a significant difference to risks and uncertainties
• evidence used to support the creation of initial and subsequent versions of RMPs

The RMP outlines the measures that the sponsor/MAH intends to take, as well as the manner in which they intend to evaluate the effectiveness of those measures. As such the sponsor/MAH should also maintain the following:

• documentation supporting the implementation and operation of the RMP
• effectiveness of the measures outlined in the RMP
• materials that support additional pharmacovigilance or risk minimization measures, including implementation of such measures, such as:
• protocols
• brochures
• educational materials
• follow-up questionnaires
• contractual agreements
• interim and final reports
• evidence of completion of the activity

Where other regulatory requirements for document retention do not apply, Health Canada recommends the sponsor/MAH retain the RMP and the records for at least:

• 5 years following the submission of an updated RMP or
• 5 years following discontinuation of the drug in Canada, if an updated RMP has not been submitted

The sponsor/MAH is also responsible for preserving data integrity. Based on how documents are preserved, the sponsor/MAH should consider having processes to:

• restrict file access to relevant personnel
• validate computerized systems and audit trails
• make periodic backups for electronic documents
• ensure documents are preserved in disaster situations

For more information on record-keeping best practices, sponsors/MAHs are encouraged to review the following:

• EMA GVP Module V (section V.B.12)
• Good pharmacovigilance practices (GVP) guidelines (GUI-0102)