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Risk management plans for prescription medicines

4 October 2012

A Risk Management Plan (RMP) is a set of pharmacovigilance activities and interventions designed to identify, characterise and manage risks relating to a medicine. It consists of:

The TGA requires sponsors of selected prescription medicine products to submit a RMP. The requirement to submit a RMP is outlined in Module 1.13 of the Common Technical Document. The TGA has adopted relevant sections of the Guideline and the requirements are outlined in EU Guideline Volume 9A - Guidelines on Pharmacovigilance for Medicinal Products for Human Use - of the Rules Governing Medicinal Products in the European Union (September, 2008).

The RMP covers the entire life cycle of the product. Therefore, the RMP will need to be periodically updated to reflect new knowledge and understanding of the safety profile of the product.

Risk management plan (RMP) questions & answers

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Version 1.3, October 2012

Version history

Version Description of change Author Effective date
V1.0 Original publication Risk Management Plans Section/Office of Product Review 03/09/2012
V1.1 Updated template Risk Management Plans Section/Office of Product Review 05/09/2012
V1.2 Updated content Risk Management Plans Section/Office of Product Review 14/09/2012
V1.3 Updated content Risk Management Plans Section/Office of Product Review 03/10/2012

Purpose

On 1 April 2009, the Therapeutic Goods Administration (TGA) introduced an initiative in which sponsors of prescription medicine products may be required to submit a Risk Management Plan (RMP). This document has been prepared to provide the prescription medicine industry with information and guidance on this initiative.

Overview of risk management plans (RMPs)

Why have RMPs been introduced?

It is recognised that not all safety issues related to a medicine will be identified during pre-marketing trials. This can occur with new chemical entities, biological products and where a sponsor applies for use in a new population, such as in children. A Risk Management Plan (RMP) identifies how safety concerns will be identified and mitigated.

Risk management plan

What is a RMP?

A Risk Management Plan (RMP) is a set of pharmacovigilance activities and interventions designed to identify, characterise and manage risks relating to a medicine. It consists of:

The RMP covers the entire life cycle of the product. Therefore the RMP will need to be periodically updated to reflect new knowledge and understanding of the safety profile of the product.

The TGA has formally adopted the European Union (EU) guideline Volume 9A - Guidelines on Pharmacovigilance for Medicinal Products for Human Use - of The Rules Governing Medicinal Products in the European Union.

The TGA requires sponsors of selected prescription medicine products to submit a RMP. The requirement is outlined in Module 1.13 of the Common Technical Document. Please note that all sponsors must comply with the requirements set out in the Australian Guideline for Pharmacovigilance Responsibilities of Sponsors of Medicines.

Risk management plan requirements in Australia

When is a RMP required?

A Risk Managmement Plan (RMP) may be submitted at any time of a product's life-cycle, that is: during both the pre-authorisation and post-authorisation phases.

The TGA can request a RMP be submitted for products which are already approved and on the Australian Register of Therapeutic Goods (ARTG) when a safety issue arises.

A RMP should be submitted:

In some circumstances, products not in the above categories may require a RMP, for example:

Sponsors are encouraged to review the European Union (EU) guideline Volume 9A - Guidelines on Pharmacovigilance for Medicinal Products for Human Use - of The Rules Governing Medicinal Products in the European Union, which outlines when a RMP is required

Sponsors should consult with the TGA on any questions they may have about their responsibilities relating to these criteria.

Please note that when an existing European Union (EU) RMP is available, the TGA strongly recommends submission of the EU-RMP with an Australian Specific Annex (ASA, see Section 5).

How should the intention to submit a RMP be identified in the streamlined submission process?

As part of the streamlined submission process, a sponsor will be required to indicate whether they will be submitting a RMP. If after reviewing the guidelines, sponsors remain uncertain whether a RMP is required, it is recommended this be discussed with the TGA at least two months prior to submission. Contact details are provided at the end of this document. When it is not mandatory to submit a RMP and the sponsor thinks it is unnecessary, the sponsor should submit a brief justification.

The intention to submit a RMP must be indicated accurately in the Pre-submission Planning Form (PPF) by completion of the information relating to CTD Section 1.13. If it is indicated that a RMP will be submitted in the PPF, a RMP will be expected by the TGA. Further information on the streamlined submission process and requirements for completion of the PPF is available from the TGA website.

If a RMP will not be submitted, either a copy of a RMP waiver must be attached to the PPF or a justification, specifically addressing the requirements, provided as to why a RMP is not required. If the justification for not requiring a RMP is deemed to be inadequate, then a RMP will be required for the submission to be accepted for evaluation.

What is a RMP waiver and when can a sponsor consider this as an option?

A RMP waiver is issued by the TGA in response to a request from a sponsor when a RMP is not mandatory. The waiver documents the TGA's agreement that, in a particular situation determined on a case by case basis, submission of a RMP is not required. If considering a request for a RMP waiver, sponsors are strongly encouraged to apply two months prior to submission in order to allow time to develop a RMP if a waiver is not granted. The waiver application is submitted to the RMP coordinator (see contact details at the end of this document) and must include a scientific justification that clearly outlines why a RMP is not required, including the safety specifications and current safety profile. A RMP waiver granted prior to the PPF does not preclude a requirement for a RMP after the evaluation of the application.

A RMP waiver does not exempt sponsors from routine pharmacovigilance practices and risk minimisation measures. The definition of routine pharmacovigilance practices (E2E) includes:

What medicines that are already on the Australian Register of Therapeutic Goods (ARTG) require a RMP?

The TGA may request a RMP for medicines that are already on the ARTG if a safety concern is identified. This will be done on a case by case basis. The TGA will notify the sponsor in writing and provide a reason for requesting a RMP.

Do generic medicines require a RMP?

A RMP is required for any generic product where the reference product has a RMP and a safety concern requiring additional risk minimisation activities has been identified with the reference medicinal product.

In practice this means a RMP will be required if:

  1. There is a RMP for the reference product and a safety concern has been identified for which additional risk minimisation activities are being conducted; or
  2. There is no RMP for the reference product, but there are ongoing safety concerns with the reference product which have required specific risk minimisation activities prior to the introduction of the requirements for a RMP. Examples of these are thalidomide, leflunomide, clozapine, lenalidomide, isotretinoin and zoledronic acid.

A sponsor should initially check whether the reference product has a RMP, which can be done by reviewing whether there is an Australian Public Assessment Report (AusPAR) for the product. If the sponsor still has questions regarding the need for a RMP they should contact the TGA. Contact details are provided at the end of this document.

Who is responsible for the RMP?

The sponsor is responsible for the RMP, which will include the following:

RMP format

The format should follow the guidelines adopted by the TGA based on those developed by the European Medicines Agency (EMA) Volume 9A - Guidelines on Pharmacovigilance for Medicinal Products for Human Use - of the Rules Governing Medicinal Products in the European Union, including the EU template for RMPs.

The TGA recommends that where an existing global or EU-RMP is submitted that an ASA (see Section 5) is included with the RMP. The ASA should identify any differences between the EU-RMP and the local implementation of risk management activities, for example: any differences between the risk minimisation activities undertaken as reflected in the content of the EU Summary of Product Characteristics (SmPC) and the proposed Australian Product Information (PI), and the reasons for the difference. This will allow the TGA to assess the appropriateness of the proposed RMP in the Australian environment.

On 1 July 2012, the EMA released new guidelines for RMP and these will replace with the Guideline on good pharmacovigilance practices: Module V - Risk management systems (EMA/838713/2011, June 2012). The TGA will accept the submission of a RMP in the new format described in this updated guideline, with the removal of Part IV of the RMP - Plans for post-authorisation efficacy studies. The old format RMPs will also be accepted during the transition period in the EU.

Sponsors should notify the TGA of their intention to submit an EU-RMP in this new format at the pre-submission stage and also in the PPF. In addition, sponsors should include a summary of any studies which have been excluded from the EU-RMP in the ASA. This summary should list the studies and may include aims, methodologies, limitations, practical applications of studies and specific timelines for planned activities (for example: estimated start, end and reporting dates for planned studies, communication program milestones. It is expected that the outcomes of post-authorisation efficacy studies will be communicated to the TGA particularly if there is a negative impact on the risk-benefit balance of the product. The TGA will formally evaluate the new EU guidelines and consult over the next 12-18 months.

What must be included in the RMP?

All requirements of the EU Guideline Volume 9A must be submitted. Particular attention should be paid to ensuring:

This is necessary to allow the TGA to assess the appropriateness and value of the planned activities.

What are examples of activities or interventions that may be included in a RMP?

There are a variety of activities that may be considered. One example of an additional pharmacovigilance activity may include an observational cohort study to further identify the occurrence of adverse events that were equivocal or not seen during pre-marketing trials. Although not detected during product development, they may be associated with the class of medicine and therefore represent a potential safety concern.

Examples of risk minimisation activities beyond routine may include communication programs, such as providing educational material to prescribers or performing routine tests. For instance, where a drug is suspected to be teratogenic, there may be a requirement to perform a pregnancy test prior to prescription and to ensure adequate contraception. Any additional risk minimisation activity needs to include a detailed outline of how the effectiveness of the activity to minimise the risk will be evaluated.

Is it possible that routine pharmacovigilance activities will be the only proposed pharmacovigilance activity?

Yes. After each safety issue has been appropriately identified and characterised, the sponsor must propose a plan on how they will manage this risk. In some cases the sponsor may propose that routine pharmacovigilance will be sufficient.

Is it possible that routine risk minimisation activities, as defined in Volume 9A, will be the only proposed risk minimisation activity?

Yes. After each safety issue has been appropriately identified and characterised, the sponsor must propose a plan on how they will manage this risk. In some cases the sponsor may propose that routine risk minimisation will be sufficient.

Can a RMP be considered a substitute for routine pharmacovigilance activities?

No. All sponsors are required to comply with the requirements set out in the Australian Guidelines for Pharmacovigilance Responsibilities of Sponsors of Medicines. Any interventions or activities proposed in the RMP may be additional to routine pharmacovigilance.

Australian Specific Annex (ASA) to the European Union Risk Management Plan (EU-RMP)

Purpose of the ASA

The ASA should provide Australian specific information that is important in assessing the 'risk' in Australia (and therefore appropriateness of proposed plans/activities), the relevance of pharmacovigilance and risk management activities in Australia, and identify and explain the reasons for any differences with activities planned overseas.

When is an ASA required?

An ASA is recommended in cases when an EU-RMP is submitted in Australia.

ASA content

Format of ASA to the EU-RMP

The ASA should be referenced as an annex in the EU-RMP - this can be after the last annex referred to in the EU-RMP.

A recommended format for the ASA is outlined below.

  1. Introduction
    1. Purpose of ASA for this RMP
    2. Background to product's registration history, for example: Orphan status, NCE, Line extension including dates and Australian Register of Therapeutic Goods (ARTG) number as appropriate
  2. Pharmacovigilance practice
    2.1 Routine pharmacovigilance systems in Australia
    2.2 Studies referenced in the RMP

    Describe involvement of Australia and applicability of global studies to the Australian environment, if not applicable or relevant to the Australian environment - include a justification.
  3. Risk minimisation plan
    1. Address how risk minimisation activities will be implemented and evaluated in Australia. If surveys or studies are referenced in the ASA, copies of outlines and protocols should be provided.
    2. Provide a justification if activities overseas are not to be implemented in Australia.
    3. Indicate how and when evaluation of risk minimisation activities, including educational activities, will be undertaken. Sponsors are responsible for showing that the measures they are using to mitigate risk are working and, if not, what actions they will take to ensure effectiveness.
  4. Contact person for RMP
    This should be the person in the sponsor company responsible for the implementation of the RMP activities within Australia, and will usually be the Australian pharmacovigilance contact person.

Evaluation of Risk Management Plans for registration of prescription medicines

Who is responsible for evaluating the RMP?

Evaluation of the Risk Management Plan (RMP) will be undertaken by the Office of Product Review (OPR) within the TGA. In some cases advice will be sought from the Advisory Committee on the Safety of Medicines (ACSOM).

In evaluating the RMP, consideration will be given to the following:

Once the evaluation process is complete, it is recommended to submit a final version of the Australian Specific Annex (ASA), confirming the risk management activities for monitoring purposes.

When will the TGA provide feedback on the evaluation of a RMP?

The process by which the RMP will be evaluated as a component of the application is according to the TGA's Business Process Reform (BPR). The TGA will issue questions on the RMP via the single round section 31 (s31) requests for information at Milestone 3. The RMP may be subject to review or consideration by the TGA's advisory committees.

RMP updates during the evaluation process

An updated RMP can be submitted along with the sponsors' response to the consolidated s31 queries. If an updated RMP is anticipated to be available during the evaluation process, it is requested that the sponsor identify this in the RMP documentation, for example: due date for next updated RMP, so this can be anticipated and planned for by the evaluator.

Any updates to the Product Information (PI) and/or Consumer Medicine Information (CMI) documents that occur during the evaluation process should be reflected in the next version of the ASA.

For changes that have no impact to the EU-RMP but impact the ASA, submission of an updated ASA is sufficient with a reference to the current EU-RMP version (for example: changes to Australian approved PI/CMI).

Will the evaluation of the RMP be included in the Australian Public Assessment Report (AusPAR)?

The AusPAR will contain a section titled Pharmacovigilance Findings, which will contain the following information:

How is the RMP referred to in the conditions of registration?

The version of the RMP and ASA reviewed will be included as a condition of registration. Also included in this condition may be sponsors' written agreements to OPR recommendations during the s31 process, which are not explicit in the RMP document, as well as any further requirements determined by the delegate. Advisory Committee on the Safety of Medicines (ACSOM), ACSOM's main role in Risk Management Plans (RMPs) is to provide advice to the TGA's Office of Product Review (OPR) on pharmacovigilance and risk management activities. ACSOM advice, if necessary, will be sought in the period between last month of round 1 evaluation (Milestone 3) and the sponsor response to questions (Milestone 4). This will allow the evaluator to combine the s31 responses and ACSOM advice into the final evaluation report - which is then made available to the delegate and the sponsor.

Risk Management Plans in the post-marketing period

What is the process for submitting RMP updates after regulatory approval?

Updates to Risk Management Plans (RMPs) should be provided as outlined in the relevant European Union (EU) guidelines Volume 9A. If there is still uncertainty about whether an update is required, the RMP coordinator can be emailed for advice.

An updated Australian Specific Annex (ASA), if available, should accompany any updated EU-RMPs when submitted and include a summary of all changes since the previous version. If no change or update to the ASA is required, then this should be identified at the start of the ASA by inclusion of a statement that all Australian specific information is unchanged. There is no requirement for the clinical delegate to be sent a copy of updated RMPs. The updated EU-RMP should be submitted to the RMP coordinator at the same time as the next Periodic Safety Update Report (PSUR) or when a new safety concern is identified at any stage of the product's life-cycle unless other requirements have been made as a registration condition.

An updated EU-RMP (or Australian RMP if no EU-RMP exists) should also be submitted:

All updated documents should be provided with a cover letter stating the reason and rationale behind the updated RMP, and key considerations or issues.

Where RMPs are not required but sent in by sponsors spontaneously (no RMP evaluated in Australia for that product), the sponsor is requested to summarise the reasons for an updated RMP being required in the EU and the change, if any, in the safety information.

Periodic Benefit-Risk Evaluation Reports (PBRERs), to be known in the EU as Periodic Safety Update Reports (PSURs)

The International Conference on Harmonisation of Technical Requirements for Registration of Pharamceuticals for Human Use (ICH) has recently drafted the ICH E2C (R2) guideline on Periodic Benefit-Risk Evaluation Report (PBRER). PBRERs are intended to replace Periodic Safety Update Reports (PSURs). In the EU, the report will continue to be named a PSUR. The consultation period for this guideline closed in May 2012. While this is still in draft, the TGA will accept the submission of both PBRERs and PSURs during the transition period. The TGA will formally evaluate the new EU guidelines for PBRERs and consult over the coming few months.

How should the effectiveness of risk minimisation activities be measured and who is responsible?

The sponsor is responsible for monitoring and evaluating the effectiveness of additional risk minimisation activities. The proposed risk minimisation activities should be dependent on an assessment of the risk, the population, and how the risk changes during the course of the post-market period.

What elements of a RMP are required when ad hoc safety issues are identified and the TGA requests a RMP?

An EU-RMP and ASA should be submitted.

If you have a registered product, but not marketed, do you need to update the RMP?

If you have a TGA approved RMP, regardless of marketing status, the RMP should be maintained and updated in accordance with relevant guidance.

Is a formal notification or Category 3 application required if the RMP is updated?

No, however, submission of a RMP update does not mean that other required processes, such as a Safety Related Notification, do not need to occur. That is, the updated RMP is not a replacement for normal mechanisms of informing the TGA about safety related issues and others.

All updated documents should be provided with a cover letter stating the reason and rationale behind the update, key considerations or issues, and a summary of changes.

If there are changes to safety information, for example: requested by the agency or based on changes to the Core Data Sheet or local safety update to the Product Information (PI), will the RMP need to be updated?

Yes, a RMP update is required for those products that have implementation of RMP as a condition of registration if the safety information affects the risk-benefit profile or prescribing practice of the product. The TGA can request a RMP (or updated RMP) at any time to address changes to safety information.

For Product Information (PI)/Consumer Medicine Information (CMI) changes with no impact on the RMP, include in the updated document package for PI/CMIs a sentence justifying why a RMP change is not required.

Acknowledgement, evaluation and feedback of the updated RMP

Where updated RMPs are required:

Who has responsibilities for monitoring compliance with the RMP commitments?

The sponsor is responsible for monitoring and ensuring compliance with RMP commitments. Once a RMP has been evaluated, the TGA will ensure that post-marketing commitments contained in the RMP are complied with. If necessary the TGA will follow up with sponsors to confirm compliance.

Contact information

Any questions and advice relating to Risk Management Plans (RMPs) should be directed to:

RMP Coordinator
Office of Product Review

Email: rmp.coordinator@tga.gov.au
Telephone: 02 6232 8841

Copyright

© Commonwealth of Australia 2012
This work is copyright. You may download, display, print and reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted under the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to tga.copyright@tga.gov.au.

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Content last updated: Thursday, 4 October 2012

Content last reviewed: Thursday, 4 October 2012

Web page last updated: Friday, 19 October 2012

URL: http://www.tga.gov.au/industry/pm-risk-management-plans.htm

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