An update on Risk Management Plans

RMPs - an evaluator’s perspective

Andreas Wortmann, PhD

Evaluator, Medicines Safety Evaluator, Risk Management Plan Section, Office of Product Review, Monitoring and Compliance Group, TGA

ARCS Scientific Congress 2014

11 September 2014

2RMPs-an evaluator’s perspective

Overview

• Risk Management Plan (RMP)/ Australian Specific Annex (ASA) format

• The evaluation process / evaluation milestones

• RMP Q&As and the ASA template

• Summary - RMP requirements pre-market

• RMP activities post-market

3

RMP requirements in Australia

• TGA follows EMA RMP guidelines• RMP submitted should be the most recent EU-RMP• Core RMP with ASA or Australian RMP only acceptable if no EU-RMP exists (has to be in the EU format)• Guideline documents available on the TGA website

– “Mandatory requirements for an effective application” and – “Risk Management Plan (RMP) Questions and Answers” (RMP Q&As)

EU-RMP

RMPs-an evaluator’s perspective

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RMP requirements in Australia

• ASA required to provide Australian specific information not included in EU-RMP• ASA should follow the format detailed in the RMP Q&As document• ASA template under discussion with ARCS working group• Specified information is required to evaluate the application in the Australian context

RMPs-an evaluator’s perspective

The Australian Specific Annex (ASA)

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Information in the ASA

• Differences in:– indication between Europe and Australia based on the same data– additional risk-minimisation, such as educational programs for patients and Health Care Professionals

(HCPs), between Europe and Australia• training/awareness of HCPs in each jurisdiction• patient’s support network…

– routine risk-minimisation between Europe and Australia• If study conducted overseas but not in Australia, is the data transferable to Australian practice? (sufficiently

similar clinical practice?)

If information is not provided it will be requested at s31 questions

Important information for the evaluation

RMPs-an evaluator’s perspective

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Information in the ASA

• Appropriateness of educational activities determined on a case by case basis• Educational materials should be directed to all HCPs as appropriate (doctors, nurses, pharmacists,

educators) and include:– how the distribution of materials will be controlled– how and at what time points the effectiveness will be assessed– what the triggers for amendments to the materials will be if risk minimisation insufficient– how and when the effectiveness will be evaluated after amendments have been made

If information is not provided it will be requested at s31 questions

Additional risk minimisation activities in Australia

RMPs-an evaluator’s perspective

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Consistency of information for evaluation

• The complete information package is required for TGA to complete an evaluation• There is no “one size fits all approach”

– difference in patient groups– difference in how/where treatment is administered– experience with similar products– overseas experience– established safety profile

• Discretion in evaluation of appropriateness of routine/additional risk-minimisation activities and evaluation of effectiveness

• Quality of ASA is improving, but frequently not all information outlined in the Q&As document is provided

Important considerations

RMPs-an evaluator’s perspective

8RMPs-an evaluator’s perspective

Australian specific annex

1. Description of routine PhV in Australia

2. Description of studies referenced in the RMP

3. Information on implementation and evaluation of risk-minimisation activities in Australia

4. Involvement of Australian patients and applicability of global studies to Australia

5. Background information on registration history

6. Details of contact person for RMP

7. Information on Australian specific risks

8. Justification for activities done overseas but not implemented in Australia

9. Difference in indication between overseas jurisdiction and Australia

10.Australian epidemiological information for target disease

25% of ASAs received contained all required information

Completeness of data provided in the ASA (~6 months period in 2013)

If all information is provided at submission fewer s31 questions and less reconciliation at milestone(M)5 less to evaluate post M5

ASA data item

5

49

8

46

8

46

11

43

13

41

13

41

17

37

19

35

21

33

21

33

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EvaluationRound 1 (M3)

Delegate in Clinical Evaluation Branch

Committee advice: Advisory Committee for

Prescription Medicines (ACPM)

Recommendations for amendments: - Table of ongoing safety concerns - CMI - PI- Risk Minimisation- Pharmacovigilance

Ongoing pharmacovigilance and risk-minimisation:

- Periodic Safety Update Review(PSUR)

submission for a specified period of time

- RMP updates for the life cycle of a product

Round 2 (Final)

reconciliation

Decision toApprove

Committee advice: ACSOV, ACSOM

Post-approval

Workflow of a RMP evaluationEvaluation

Round 2 (M5)

- Reconciliation of s31 response to issues raised in round 1 report

- Incorporation of advice: ACSOV, ACSOM,

Clinical, Non-clinical

s31 response

Round 1 report

RMP team resources allocated in the SSP by- data is available for evaluation - timeframe for finalisation of reports predictable

No resources allocated in the SSP- data is submitted while application progresses- timeframe for evaluation varies on a case by case basis

Finalisation of RMP issues at M3 & s31 questions as few as possible outstanding issues after M5

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During the evaluation process

• ACSOM/ACSOV advice may be sought if considered necessary (usually between M3 and M5)• Summary table of ongoing safety concerns in the RMP is further informed by the clinical and non-clinical

evaluators• Ongoing communication with the delegates as required

The RMP evaluation may be further informed by other areas of TGA and external review

RMPs-an evaluator’s perspective

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Requirements during the evaluation

• Provide comments on PI/CMI recommendations• Address any of the recommendations made in the RMP reports• Provide tracked changes of updated documents, including EU-RMP, ASA, CMI and PI & summary table of

changes• Ideally provide all updated documents at M4• If updated documents cannot be provided at M4, specify when they will be submitted• No additional data during submissions outside the prescription medicines registration process (PMRP)

milestones unless previously agreed (incl. submission to ACSOM)

How to make the process most efficient

RMPs-an evaluator’s perspective

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Items for improvements in the RMP/ASA

• Misclassification of risk-minimisation activities, pharmacovigilance activities, routine and additional activities

• Submission of partially updated RMPs (lots of cross referencing within the document all should be updated)

• Submission of “Australian RMP” (partly modified EU-RMP)

• Avoid statements which are imprecise such as:– “recommendations have been acknowledged”, but no outcome is described; – “which of these recommendations should we address”, without addressing recommendations at s31– “is considering whether to”, rather than “commits to”.

• Anything referenced in the RMP/ASA should be included in the annexes• Submission of one RMP for a product with more than one indication

What we frequently query during the evaluation

RMPs-an evaluator’s perspective

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RMP Q&As and ASA template document

• RMP Q&As revised and sent out for consultation to provide clearer guidance (various minor changes compared to previous version of the RMP Q&As)

• Proposal to provide an ASA template (developed by ARCS working group and TGA)

Improved understanding of requirements for RMP submission and expectations by OPR

Some changes envisaged in the updated ASA template• Addition of table detailing risk-minimisation measures in Australia and in the EU and justification for material

differences (including wording pertaining to safety concerns in the PI (CMI))• Addition of table summarising risk-minimisation and pharmacovigilance activities proposed for Australia

RMPs-an evaluator’s perspective

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Summary – RMP requirements (pre-market)• Information provided should follow the current TGA guidelines (RMP Q&As, mandatory requirements)• Provide sufficient background information to explain any differences in RMP activities between Europe and

Australia• All recommendations need to be addressed• Provide all required information at submission or at s31 response• As few as possible outstanding issues after M5• Provide tracked changes to documents and/or summary table of changes• No submission of data during evaluation unless requested by TGA or by prior agreement

RMPs-an evaluator’s perspective

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RMP activities post-market• Submit updated RMPs if risk/benefit changes; this is applicable over entire life of a product • Include summary of changes when submitting updated RMPs• Submission of updated RMPs together with PSURs/PBRERs, with cover letter stating how PSUR data impact

on RMP (for the first three years)• If RMP format changed since last submissions provide summary of changes & explain why format changed• No formal process for evaluation and notification of updated RMP

– acknowledgement of RMP provided by RMP coordinator– feedback/questions provided if considered necessary following evaluation

RMPs-an evaluator’s perspective