PRAC rapporteur Risk Managment Plan assessment … · Web viewConsider whether the MAA has analysed...

<PRAC Rapporteur> Risk Management Plan (RMP) Assessment Report (For initial application, recommended for extension of indication, major line extension and optional for others)

[Active substance(s) (INN or common name)]

[Pharmaco-therapeutic group (ATC Code)]

[Marketing Authorisation Holder or Applicant]:

Number of medicinal products to which this RMP refers: Choose an item.

Date of final sign off of first RMP Version numbercovered by this AR

Date of final sign off of last RMP Version numberCovered by this AR

<This assessment report is dated Click here to enter a date. and is the Choose an item. >

PRAC Rapporteur RMP assessment report /21

Click here to enter a date.

Click here to enter a date.

ADMINISTRATIVE INFORMATIONName of the (PRAC) Rapporteur Name

Email:

(PRAC) Rapporteur contact person: Name:

Tel:

Email:

Names of the (PRAC) Rapporteur’s assessors Name

Email:

Name

Email:

Name

Email:

Name of the (PRAC) Co-Rapporteur Name

Email:

(PRAC) Co- Rapporteur contact person: Name:

Tel:

Email:

EMA Risk Management Team Leader/MS Risk Management contact point

Name

Email:


Table of contents 1. List of abbreviations...........................................................................52. Background information on the procedure............................................53. Part I “Product overview”....................................................................64. <PRAC Rapporteur>< Assessor> current recommendations to PRAC following the <initial assessment><responses to the LoQ><responses to the list of outstanding issues><request for supplementary information>. .74.1. Current recommendations on conditions or restrictions with regard to the safe and effective use of the medicinal product.....................................................................................74.1.1. Risk management system..............................................................................................84.1.2. Additional risk minimisation measures...........................................................................94.1.3. Obligation to conduct post-authorisation measures.......................................................94.2. PRAC discussion..............................................................................................................105. Safety Specification...........................................................................105.1. Epidemiology of the indications and target population...................................................105.2. Non-clinical part of the safety specification....................................................................105.3. Clinical trial exposure......................................................................................................105.4. Populations not studied in clinical trials..........................................................................105.5. Post - authorisation experience.......................................................................................105.6. Additional EU requirements for the safety specification..................................................105.7. Identified and potential risks...........................................................................................115.7.1. New information (post authorisation RMPs only).................................................115.7.2. Assessment of identified and potential risks................................................................115.7.3. Rapporteur’s conclusions on Module SVII Identified and potential risks:......................115.8. Summary of the safety concerns....................................................................................115.9. Conclusions on the safety specification..........................................................................126. Part III Pharmacovigilance plan..........................................................126.1. Summary of planned additional PhV activities (if appropriate).......................................126.2. Additional pharmacovigilance activities to assess the effectiveness of risk minimiation measures (see also section 7.1).............................................................................................136.3. Studies and other activities completed since last update of PhV Plan.............................136.4. Overall conclusions on the PhV Plan...............................................................................137. Part IV “Plans for post-authorisation efficacy studies”........................137.1. Applicability of efficacy to all patients in the target population.......................................137.2. Summary of Post authorisation efficacy development plan.............................................148. Part V “Risk minimisation measures”.................................................148.1. Additional risk minimisation measures............................................................................148.2. Assessment of effectiveness...........................................................................................158.3. Conclusions on risk minimisation measures....................................................................159. Part VI “Summary of activities in the risk management plan by medicinal product”...............................................................................................159.1. <Product name>............................................................................................................159.1.1. Summary of safety concerns........................................................................................16


9.1.2. Summary of additional risk minimisation measures by safety concern (if any)..........169.1.3. Summary of changes to the risk management plan over time.....................................169.1.4. Overall conclusions on Public Summary.......................................................................1610. PRAC Rapporteur’s initial conclusions...............................................1611. <List of questions><list of outstanding issues><request for supplementary information>.................................................................1712. Assessment of responses to the <List of questions><list of outstanding issues><request for supplementary information>...............1713. PRAC Rapporteur’s conclusions following the response to the <List of questions><list of outstanding issues><request for supplementary information>........................................................................................1814. <List of questions><list of outstanding issues><request for supplementary information>.................................................................1815. Assessment of responses to <List of questions><list of outstanding issues><request for supplementary information>..................................18


1. List of abbreviationsAbbreviation

Non-abbreviated form

MAH Marketing Authorisation Holder

2. Background information on the procedure < Name of MAH/MAA> submitted a RMP version < >Choose an item.

The procedure started on Click here to enter a date.

Select the following sentences as appropriate

<The RMP was updated following a List of Questions>

<The RMP was updated following a List of Outstanding Issues>

<The RMP was updated following a request for supplementary information>


3. Part I “Product overview”Invented name(s) in the European Economic Area (EEA)

Authorisation procedure Choose an item.

Authorisation number (s)

Brief description of the product including:

chemical class

summary of mode of action

important information about its composition (e.g. origin of active substance of biological, relevant adjuvants or residues for vaccines

Indication(s) in the EEA

Current (if applicable)

Proposed (if applicable)

Dosage in the EEA



Pharmaceutical form(s) and strengths




Is the product subject to additional monitoring in the EU? Yes No

Country and date of first authorisation worldwide

Country and date of first launch worldwide

dd/mm/yyyy

dd/mm/yyyy

Post authorisation only

4. <PRAC Rapporteur>< Assessor> current recommendations to PRAC following the <initial assessment><responses to the LoQ><responses to the list of outstanding issues><request for supplementary information>This section should be completed each time the RMP is assessed eg initially and after each set of responses. Please select the appropriate option above to reflect what stage the procedure is at

<The RMP is acceptable>

or

<The RMP is acceptable with minor revisions required for the next update.>

The points should be detailed and if necessary the update period specified in 4.2.1.

or

<The RMP could be acceptable provided an updated RMP and satisfactory responses to the <list of questions><list of outstanding issues><request for supplementary information> at the end of this assessment report are submitted>

or

<The RMP is not acceptable>

4.1. Current recommendations on conditions or restrictions with regard to the safe and effective use of the medicinal product

This section should be completed each time the RMP is assessed so that the recommendations to PRAC always reflect the current status.

Conditions or restrictions with regard to the safe and effective use of the medicinal products now have 3 sections:

RMP

Additional risk minimisation measures

Obligation to conduct post-authorisation measures.

There is default text regarding RMPs in the current CAP Opinion templates which should be routinely included as a condition in all MAs to make them legally enforceable

The statement below can be included if required in the early stages of the procedure provided this is not the final RMP AR for the procedure

<The RMP needs revision but the preliminary view is that>


4.1.1. Risk management system

The following is part of the CHMP Opinion template and will appear automatically for centrally authorised products.

An updated RMP should be submitted:

At the request of the European Medicines Agency;

Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

For MRP/DCP/NAPs this should be included (if required)

<An updated RMP should be submitted:

At the request of the national competent authority;

Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

Next update to the Risk management system

“Routine” updates to the RMP are no longer allowed by the EC so updates will normally only occur when triggered – eg by a significant change to the MA, or a new safety concern. When justified on a proportionate risk based approach, the PRAC Rapporteur/assessor may advise a deadline for the submission of the next update to the RMP in which case the sentence below should be included along with an appropriate timescale. For less urgent updates, ‘with the next PSUR or variation’ may be an appropriate timeframe. If the recommendation to PRAC is that the “RMP could be acceptable” and the RMP was submitted as either a stand-alone RMP or with a PSUR, then a time-scale should be provided and justified. “With the response to the LoQ etc” should only be chosen during a procedure eg initial MAA, variation etc.

<An updated RMP should be submitted <by/within {specify timescale}><with the next PSUR><with the next variation><with the response to the <list of questions><list of outstanding issues><request for supplementary information>>


4.1.2. Additional risk minimisation measures

<no additional risk minimisation measures are necessary>

or

< The <PRAC Rapporteur><assessor> considers that the following additional risk minimisation measures are necessary for the safe and effective use of the product:

If this option is chosen Select all that apply

<DHPC addressing <points to be addressed>>

< Educational material for healthcare professionals to address the risk(s) of

list safety concerns to be addressed>

< Educational material for <patients><and/or carers> to address the risk(s) of

list safety concerns to be addressed

<Pregnancy prevention plan>

<Patient alert card>

<Patient monitoring card>

<Other>

Or Post authorisation only

<The <PRAC Rapporteur><assessor> considers that <the following> conditions or restrictions are no longer necessary for the safe and effective use of the medicinal product>[specify any measures no longer considered necessary]

4.1.3. Obligation to conduct post-authorisation measures

This relates to imposed studies (Annex II conditions for CAPs)

<no conditions are necessary>

[Or if new PhV studies or activities are needed, for EACH new study/activity which should be an Annex II condition]

< The <PRAC Rapporteur><assessor> recommends that a <study><activity> to investigate <name safety concern(s)> should be a condition of the MA>

[Optional statement]

< The <PRAC Rapporteur><assessor> recommends that this should take the form of a < Choose an item. >


4.2. PRAC discussion

This RMP need discussion during the PRAC Plenary Yes No

Provide brief outline of areas for discussion and give references to relevant sections of AR.

ASSESSMENT OF THE PARTS OF THE RMP

5. Safety Specification

5.1. Epidemiology of the indications and target population

5.2. Non-clinical part of the safety specification

Briefly summarise the important non-clinical findings eg on key target organs. For any medicine intended for use by women of reproductive age always include repro tox findings. Comment on the overall findings and their relevance to human use

5.3. Clinical trial exposure

5.4. Populations not studied in clinical trials

Comment on the relevance of the clinical trial population to the intended target population (inclusions, exclusions, limited numbers, trial setting, use in special populations. Comment on implications of scarce or missing information in relation to use in the target population

5.5. Post - authorisation experience

Comment on any regulatory action for safety reasons. Comment on any post-authorisation use in the populations with no or limited exposure during clinical trials. Comment on any off-label use

5.6. Additional EU requirements for the safety specification

Potential for harm from overdose, transmission of infectious agents and potential for misuse for illegal purposes

Potential for medication errors

This is one of the important parts of the safety specification.

Consider whether the MAA has analysed adequately any medication errors which have occurred in the clinical trial population? What are the implications?


Assess common sources of medication errors (e.g. product name, presentation, instructions for use, labelling) and discuss the potential for serious harm. Are there similar products containing the same active substance on the market where as a result of confusion (e.g. different strength, posology or method of reconstitution) medication error could occur? If a device is involved, what are the possible consequences of device failure? Also consider whether there are any important implications for special patient populations – eg problems in measuring a dose for small children. If appropriate, medication error should be included as a safety concern (important identified or potential risk). Consideration should be given as to whether additional PV activities to identify the frequency or causes of medication error and/or risk minimisation measures are necessary to minimise the risk. If required, also mention in the appropriate section

Potential for off-label use

Specific paediatric issues

Comment on whether there is a current or proposed paediatric indication. What is the likelihood of off-label paediatric use and based on the likelihood, should use in children be a safety concern? Are there issues from any PIP which needs to be discussed in the RMP?

5.7. Identified and potential risks

5.7.1. New information (post authorisation RMPs only)

Newly identified safety concerns (from table SVII.1 of the RMP)

Comment on whether there have been newly identified safety concerns and any implications for the rest of the RMP.

Recent results from studies

Comment on whether there have been recent study reportsand any implications for the rest of the RMP.

5.7.2. Assessment of identified and potential risks

Comment on whether all important risks related to the active substance, formulation, route of administration, target population, specific sub-populations and the potential for interaction been included. Have risks from other products in the same pharmacological class been discussed?

5.7.3. Rapporteur’s conclusions on Module SVII Identified and potential risks:

5.8. Summary of the safety concerns

Copy and paste table from module SVIII.

Table 1: Summary of the Safety Concerns (table from MAH RMP module SVIII)


Summary of safety concerns

Important identified risks <.> ListImportant potential risks <.> ListMissing information <.> List

Comment if needed

5.9. Conclusions on the safety specification

Having considered the data in the safety specification

<The PRAC Rapporteur><The assessor> agrees that the safety concerns listed by the MAH are appropriate>

or

<The PRAC Rapporteur><The assessor> considers that the following issues should be addressed :>

<The PRAC Rapporteur><The assessor> considers that> <should also be <a> safety concern(s)>

<<The PRAC Rapporteur><The assessor> considers that the following should not be <a> safety concern(s)>

[If the second option is chosen, the issues to be addressed must be included in section 11]

6. Part III Pharmacovigilance planComment on whether the MAA/H has discussed all the appropriate safety concerns from Module SVIII and whether all areas requiring confirmation or further investigation have been identified.

6.1. Summary of planned additional PhV activities (if appropriate)

Table 2: on-going and planned studies in the Post-authorisation Pharmacovigilance Development Plan (copy table III.5.1 from the RMP)

Study/activity

Type, title and category (1-3)

Objectives Safety concerns addressed

Status

(planned, started)

Date for submission of interim or final reports (planned or actual)

Comment specifically as to whether all studies are in the correct category. Are the objectives and milestones appropriate?


6.2. Additional pharmacovigilance activities to assess the effectiveness of risk minimiation measures (see also section 7.1)

Comment whether any proposed activity is appropriate and proportionate to the importance of the risk minimisation measure or if activities are required

6.3. Studies and other activities completed since last update of PhV Plan

Comment on any completed studies/activities and the effect on the RMP

6.4. Overall conclusions on the PhV Plan

The <PRAC Rapporteur><assessor>, having considered the data submitted, is of the opinion <that there are still outstanding issues regarding the RMP but a preliminary view is> that:

<routine pharmacovigilance is sufficient to identify and characterise the risks of the product>

or

< the proposed post-authorisation PhV development plan is sufficient to identify and characterise the risks of the product>

or

< the proposed post-authorisation PhV development plan is not sufficient to identify and characterise the risks of the product and the <MAH><MAA> should propose PhV studies/activities as detailed in section <11><13><15>

Or if nothing has been proposed

<the <MAH><MAA> should propose a post-authorisation PhV development plan>

The <PRAC Rapporteur><assessor> also considered that

[Choose one of the following]

< routine PhV remains sufficient to monitor the effectiveness of the risk minimisation measures>

or

< the study(ies) in the post-authorisation development plan <is><are>sufficient to monitor the effectiveness of the risk minimisation measures >

or

<the <MAH><Applicant> should propose a study to monitor the effectiveness of <> [state which additional risk minimisation measures should be studied and include question in section 11]

7. Part IV “Plans for post-authorisation efficacy studies”

7.1. Applicability of efficacy to all patients in the target population

Comment on whether the medicinal product might be expected to have different efficacy in any sub-populations, and in particular those not studied.


7.2. Summary of Post authorisation efficacy development plan

Table 3: Summary of Post-authorisation efficacy development Plan (copy from IV.3 of the RMP)

Study

(type and study number)

Objectives Efficacy concerns addressed

Status

(Planned, started, completed, results submitted)

Date for submission of interim or final reports (planned or actual)

8. Part V “Risk minimisation measures”The RMP may cover more than one medicinal product. In some circumstances risk minimisation measures may be specified per product, or certain risks may not be relevant to all products. Copy and paste table from section V.3 of the RMP; for older-style RMPs, copy and paste the risk minimisation plan from section 4.

Table 4: Proposal from MAH for risk minimisation measures (copy from V.3 of RMP)

Safety concern Routine risk minimisation measures

Additional risk minimisation measures

Comment on whether proposals are acceptable

8.1. Additional risk minimisation measures

State which additional risk minimisation measures are needed and which safety concerns they should address. Additional risk minimisation measures should only be included in the RMP if the proposed measures are necessary for the safe and effective use of the product. Request the MAH to remove any items which do not come into those categories. (There is nothing to stop a MAH producing extra material, but it should not be part of the agreed RMP)


8.2. Assessment of effectiveness

8.3. Conclusions on risk minimisation measures

The <PRAC Rapporteur><assessor>, having considered the data submitted, was of the opinion <that there are still outstanding issues regarding the RMP but a preliminary view is> that:

Choose one of the following

<the proposed risk minimisation measures are sufficient to minimise the risks of the product in the proposed indication(s)>

Or if there needs to be some other risk minimisation measures (either routine or additional) added

<the proposed risk minimisation measures are not sufficient to minimise the risks of the product> and supplementary risk minimisation measures are required relating to:

List safety concerns and ensure questions added to List of Questions.

Or (when the risks cannot be brought to a satisfactory level)

the proposed risk minimisation measures are not sufficient to minimise the risks of the product in the proposed indication(s)

9. Part VI “Summary of activities in the risk management plan by medicinal product” A summary should be provided for each product in the RMP. Repeat section 9.1 for each product

9.1. <Product name>

Refer to the MAH’s RMP summary in section VI that includes key elements of the RMP in lay language and consider whether the following sections are balanced and suitable for publication:

VI.2.1 Overview of disease epidemiology

Comment on the appropriateness of the proposed text for the lay reader


Fill in blue box only for post-authorisation RMPs

Assessment of effectiveness of risk minimisation activities

Assessment of causes of risk minimisation measure failure (if applicable)

VI.2.2 Summary of treatment benefits


VI.2.3 Unknowns relating to treatment benefit


9.1.1. Summary of safety concerns

Important identified risks


Important potential risks


Missing information


9.1.2. Summary of additional risk minimisation measures by safety concern (if any)

Consider whether the MAH’s summary of additional risk minimisation measures is balanced and suitable for publication:

9.1.3. Summary of changes to the risk management plan over time

Does the table adequately reflect the major changes to the RMP over time?

9.1.4. Overall conclusions on Public Summary

10. PRAC Rapporteur’s initial conclusions If a list of questions is anticipated use sections 10-12. It is important to fill in section 10 so that a record of the conclusions on the RMP at each stage of the procedure is maintained as section 4 will always show the most recent conclusions.


or


or



or


11. <List of questions><list of outstanding issues><request for supplementary information><not applicable>

Or

<The MAH/MAA should provide an updated RMP answering the following questions and points:>

<major objection>

List

<other objection>

List

12. Assessment of responses to the <List of questions><list of outstanding issues><request for supplementary information>For each question

Question:

Assessment of response

Conclusions and effect on RMP

Discuss whether issue resolved, note which parts of the RMP are affected by the response and any resulting changes to previous conclusions on that part or section.

Overall Assessment of impact of responses on the RMP

State the effect that the responses as a whole have had on the RMP. In particular state whether Parts II, III, IV, V and VI are now acceptable. Update section 4 on the conclusions and recommendations to PRAC each time the AR is updated.

If a further round of questions is anticipated use sections 13-15 (and repeat as necessary. It is important to fill in section 13 so that a record of the conclusions on the RMP at each stage of the procedure is maintained as section 4 will always show the most recent conclusions.


13. PRAC Rapporteur’s conclusions following the response to the <List of questions><list of outstanding issues><request for supplementary information>This needs to be filled in to keep an audit trail as the current recommendations in section 4 will change during the course of the procedure.


or


or


or


14. <List of questions><list of outstanding issues><request for supplementary information><not applicable>

Or

<The MAH/MAA should provide an updated RMP answering the following questions and points:>

<major objection>

List

<other objection>

List

15. Assessment of responses to <List of questions><list of outstanding issues><request for supplementary information>For each question

Question:

Assessment of response

Conclusions and effect on RMP


Discuss whether issue resolved, note which parts of the RMP are affected by the response and any resulting changes to previous conclusions on that part or section.

Overall Assessment of impact of responses on the RMP

State the effect that the responses as a whole have had on the RMP. In particular state whether Parts II, III, IV, V and VI are now acceptable. Complete section 4 on the conclusions and recommendations to PRAC each time the AR is updated.


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