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Risk management plans for medicines and biologicals

Australian requirements and recommendations

29 March 2019

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Risk Management Plan - Australia-Specific Annex

Product details

Active ingredient(s) (INN):

Product name(s):

Sponsor name:

ASA version number:

ASA version date:

Related EU-RMP version*:

Version #.# (date, data lock point)

Pharmaco-therapeutic group (ATC Code):

*Can be changed to 'core' or 'global' RMP if no EU-RMP is available

1. Product overview

1.1. History of RMPs submitted in Australia

In this section, provide a tabulated history of EU RMP and ASA versions previously submitted for evaluation in Australia, with a summary of changes between versions, unless this is clearly indicated in the EU RMP. An example table format is shown below.

State whether the medicine is currently, or is expected to be, included in the Black Triangle Scheme in Australia.

Table 1: History of RMPs submitted in Australia (example)
EU-RMP version ASA version Date Submitted Application or update Major changes to the ASA/EU-RMP* from previous version

EU-RMP 0.5

ASA v1.0

5/2/16

PM-2016-#####-1-1

Draft EU RMP, first ASA version

EU-RMP 1.0

ASA v1.0

10/6/16

PM-2016-#####-1-1

First approved EU RMP submitted with s31 response

EU-RMP 1.5

ASA 1.1

5/6/17

RMP update

Changed 'Hepatotoxicity' from important potential risk to important identified risk in line with EU RMP under evaluation

EU-RMP 2.0

ASA 1.5

14/9/18

PM-2018-#####-1-1

Extension of indication to psoriatic arthritis. No change in safety concerns or additional risk minimisation activities.

*it is acceptable to refer to the table in Annex 8 of the EU RMP if changes to the EU RMP are clearly indicated there.

2. Safety specification

2.1. Epidemiology of the indication(s) and target population(s)

Provide a brief summary of Australian epidemiological information, where available, for each indication, commenting on whether there are any important differences between Australia and the EU in:

  • incidence and prevalence
  • demographics of the target population (age, sex, race/ethnic origin)
  • risk factors for the disease
  • mortality and morbidity (natural history)
  • main treatment options

This section should include information on the use of the product in Australia, relevant to assessing the adequacy of the risk management system in Australia, such as:

  • the proposed setting of use of the product (hospital, home, specialist treatment centre, etc) and the types of health professionals who will prescribe and be involved in the product's use
  • whether use in rural or remote settings presents any challenges to management of risks (such as monitoring and follow-up)
  • whether use of the product relies on or is affected by access to diagnostic tests or other technologies that may not be widely available
  • whether there are specific risk management considerations for Aboriginal or Torres Strait Islander people (such as a higher prevalence of risk factors for important identified or important potential risks) or other groups
  • whether there are any differences in Australia that may affect the likelihood of medication errors or misuse for illegal purposes

For generic or biosimilar medicines, or fixed-dose combination products not including a new chemical entity, a summary of epidemiology is not required in the Australia-specific annex. However, this section should identify and discuss any differences in indications and presentations of the generic or biosimilar to the innovator and other generic or biosimilar versions of the medicine. If there are differences, the impacts of these differences should be considered, for example:

  • potential harms from foreseeable off-label use (for example in a patient group for which the innovator provides a specific presentation, but this presentation is not planned for the generic or biosimilar version of the medicine)
  • potential for medication error

2.2. Summary of the safety concerns

State clearly and justify any differences between the summary of the safety concerns in the EU RMP and the summary of safety concerns proposed for Australia.

If you propose to omit any of the risks that appear in the EU RMP from the Australian summary of safety concerns, or to classify any of the risks differently, provide a justification.

If there are any Australia-specific safety concerns, provide further information in section 2.2.1.

2.2.1. Australia-specific safety concerns

Include details of any safety concerns for Australia that are additional to those proposed in the EU-RMP. This should include:

  • why the additional safety concern is included in the ASA (e.g. TGA requirement, concern is specific to the Australian population)
  • a detailed description of the safety concern

The Australia-specific safety concern(s) should be described in the same detail as used in the EU-RMP, as shown below:

<Australian important identified/potential risk>

Potential mechanisms

Evidence source(s) and strength of evidence

Characterisation of the risk

Risk factors and risk groups

Preventability

Impact on the risk-benefit balance of the product

Public health impact

<Australian missing information>

Evidence source

Population in need of further characterisation or Anticipated risk/consequence of the missing information

2.2.2. Proposed changes to Australia-specific safety concerns

This section can be used to request or record changes to Australia-specific safety concerns. If used, the section should follow the requirements for SVII.2 of the EU RMP (Rev 2):

<<Risk 1> previously classified as <important identified risk> <important potential risk> <missing information> is to be reclassified as <important identified risk> <important potential risk> <missing information> or <is removed from the list of safety concerns>>

Reasons for the reclassification or removal from the list of safety concerns:

<Changes in the level of scientific evidence for the causal association or risk-benefit impact>

For new proposals from the sponsor, discuss briefly the level of scientific evidence that has led to this re-classification/removal.

3. Pharmacovigilance plan

For biologicals, replace 'pharmacovigilance' with 'biovigilance' throughout the ASA.

3.1. Routine pharmacovigilance activities in Australia

Provide a brief summary or list of routine pharmacovigilance activities, beyond adverse reaction reporting and signal detection, that will be implemented in Australia, such as:

  • specific adverse reaction follow-up forms
  • enhanced passive surveillance
  • observed vs expected analyses
  • cumulative reviews of adverse events of interest

State clearly and justify any differences between routine activities described in the EU RMP and those proposed for Australia.

If there are Australia-specific safety concerns, describe the corresponding routine pharmacovigilance activities (beyond adverse reaction reporting and signal detection).

If specific adverse reaction follow-up forms are to be implemented, state whether the forms implemented in the EU (which should be included in Annex 4 of the EU RMP) will be used in Australia. If different forms are planned for use in Australia, attach them to the ASA.

If follow-up forms do not contain a field for recording Aboriginal and Torres Strait Islander ethnicity, describe how you will seek this information.

For biologicals, a detailed description of the biovigilance system in Australia should be provided, including:

  • a summary of the sponsor's routine biovigilance activities
  • details of the elements of the biovigilance system needed to support the additional biovigilance activities included in the RMP, and
  • details of procedures for traceability of products from donor to recipient, and recipient to donor, to investigate and act on possible disease transmission.

3.2. Additional pharmacovigilance activities

State clearly and justify any differences between additional pharmacovigilance activities proposed in the EU RMP and those proposed for Australia. If all of the additional pharmacovigilance activities included in the EU RMP are considered to apply to Australia, state this.

3.2.1. Australia-specific additional pharmacovigilance activities

This section should:

  • indicate whether there are additional pharmacovigilance activities for each Australia-specific safety concern, and
  • provide the detail of any Australia-specific pharmacovigilance activities (which may be for Australia-specific safety concerns, or for safety concerns listed in the EU-RMP).

If there are no additional safety concerns for Australia or no Australia-specific pharmacovigilance activities for safety concerns listed in the EU-RMP then this can be simply stated.

Studies to evaluate the effectiveness of additional risk minimisation activities in Australia should be listed in Section 5.4.

For any additional pharmacovigilance activity that forms part of the Australian pharmacovigilance plan and is not described in the EU RMP, complete the summary using the format required in III.2 of the EU RMP, and provide the protocol in Annex 2 of the ASA, as shown below:

<PASS short name> summary

Study short name and title:

Rationale and study objectives:

Indicate the rationale for conducting the study (include also all the safety concerns addressed).

Present briefly the study objectives.

Study design:

State the study design. e.g. randomised clinical trial extension, observational chart-review, cohort study, self-controlled case series.

Study population:

Present briefly the population included in the study, in line with the inclusion and exclusion criteria.

Milestones:

Include all requested milestones for reporting to the TGA (e.g. protocol submission, interim reports, and final report submission) as well as major milestones from study protocol (e.g. start and end of data collection, interim progress reports, final study report completion, date of publication).

3.3. Summary table of additional pharmacovigilance activities

Provide a complete overview of the ongoing and planned additional pharmacovigilance activities for Australia, including those in the EU RMP and any further activities described in section 3.2.1 of the ASA.

Indicate whether TGA has required submission of any study protocols or reports and provide estimated dates.

The TGA does not routinely require submission of all clinical study reports from additional pharmacovigilance activities. Sponsors are expected to include information from additional pharmacovigilance activities in PSURs and update the RMP to reflect important new safety information as it emerges.

In some cases TGA may require submission of data from specific routine or additional pharmacovigilance activities, particularly for activities requested by the TGA. The timing of and method for submission of this data will be determined during the evaluation.

Sponsors must also comply with the pharmacovigilance reporting requirements in 'Pharmacovigilance responsibilities of medicines sponsors: Australian recommendations and requirements'.

For each additional pharmacovigilance activity, state whether Australian patients are included.

Table 2: Ongoing and planned additional pharmacovigilance activities (example)
Study and status Summary of objectives Safety concerns addressed Study location; Australian patients? Submission to TGA*
Required? Deliverable and due date

E.g. STUDY1

Planned

To evaluate…

Important potential risk 1

Multinational; yes

No

n/a

E.g. Registry1

Planned

To evaluate risk of non-melanoma skin cancer in…

NMSC

Australia; yes

Yes

Annual report with each PSUR

*refers to requirement to submit clinical study protocols or reports as a condition of registration or to fulfil RMP commitments. Sponsors must also comply with the reporting requirements in 'Pharmacovigilance responsibilities of medicines sponsors: Australian recommendations and requirements'.

4. Clinical study plan for provisional registration

For applications for provisional registration, include an overview of the clinical study plan.

Attach the study protocols to the ASA, or provide a reference to the location of the protocols in another part of the eCTD dossier.

See the TGA Guidance 'Provisional registration process' for further information and an example format for the clinical study plan overview.

5. Risk minimisation plan

5.1. Routine risk minimisation activities

This section should describe the routine risk minimisation used for each safety concern. You should provide a reference to the PI and CMI section and identify and justify any material differences between the statements in the SmPC and PL, and PI and CMI.

State whether the CMI will be included in the pack, and whether the pack will contain any other risk communication materials, such as a patient alert card, pack insert or instructions for use.

Table 3: Routine risk minimisation activities
Safety Concern Routine risk minimisation activities Differences between EU and Australian activities with justification

Important identified risks

Risk 1

PI section: [e.g. 4.4]

CMI section: [e.g. 'While you are taking [product]']

Other measures: [e.g. , pack size, package leaflet, warning statement on pack]

Important potential risks

Risk 2

PI section: [e.g. 4.4]

CMI section: [e.g. 'While you are taking [product]']

Other measures: [e.g. , pack size, package leaflet, warning statement on pack]

Missing information

Missing info 1

PI section: [e.g. 4.4]

CMI section: [e.g. 'While you are taking [product]']

Other measures: [e.g. , pack size, package leaflet, warning statement on pack]

5.2. Additional risk minimisation activities

This section should describe the additional risk minimisation activities to be undertaken in Australia.

For innovator medicines, state clearly and justify any differences between additional risk minimisation activities planned for the EU and Australia. If you propose to implement all of the additional pharmacovigilance activities included in the EU RMP, state this.

For generic or biosimilar medicines, state clearly and justify any differences between additional risk minimisation activities conducted for the innovator medicine (if known) and your product.

<Removal of additional risk minimisation activities>

If you propose to remove an additional risk minimisation activity in Australia, you should provide a justification. The justification may refer to information provided in the EU RMP. If the justification relies on evidence presented in the EU RMP (such as from the evaluation of effectiveness of risk minimisation activities), you should provide a rationale for the applicability of the evidence in Australia and preferably using supporting evidence from Australia.

Rationale for the removal:

Include justification when an additional risk minimisation activity is proposed to be removed from the RMP.

5.2.1. Australia-specific additional risk minimisation activities

This section should:

  • indicate whether there are additional risk minimisation activities for each Australia-specific safety concern, and
  • provide the detail of any Australia-specific additional risk minimisation activities.

If there are no additional safety concerns for Australia and/or no Australia-specific risk minimisation activities for safety concerns listed in the EU-RMP then this can be simply stated.

For any additional risk minimisation activity that forms part of the Australian risk minimisation plan and is not described in the EU RMP, complete the summary below and provide draft key messages of the activity in Annex 3 of the ASA.

<Additional risk minimisation 1>

State type and/or title of risk minimisation activity

Objectives:

Include objectives including a list of risks addressed.

Rationale for the additional risk minimisation activity:

Include justification on why the particular additional risk minimisation is considered needed.

5.3. How additional risk minimisation activities will be implemented in Australia

Provide a table describing the implementation of all planned additional risk minimisation measures for Australia, including:

  • the target audience for each activity
  • how it will be implemented (including how materials will be disseminated)
  • anticipated timeframes for implementation (such as expected start date for activity/dissemination and frequency of repetition, if relevant)

If it is not possible to include all relevant details in the table (e.g. for more complex additional risk minimisation activities such as controlled access programs), provide additional information in Annex 3 of the ASA.

Provide copies of draft Australian educational materials in Annex 3. Materials should be provided with content and intended layout, including images and graphic presentations of information. For digital additional risk minimisation tools, provide content and images of the on-screen layout of the information, and/or the login details or access codes to enable the TGA to evaluate the safety content in the format in which it is provided to the end user.

Table 4: Australian implementation of additional risk minimisation activities (example)
Additional risk minimisation activity Target audience Implementation details, including method(s) of dissemination Time-points for and frequency of dissemination

e.g. health professional guide and checklist

GPs

pharmacists

Paper copies posted to GPs and pharmacists on sponsor-held mailing list

At launch

Mailing list reviewed every 6 months and brochure mailed to new additions

Repeat mail at 18 months after launch

e.g. patient guide

patients

Paper copies posted to GPs to provide to patients (initial mailing of 5 copies); GPs can re-order through sales reps and Medical Information

Electronic copies available through patient support program website

At launch

Mailing list reviewed every 6 months and brochure mailed to new additions

Repeat mail at 18 months after launch

5.4. How additional risk minimisation activities will be evaluated in Australia

Describe the evaluation of each additional risk minimisation activity to be conducted in Australia, including:

  • how and when each activity will be evaluated
  • how and when evaluation results will be reported to the TGA

You must demonstrate that your risk minimisation programme has been implemented as planned and is effective, and if not, what actions will be taken to improve effectiveness. Your plan(s) to measure effectiveness should include a clear description of what defines success prior to implementation.

In your evaluation plan you should consider the use of both process and outcome indicators.

Process indicators include measures of:

  • reaching the target population
  • assessing clinical knowledge
  • assessing clinical actions

Outcome indicators are measures of:

  • the safety outcome of the risk minimisation programme, such as the frequency and/or severity of adverse reactions

Methods to measure the effectiveness of risk minimisation activities should be proportionate to the risks being minimised.

If you propose to use an evaluation conducted in another market to contribute to the evaluation of activities in Australia, you should provide a justification for the applicability of this information. Consider any differences between the interventions implemented in Australia and Europe, and factors that may influence clinical knowledge or actions such as differences in the target audience, local guidelines, and reimbursement constraints. If we accept process indicators from other markets, we will usually also require evidence of effective implementation of the intervention(s) in Australia.

How to access a pdf document

Refer to Guideline on good pharmacovigilance practices (GVP):Module XVI- Risk minimisation measures: selection of tools and effectiveness indicators (Rev 2) (pdf,376kb) for further detail about developing an evaluation plan.

The timeframes for reporting the outcomes of studies evaluating the effectiveness of risk minimisation activities will be determined during the evaluation process.

To assist you to record a specific, measurable and time-bound evaluation plan for your risk minimisation activities, we suggest you use the following table format. Protocols for evaluation activities should be attached to the ASA.

Table 5: Evaluation of additional risk minimisation activities (example)
Additional risk minimisation activity Evaluation plan and criteria for success Submission of results to TGA: deliverable and timeframe

e.g. Health professional guide and checklist

Initial and 2nd distribution completed to at least 90% of target audience

EU survey of GP and pharmacist knowledge, criteria as per protocol in EU RMP

Australian drug utilisation study using GP prescribing data (see attached protocol)

Evaluation report (incl PASS results, DUS outcomes and distribution information) to be submitted to TGA by 24 months after first supply

e.g. Patient guide

Guide tested with consumers prior to finalisation and distribution

Initial and 2nd distribution to GPs completed

Final materials provided for TGA review with results of testing, prior to distribution

Distribution information to be included in evaluation report to be submitted to TGA by 24 months after first supply

6. Summary of the RMP in Australia

Include a tabulated version of the summary of safety concerns for Australia (including the EU RMP summary of safety concerns and any Australia-specific safety concerns), and the associated routine and additional activities relevant to Australia.

  • for pharmacovigilance activities, the activities relevant to Australia can include both local and international activities.
  • for risk minimisation activities, only activities being conducted in Australia should be listed.

Australia-specific safety concerns should be indicated with an asterisk (*). We recommend that you use the table format below.

Table 6: Summary of the RMP in Australia (example)

Important Risks and Missing Information

Safety concern

Routine pharmacovigilance activities†

Additional Pharmacovigilance Activities^

Routine risk minimisation activities

Additional Risk Minimisation Activities#

Important identified risks

Hepatotoxicity

Targeted follow-up

None

Yes

HCP education

...

Important potential risks

Medication error

Targeted follow-up

EU patient registry

Yes

Dosing card;

Patient alert card

QT prolongation

Clinical Trial #### (includes Australian patients)

None

Missing information

Use in pregnancy

EU patient registry

Yes

None

Use in children

None

Yes

None

† only include routine pharmacovigilance beyond adverse reaction reporting and signal detection

^ = All pharmacovigilance activities relevant to Australia should be listed, including those conducted overseas where the outcomes will be generalisable to Australian patients.

# = Only additional risk minimisation activities that will be conducted in Australia should be included in the table.

7. References

Annexes

ANNEX 1. Follow-up forms to be implemented in Australia
ANNEX 2. Study protocols for planned Australian pharmacovigilance studies
ANNEX 3. Additional risk minimisation materials

Include draft versions for new submissions.

Include the key message(s) for additional risk minimisation materials if key messages are not included in the EU RMP.

Include protocols for any studies to assess the effectiveness of additional risk minimisation activities (if not attached to the EU RMP).

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