Risk Management Plans-RMPs Part 2

Sep 18, 2013

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

We are now continuing with our overview of EU Risk Management Plans.   The references are repeated here.

Although they have been in existence for several years, the new Good PV Practices Module 5 released by the EMA in July 2012 (https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129134.pdf) made significant changes in the requirements and in how the RMP is prepared.  This is clearly a very complex document running 80 pages.

In addition there are 14 guidances and templates on how to prepare each section of the RMP available on this website both individually and as an integrated version (https://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/11/WC500134743.doc).

Note that there is an old template also available on the website from 2006.  This is out of date and should not be used any longer. Rather the templates in the individual guidances/integrated version is to be used.

In August 2013, the EMA made two significant changes to the 2012 requirements (https://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000360.jsp&mid=WC0b01ac058067a113).   These are addressed at the end of this posting.

Part 2

  • Module SVII: Identified and Potential Risks: This section is prepared somewhat differently if the product an “Advanced Therapeutic Medicinal Product (ATMP)”.  Refer to the module for information on the ATMPs.  The EMA specifically notes that this section should be concise and not a “data dump” with only important risks discussed.The concept of an “important risk” is defined by the EMA here as one which “which is clinically important and which is/is likely to be included in the contraindications, or warnings and precautions section of the summary of product characteristics (SmPC)… In addition, risks, which whilst not normally serious enough to require specific warnings or precautions, but which occur in a significant proportion of the treated population, affect the quality of the treated person’s life, and which could lead to serious consequences if untreated,” should also be included.
    • Newly identified safety concerns since the previous submission of the RMP: For each safety concern, a table with the details, source, and any new studies proposed in the PV plan and new risk minimization actions listed.
    • Recent study reports with implications for safety concerns.
    • Details of important identified and potential risks from clinical development and post-authorization experience:
      • Risks relating to the active substance
      • Risks related to a specific formulation, indication or route of administration
      • Risks relating to a specific target population
      • Risks associated with switch to non-prescription (OTC) status
    • For each identified and potential risk provide where possible:
      • Frequency with 95% confidence interval
      • Seriousness/outcomes
      • Severity & nature of risk
      • Background incidence/prevalence
      • Risk groups or risk factors
      • Potential mechanisms
      • Preventability
      • Impact on quality of life
      • Potential public health impact
      • Source of evidence
      • MedDRA terms to be used for post-marketing surveillance
    • Identified and Potential Interactions: including the interacting substances, effect of the interaction, evidence source, mechanisms, potential health risk.
    • Pharmacological class effects if any both identified and potential

Comments: This section represents the heart of the RMP.  It is here that the known and potential risks, also called “safety concerns”, are enumerated and spelled out with careful analysis of each. Arguably everything else in the whole RMP is simply commentary about these risks.  Risk minimization measures, which may be required and which are discussed later in the RMP, relate back to the risks defined in this section. From a public health point of view, this is where the major effort in the document should be put.


  • Module SVIII Summary of the Safety Concerns: This section represents the conclusions drawn from this module and should include tables of safety concerns broken down into: important identified risks, important potential risks and missing information.  It may also be appropriate to break the concerns down by whether the concern relates to the: active substance, specific formulations or routes of administration, target population or OTC status.

Commentary: This again is the heart and key part of the document.  The risks that are identified here will be followed in subsequent RMP updates, PSURs, pediatric plans, labeling etc.

Part III: The Pharmacovigilance Plan (PhV Plan or PVP)

The PVP gives details of the PV activities and/or studies to be done to identify or characterize the safety concerns.  It will be tailored to each product.  In some cases, perhaps in most cases, routine drug safety post-marketing surveillance will suffice.  For some drugs or risks additional measures may be needed.  This section then reviews each safety concern and determines whether there is a need for additional surveillance beyond the routine.  If yes, details and milestones are given.

  • Safety Concerns and Overview of Planned PV Actions: For each safety concerned (numbered 1, 2 etc.) a table with areas requiring confirmation or further investigation, the proposed routine and additional PV activities and the objectives of these measures.
  • Additional PV Activities to Assess Effectiveness of the Risk Minimization Measures: For each risk minimization a table with the component measured, the activities and the rationale.
  • Studies & Other Activities Completed Since the Last Update of the PVP: A table for each activity.
  • Details of Outstanding Additional PV Activities: Includes tables of imposed activities, specific obligations, required additional PV activities to address specific safety concerns or to measure effectiveness of risk minimization measures, stated additional PV activities (e.g. drug utilization studies).
  • Summary of the PVP with tables:
    • On-going and planned additional PV studies/activities in the PVP
    • Table of completed studies/activities in the PVP

Comment: This is another key part of the RMP.  It is here that the company and the health authorities actually try to figure out what to do.  Most of the PV Plans will be routine post-marketing safety surveillance.  But some drugs will need more surveillance activities (e.g. additional blood tests or a pregnancy test).  Note that these surveillance activities are not the same thing as risk minimization activities which are actions to actually decrease risk as opposed to these increased surveillance plans whose aim is to better pick up and diagnosis risk – not prevent it directly.

Part IV: Plans of Post-Authorization Efficacy Studies

  • Applicability of efficacy data to all patients in the target population: This section discusses whether there are any gaps in the efficacy knowledge regarding the target population and whether there is need for further efficacy studies after marketing.  New data may be needed if the trial data does not cover the entire target population (EMA gives the example: “if 90% of patients in the trials were Caucasians, discuss whether efficacy is likely to be the same in other races”).  Other issues include evaluation of whether the use in general clinical practice is different from the clinical trial hospital out-patient setting, long term efficacy and whether there might be variability in sub-populations.
  • Tables should be provided covering:
    • Efficacy studies that are obligations or conditions of the MA
    • Other efficacy/effectiveness studies
    • Summary of Post-Authorization Efficacy Development Plan: This is a set of tables listing all studies ongoing and planned.
    • Summary of Completed Post-Authorization Efficacy Studies

Comments: This section makes the distinction between efficacy and effectiveness as noted above.  The EMA has not yet really clarified what it wants and expects in terms of post-authorization clinical efficacy/effectiveness trials.  It’s likely that this will have to be handled on a drug to drug basis and customized for each product.

Part V: Risk Minimization Measures

In this section, each safety concern noted in Module SVIII “summary of the safety specification” is addressed.

  • Risk Minimization Measures by Safety Concern: Each concern should have a table:


Safety Concern 1
Objective of the risk minimization measures
Routine risk minimization measures Proposed new SmPC text;Other routine risk minimization measures
Additional risk minimization measures Objective, justification, proposed action & rationale
How the effectiveness of the measures will be measured
Criteria for judging the success of the proposed measures
Planned dates for assessment
Results of effectiveness measurement
Impact of risk minimization
  •  Risk Minimization Failure (if applicable): Include a table with each concern and minimization measure that failed with an analysis of each.  This should be followed by a table of the revised proposal for risk minimization by safety concern.

Comment: This is interesting!  Human nature usually responds to failures by burying them!  Here the EMA wants a clear discussion of the failure of minimization efforts (e.g. women became pregnant on a product that is absolutely contraindicated in women of child bearing age).  Whether this will prompt law suits remains to be seen.


  • Summary Table of Risk Minimization Measures: A summary table with each safety concern, each routine risk minimization measure and reach additional measure.

Comment: In US parlance, these would be “ETASUs” or elements to assure safe use” and include limited prescribing or dispensing, obligatory consent or registries etc. Here EMA wants the detailed thought process for each action to be explained and specifically tied to a safety concern or risk.

Part VI: Summary of the Risk Management Plan by Product

If there is more than one product in the RMP each should have a separate section here.  This is a summary of the tables in the previous sections:

  • Summary Tables
    • Summary table of safety concerns: Table from Part I: SVIII
    • Table of ongoing and planned studies in the post-authorization PV Development Plan: Table from III.5.1
    • Summary of post authorization efficacy development plan: Table IV.3 from Part IV
    • Summary table of risk minimization measures: table from Part V: V.3
    • Elements for a Public Summary: This section covers the elements of Part II Module I in lay language to be made public.

Comment: Like the FDA, which puts the REMS online, the EMA puts or will put RMPs online with much more detail than FDA does with REMS.

Part VII: Annexes

Annex 1 – EudraVigilance Interface. 3

Annex 2 – SmPC & Package Leaflet 4

Annex 3 – Worldwide marketing authorisation by country (including EEA) 5

A3.1     Licensing status in the EEA. 5

A3.2     Licensing status in the rest of the world. 5

Annex 4 – Synopsis of on-going and completed clinical trial programme. 6

Annex 5 – Synopsis of on-going and completed pharmacoepidemiological study programme. 7

Annex 6 – Protocols for proposed and on-going studies in categories 1-3 of the section “Summary table of additional pharmacovigilance activities” in RMP Part III 8

Annex 7 – Specific adverse event follow-up forms 9

Annex 8 – Protocols for proposed and on-going studies in RMP Part IV. 10

Annex 9 – Newly available study reports for RMP Parts III & IV. 11

Annex 10 – Details of proposed additional risk minimisation measures (if applicable) 12

Annex 11 – Mock-up of proposed additional risk minimisation measures (if applicable) 13

Annex 12 – Other supporting data (including referenced material) 14

Comment: These appendices (annexes in EU English) are complex and clearly indicate that the RMP needs to be periodically updated as new information becomes available.  It is not an easy set of documents to prepare.

The latest changes by EMA

As noted by at the very beginning of the first posting, the EMA made two changes in August 2013 which they consider important:

Risk Based Approach to RMPs: The EMA which had originally decide on having RMPs updated on a fixed time basis is now taking a risk based approach.  An update RMP will now have to be submitted:

  • At the request of the Agency or a 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 a result of an important pharmacovigilance or risk-minimization milestone being reached.

Changes to “important missing information”: This is, it seems, mainly a sematic change.  Safety concerns are now classified as:

  • Important identified risks
  • Important potential risks
  • Missing information

The word “important” is now gone from the last bullet.  EMA explains it, rather legalistically, as  “This change was introduced to avoid misunderstanding with regard to Article 12 of Regulation  (EC) No 726/2004 which states that a marketing authorisation should be refused if the applicant has not properly or sufficiently demonstrated the quality, safety or efficacy of its product.

The concept of a safety concern has not changed; it is still missing information that could be clinically important and that needs to be captured. The only change is the way that this concept is expressed.”

This is not at all clear.  Perhaps it means that if there is important missing efficacy information the drug could/would be refused authorization which is not necessarily EMA’s intent.  In any case, as EMA states, “missing information that could be clinically important” is what they are concerned about and still needs to be noted.

Overall Comment: Finally, this is a very very complex document to prepare well.  It may require a team effort with epidemiologists, toxicologists, pharmacologists, clinical research, drug safety/PV, regulatory and labeling personnel involved.  Most companies will not have a lot of time to prepare it before an MA is submitted or if it is requested during the product’s post-marketing lifecycle phase.  Clearly this will increase costs and will require more personnel and resources.  Whether it improves the public health remains to be seen.